Handbook of Nanoparticles 9783319131887

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Nanoparticles by Laser Ablation of Bulk Target Materials in Liquids N. G. Semaltianos* Department of Physics, Aristotle University of Thessaloniki, Thessaloniki, Greece

Abstract The debris which is generated following laser ablation of a bulk target material by an intense laser beam consists under certain conditions of nanoparticles. This technique has been established and developed especially in the last few years as an alternative method for the synthesis of nanoparticles with desired physicochemical and structural properties in the same way as other techniques such as colloidal chemistry, electrochemistry, spark current decomposition, and others are used for that purpose. In case the target material is immersed in liquid, a nanoparticle colloidal solution is formed. The main advantages of this method are that it does not require the use of chemical precursors for nanomaterial synthesis, it produces nanoparticle colloidal solutions which are stable without the need of adding into them any stabilizing surfactants and nanoparticles with bare (ligand-free) surfaces which are highly surface active, and it allows for an in situ functionalization of the synthesized nanoparticles with the desired ligands. In addition, the ablation plasma plume experiences an additional compression by the liquid which may result in the formation of nanoparticles which are characterized by metastable material phases, difficult or impossible to be produced by other methods. This chapter outlines the fundamental principles of the method and reviews the synthesis of nanoparticles out of different materials ranging from metals to semiconductors and ceramics, techniques for adjusting the sizes and size distribution of the nanoparticles such as particle fragmentation, the synthesis of alloy nanoparticles and magnetic nanoparticles, issues of productivity scaling up, and the synthesis of other nanomaterials.

Introduction Nanoparticles (NPs), i.e., particles with dimensions in the nanometer range, are important nanomaterials (NMs) for use in a number of applications in physics, chemistry, engineering or biology. This is mainly due to the fact that they have a large surface-to-volume ratio which has as a result a larger percentage of atoms lying on the surface of the material than in its bulk which essentially means that “a large surface within a small volume” is available for interactions and also because they have unique physicochemical properties which are size dependent. There are many methods for NP synthesis which are usually based on sol–gel colloidal chemistry, plasma precursor decomposition, spark current decomposition of metallic wires, electrochemical etching, etc. A technique which has been established as an alternative method for NP synthesis involves the formation of NPs by the debris which is generated as a result of laser ablation of a bulk target material. In case the material lies within a liquid, the NPs are collected in the form of a NP colloidal solution [1] (Fig. 1). The main characteristic of this method is that no chemical precursors are needed for NM synthesis which leads to the formation of NP colloidal solutions with reduced reaction by-products – chemical precursors are expensive, toxic, and pyrophoric and they also result to the contamination of the colloidal solution and the appearance of undesirable ligands on the NP surfaces. The colloidal solutions could be utilized in applications, directly after formation, without the requirement of time-consuming and solvent*Email: [email protected] Page 1 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

LASER

laser beam lens

liquid nanoparticles bulk target material

Fig. 1 The simplest experimental setup for the production of NPs by laser ablation of a bulk target material in liquid

wasting multistep “washing” procedures which usually involve centrifugation of the solution, decantation, and solvent exchange. The colloidal solutions are kept stable against nanoparticle agglomeration without the need of adding into them any stabilizing surfactants. Overall, it is an easy, fast, and straightforward method for NP synthesis/generation as compared to other methods and can be applied in practice with a wide range of target/liquid combinations. By laser ablating multielement target materials, NPs with complex stoichiometries can be synthesized, difficult or impossible to be produced by any other method. The NPs can be functionalized in situ during their formation with the desired ligands from molecules which are contained in the liquid, or they are produced by chemical reactions which are induced by the laser ablation process, and this is much more efficient than the ligand-exchange procedures of surfactant-stabilized NPs. The sizes, size distribution, shapes, and the physicochemical and structural properties of the NPs are determined and controlled by the choice of the liquid in which ablation takes place in combination with the laser ablation parameters such as pulse width, wavelength, fluence, pulse repetition rate, or ablation time duration. In this chapter the fundamental characteristics of the method of generation/synthesis of NPs by laser ablation of bulk target materials in liquids are presented.

Laser Ablation Plasma Plume Expansion in Liquid. When an intense laser beam with fluence greater than the so-called ablation threshold of a material is incident onto the material’s surface, ablation (detachment) of the material occurs via different mechanisms, that is, vaporization and boiling, explosive boiling, or fragmentation [2]. The different thermodynamic trajectories which the system follows that lead to the different ablation mechanisms are depicted schematically in the density-temperature (ϱ-T) diagram (Fig. 2). Different paths are mainly dependent on the heating rate of the material by the laser pulse, which in turn is determined by the pulse width in relation to the electron–phonon coupling time constant of the material te-ph (typically on the order of 1 ps), while the laser energy determines the maximum temperature the material attains. For ultrashort pulses (tL
te-ph) the system follows initially vertical paths in the ϱ-T diagram while for longer pulses (tL > te-ph) the system follows curved paths in the diagram. For long-width pulses (>100 ns) the system is heated and Page 2 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015 T

A⬙ U V

A⬘ B⬘

X Y

W

Z

M G

L+G

L

C K B A

ρ

Fig. 2 Temperature-density (T-ϱ) diagram which depicts the different thermodynamic trajectories which the system follows, determining the different ablation mechanisms, under fs (dashed-dotted line), ps (dotted line), and ns or longer (thick solid line) laser irradiation. Thin solid line: binodal; dashed line: spinodal; cross: critical point. L: liquid; G: gas (Reprinted with permission from Ref. [2]. Copyright (2003), American Physical Society)

expands slowly along the binodal (C ! W), in which liquid and gas phases coexist and the material is ablated via boiling and vaporization. For shorter pulses in the ns to hundreds-of-ps regime, rapid heating pushes the system into the metastable region of the spinodal decomposition (infinitesimally small fluctuations in density will lead to phase separation) (K ! M) and the material is ablated via explosive boiling (phase explosion). For even shorter pulses of tenths of ps and high energies the system enters into the gas-phase region above the critical point without crossing the binodal (B ! V) and the material is ablated via fragmentation. For fs pulses the material is heated without a change in its density (isochoric heating) and this leads to the buildup of a strong pressure within it, which is later released by mechanical expansion causing for high fluences the breaking-up of the supercritical fluid through fragmentation (A ! A00 ! U). For lower fluences close to the ablation threshold the expansion is too slow to cause fragmentation, and the system is pushed to the metastable region near the spinodal limit (A ! A0 ! W ! Y) by adiabatic cooling. The superheated material is then converted into a mixture of liquid and gas (Y ! Z). Time-resolved shadowgraph imaging of laser ablation of bulk targets in liquids can reveal the different stages of the laser ablation process. An example is shown in Fig. 3 for 10 ns laser ablation of a Ag target in aqueous solution of polyvinylpyrrolidone (PVP) [3, 4]. Upon incidence of the laser pulse on the material and absorption of the radiation from it, a nonequilibrium plasma plume of the ablated material is formed, consisting of the material’s species such as ions (single or multivalent), neutral atoms, and clusters (Fig. 3a). The temperature and pressure of the plasma plume are usually of the order of 1,000 K and 1–10 GPa, respectively. After formation of the plume, its high temperature results in the ionization and vaporization of the liquid (in the case of water) at the plume-liquid interface and its conversion into water vapor and atomic and molecular hydrogen or oxygen (“water plasma”). In the case of hydrocarbon liquids such as ethanol, acetone, toluene, etc., the high temperature of the plume may lead to thermochemical decomposition (pyrolysis) of the liquid leading to carbon generation. In the case of other liquids different molecular or atomic species can be produced. Due to the sudden expansion of the plume initially at supersonic velocity two shock waves are generated which travel into two opposite directions, one in the solid target and the other one through the liquid (Fig. 3b). The main difference between laser ablation in liquids as compared to the vacuum or air/gas ablation is that as the plume expands in the liquid it

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

a Solution

2 mm Δt = 0 ns Laser

b

1 μs

c

200 μs

d

300 μs

Silver Target

Fig. 3 Time-resolved shadowgraph images of the laser ablation of a Ag target in aqueous solution of PVP showing (a) optical emission, (b) shock wave, (c) cavitation bubble, and (d) secondary shock wave generated at the bubble collapse (Reprinted from ref. [3], Copyright (2008) with permission from Elsevier)

experiences a “compression” by the liquid. This effect results in the plume having, at the initial stages of expansion in liquid, higher temperature, pressure, and density as compared to air/gas expansion, which in turn favors the nucleation and growth of NPs. The liquid-confined plume as well as the high-pressure shock wave can etch the material’s surface causing a secondary ablation process. The plume expands and adiabatically cools releasing its energy to the environment and to the target. This process occurs in a timescale of the order of 0.1–100 ns. During the plume expansion the materials’ plasma is mixed with the plasma which is created by the liquid decomposition. The NPs are formed by the nucleation and growth of plume species or ejected directly from the target material in the form of liquid droplets. The expanding plume is eventually extinguished. Due to the expansion of the liquid plasma around the plasma plume which initially has high pressure and temperature, a cavitation bubble is generated which surrounds the ablated material (Fig. 3c). The bubble expands, and its temperature and pressure decreases. The bubble reaches its maximum size when the gas inside the bubble comes in equilibrium with the surrounding liquid. Then the bubble starts shrinking. Upon collapse of the cavitation bubble a second shock wave is generated (Fig. 3d). The cavitation bubble dynamics is significantly altered by the shape of the irradiated target while the thermodynamic parameters of the vapor are unaffected [5]. The thermodynamic state of the plasma with high temperature, pressure and density in which the plasma is driven due to the confinement by the liquid may favor the formation of metastable material phases in the NPs, i.e., the plasma plume species may be taken in a region of the equilibrium phase diagram of the NP material in which material phases which are thermodynamically unstable under normal conditions of pressure and temperature exist [1]. When later the plasma expansion is quenched, these metastable phases are “frozen” in the synthesized NPs. This is another unique characteristic of the method of synthesis of NPs by laser ablation of bulk target materials in liquid as compared to the other methods of synthesis but also to the laser ablation in air/gas ambient that NPs with material phases difficult or impossible to be produced by other methods can be synthesized. Examples are the synthesis of FeO NPs by laser ablation (10 ns, 1,064 nm, 10 Hz, 80 mJ) of a bulk Fe target in aqueous solution of poly(vinylpyrrolidone) (PVP) [6] which is described by the reaction: Fe(clusters) + 2H2O ! Fe(OH)2 + 2H2" and Fe(OH)2 ! (high P and T) ! FeO + H2O and in analogy the synthesis of TiO NPs by laser ablation of a bulk Ti target in DI water (10 ps, 1,064 nm, 50 kHz, 2.1 J/cm2) [7]. These are metastable oxides of the metals and can only be obtained by quenching from high temperatures sintered powders of the metals/metal dioxides, a method which in any case leads to the formation of irregular shape micrometer-size particulates of the material instead of nanometer-size spherical particles. Another example is the synthesis of nanodiamonds by laser ablation in water of a carbon target made out of pyrolytic graphite [8].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Nanoparticle Surface Charge Generation It is generally believed that the surfaces of metallic NPs generated by laser ablation in water are partially oxidized resulting in the appearance of also the cations of the respective metal on the NP surfaces (e.g., Au+ or Au+3 species in addition to Au0 in case of Au NPs [9]). This in turn has as a result the direct appearance of hydroxyl groups on the NP surfaces via hydrogen bonds. The hydroxyl groups are formed by the water dissociation at the plasma plume–liquid interface. Thus in the case of Au NPs in water, there is formation of Au–OH species [9]. Then the NP surfaces may get protonated or deprotonated and exhibit a positive or a negative z-potential, respectively, depending on the pH of the solution according to the H þ , pK a2 OH , pK a1 equilibrium reaction: M–OH2+ ƒƒƒƒ M–OH ƒƒƒƒƒ! M–O + H2O (Fig. 4a). The probability of protonation or deprotonation and the net amount of charge in each case depend on the pKa value of the species on the NP surface in relation to the pH of the solution. If the solution is acidic (excess of H+ in the solution and pKa2 > pH), the NP surfaces are protonated and the z-potential becomes highly positive resulting in the formation of M-OH2+, but if the solution is alkaline (excess of OH in the solution and pKa1 < pH), the NP surfaces are deprotonated and the z-potential becomes highly negative resulting in the formation of M–O species. In practice this is done by making ablation of the target material in aqueous solution of an acid or a base such as HCl or NH4OH, respectively. In the case of laser ablation of Au in water, the NPs were found to be partially oxidized forming almost exclusively Au–O species at pH > 5.8 and thus be negatively charged, while the number of Au–OH was increasing at pH < 5.8 [9]. This has as a result that the NPs colloidal solutions are stable against agglomeration due to the electrostatic repulsion between the NPs and thus without the need of adding into the solution any stabilizing surfactants. This is another advantage of the method of synthesis of NPs by laser ablation of bulk target materials in liquids. By further adding into the solution a cationic surfactant such as cetyltrimethylammonium bromide (CTAB), it was found that the NPs aggregate because the CTA+ ions bind on their surfaces and they neutralize the negative charge of the NPs [10]. The net charge on the NP surfaces determined by the pH of the solution has an effect on the final average size and size distribution of the NPs. The H+ or OH radicals in the solution interact with the surfaces of the nanocondensates and control their growth. Thus it was found that the average diameter of Al2O3 NPs was increasing and then decreasing with the pH of the solution, passing through a maximum at pH = 11 corresponding to the isoelectric point (pI) of Al2O3 NPs solution where the z-potential (or more accurately the net surface charge) becomes zero providing with a minimum degree of NP stabilization [11]. For highly acidic or alkaline solutions, the formation of a net positive or negative charge on the NP surfaces decreases the probability of agglomeration resulting in NP solutions with small average diameters. This implies that the presence of specific molecules in the solution and their concentration can be used as an additional parameter for the adjustment of the NP sizes and size distribution. In addition to the effect of pH of the solution on the formation of an effective charge on the surfaces of ligand-free NPs generated by laser ablation, charge on the NP surfaces could also be formed by ions in a solution of inorganic salts (diluted electrolytes) such as NaCl or NaBr [12]. Since no stabilizing or size quenching effect was observed in samples containing other also Na-based salts such as Na2SO4 or NaF, it was concluded that the effect was due to the anions Cl or Br rather than to Na+ because of their larger ion diameter and better polarizability which favors dating and covalent binding to evenly large gold atoms (the cations are densely hydrated). Thus an increase of the negative surface charge on the NP surfaces was found to take place by the replacement either of the hydroxyls or of the oxygen atoms on the NP surface by the anions via a ligand-exchange process in which the bonds Au–O–Au break with the formation of Au–X and Au–O species (or the bond Au–OH with the formation of Au–X species) or via the specific

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

a

pH effect Increasing pH

OH Au OH Au

OH Au

Au OH

O– Au –

Au

excess OH

Au O–

OH

Decreasing pH

OH Au OH Au

OH Au OH2+ Au

Au OH excess H+

Au

Au OH2+ Au OH2+

OH

b

Au O–

ion effect Oxygen substitution

O– Au Au

Au

Au O Au

Au

X– (X–=Cl–, Br–)

O– Au Au Au Au

OH

OH

O– Au O Au

Au Au OH

O–

Specific adsorption

Au Au

Au X– Au O–

X– (X–=Cl–, Br–)

X– Au X– Au

Au Au O Au Au OH

Fig. 4 Mechanisms of surface charge generation on ligand-free Au NPs by (a) pH changes and (b) specific ion effects (Reproduced in part from Rehbock et al. [12] with permission of the PCCP Owner Societies)

adsorption of the halide anions on the NP surface controlled by both electronic and chemical forces and formation of bonds with the Au atoms resulting in the formation of Au–X species [13] (Fig. 4b). Again as in the case above in which the value of the pH provides with a parameter for the control of the NP sizes and size distribution in addition to the laser ablation parameters, electrolyte solutions can also be used for that purpose in order to provide with a size quenching effect. This is very important especially in the application of noble metal NPs in toxicology and biology and in particular reproduction biology since size control of surface-ligand-free NPs (as these are synthesized by laser ablation) can be achieved without the need of using artificial surfactants which might interfere with toxicity assays such as the case of citrate ligands or CTAB. Thus it was found that the NP average diameter was decreasing linearly from ~30 nm to ~7 nm as the ionic strength of the solution was increasing from 1 to 50 mM and then staying almost constant at this value for a further increase of the ionic strength up to ~2,000 mM. The solutions were also showing a considerably reduced aggregation with increasing ionic strength [12]. As the ionic strength decreases, the total surface area which can be stabilized by the charges is diminished, thus leading to bigger NPs. It was also concluded that the formation of NPs at the initial stages of the plume formation was not affected by the ions since NPs with a minimum diameter of 5 nm were always obtained irrespective of the ionic strength and this was attributed to the fact that the initial nucleation and coalescence processes are taking place in a very short time scale before the ions start to have any influence.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Ablated Material–Liquid Interactions Nanoparticle Surface Functionalization Surface functionalization of the produced NPs can be achieved by the physical interaction of the NPs with dissolved surfactants in the liquid such as in the case of sodium dodecyl sulfate (SDS) molecules. The SD anions coordinate with the NP surfaces via electrostatic interaction and form a molecular layer which limits the growth of the embryonic NPs and provides with a control of their sizes and size distribution. The NPs capped with long carbon chains are kept prevented from aggregating due to steric hindrance [14]. Other examples include laser ablation of a Au target in solution of dextran [15] (Fig. 5a) or of a Cu target in aqueous solutions of aromatic ligands such as 1,10-phenanthroline and 4,4'-bipyridine [16]. It is assumed that the Cu NPs are positively charged and that the bidentate ligands bind onto them via the lone pair of electrons of the nitrogen atoms. Other examples include laser ablation of a Ag target in aqueous solutions of starch, gelatin, or chitosan [17] or laser ablation of Au target in chloroform solution of 5,10,10,15,20-tetrakis-4-pyridylporphine (TPyP) [18] in which it is suggested that a kind of sandwichtype complexes consisting of TPyP2/Au3+/Cl is formed on the surfaces of the Au NPs. In situ functionalization of Ag NPs with citrate ligands was achieved by carrying out laser ablation of the target in aqueous solution of sodium citrate [19]. The citrate anions coordinate to the positively charged partially oxidized Au NPs and form a molecular layer. This work also showed that the stability of NP colloidal solutions is achieved by using only a trace amount of ligands as compared to solutions of NPs synthesized by using chemical methods which provides with a major advantage because the use of high concentration of ligands requires challenging procedures for ligand removal/exchange or for decreasing their concentrations to values comparable to laser-generated solutions. Thus in the case of Ag NPs, citrate ligands with a concentration of only 5 % of ligand concentration which is necessary in chemical synthesis are the optimum in order to achieve a complete and a homogeneous adsorption to suspended barium sulfate microparticles (MPs) (a system important in polymeric biomedical devices). In situ functionalization of Au NPs with biomolecules (bioconjugation) was achieved by carrying out laser ablation (800 nm, 120 fs, 5 kHz, 50–200 mJ) of the target in aqueous solution of the biomolecule [20]. Most biomolecules bear electron donor moieties such as NH2, COOH, SH, S-S, etc., and thus they coordinate easily with the partially oxidized NP surfaces which bear positive charge and act as electron acceptors. Thus it was shown that 20 mg of thiolated single-stranded oligonucleotide-functionalized Au NPs can be produced in less than 1 min at optimum laser and process parameters without degradation of the oligonucleotides. It was further shown that due to the ligand-free laser-generated NP surfaces, the conjugation efficiency of laser-based bioconjugation was by almost four times higher in terms of the surface coverage (reaching 29 pmol/cm2) as compared to the standard techniques of ex situ conjugation, by adding the nucleotides into the NP colloidal solution after formation [21]. Lately, bioconjugation of Au NPs with suitable substances present in the cell culture media and biofluids, such as bovine serum albumin (BVA), was achieved in a liquid flow and by injecting the substance into the sample stream after some time of producing the NPs (delayed bioconjugation), by ablating a Au wire in a specially designed ablation chamber [12].

Laser Ablation Plasma Plume–Liquid Interactions The laser ablation process of a bulk target material immersed in a liquid is also characterized by chemical reactions which take place between the material’s laser ablation plume (plume plasma) and the liquid, and they lead to the synthesis of new materials by the combination of chemical elements from the target material and the liquid. The species which are formed by the decomposition of the liquid at the plume–liquid interface (“liquid plasma”) can react with the plume plasma species at the region of the interface. The liquid plasma species could also be mixed with the plume plasma and interact with them Page 7 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

a

100

Diameter (nm)

D=0.76*R–0.54

10

1 1E-4

B

A 1E-3

C 0.01

D 0.1

Dextran to gold molar ratio (R)

b

c

Fig. 5 Mechanisms of interaction between the ablated material and the liquid: (a) molecules which are dissolved in the liquid solution bind onto the NP surface as ligands and control the sizes of the NPs and stability of the colloidal solution (dextran molecules bind onto the Au NPs by laser ablation of the target in aqueous solution of dextran) (Reprinted with permission from Besner et al. [15]. Copyright (2009) American Chemical Society), (b) interaction of the material laser ablation plasma plume with the liquid plume leads to the synthesis of NPs which are of different compound than the bulk target material (a-C3N4 NPs are produced by laser ablation of a graphite target in liquid ammonia) (With kind permission from Springer Science + Business Media: Yang et al. [24]), and (c) thermally induced chemical decomposition reaction of dissolved molecules in the solution takes place on the surface of the just formed, still hot NPs (silica-coated Au NPs are produced by laser ablation of the target in TEOS solution) (Reproduced from Salminen et al. [26] with permission of the PCCP Owner Societies)

within the volume of the laser ablation plume. Furthermore due to the extremely high velocity of the laser ablation plume and the extremely high pressure in front of it, injection of atomic species takes place from the plume into the liquid which subsequently cluster on a micrometer time scale, and then chemical reactions take place in the liquid between the clusters and liquid molecules [1]. An example is the laser

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

ablation (1,064 nm, 9 ns, 10 Hz, 5 J/cm2) of an Fe target in organic solvents in which different oxide and carbide NPs could be obtained [22]. In tetrahydrofuran, ~79 % of the synthesized NPs had a core–shell structure with a cubic-Fe core and magnetite (Fe3O4) or maghemite (g-Fe2O3) shell of ~4 nm thickness independent of the particle size (average diameter of ~20 nm) due to the presence of dissolved atmospheric oxygen in the solution. In acetonitrile and dimethylformamide, also magnetite/maghemite NPs were obtained, with an average size of 29  10 nm and 30  15 nm impeded in amorphous carbon originating from the pyrolysis of the organic solvent. However in dimethyl sulfoxide only cubic-Fe NPs impeded in an amorphous carbon matrix could be obtained with an average size of 4.7  2.3 nm. This matrix in turn was very effective in preventing the air oxidation of the NPs. In toluene, core–shell NPs with an average size of 14  9 nm could be obtained, composed of an amorphous iron or amorphous iron carbide core and a graphitic shell. In ethanol, two different populations of NPs were obtained, one composed of Fe3C with a size of tens of nanometers and the other composed of magnetite with sizes of the order of 1 nm. Similarly onion-like graphitized carbon-encapsulated Co3C core/shell NPs were synthesized by laser ablation of a Co target in acetone [23]. Laser ablation (532 nm, 15 ns, 10 Hz, 120 mJ) of a graphite target in liquid ammonia solution leads to the synthesis of carbon nitride NPs (a-C3N4) according to the reaction: 4NH3 + 3C ! C3N4 + 6H2 [24] (Fig. 5b). Inorganic fullerene-like MoS2 NPs (10–15 nm) were obtained by laser ablation of a MoS2 target in water [25]. In this case it was found that the MoS2 NPs are formed together with MoO3 NPs which act essentially as precursors to their formation. The collapse of the cavitation bubbles which are created by the interaction of the plasma plume with the liquid causes the dissociation of MoS2 and of the water into molybdenum ions and reactive oxygen species which react together with the formation of MoO3. Sulfur is also present in the system in the form of linear chains. Then the MoO3 NPs are converted to MoO3-x suboxide which undergoes sulfidization producing MoS2 according to the reactions: MoO3 + (x/2)S ! MoO3-x + (x/2)SO2 and then MoO3-x + ((7x)/2)S ! MoS2 + ((3x)/2)SO2. These reactions are taking place at high temperatures during the ablation process. When ablation is done in an oxygen-free solvent such as n-decane, no MoS2 NPs are formed because no MoO3 is produced during the ablation plasma plume generation. In the case of ablation in water, the reactive oxygen species also originate from molecular oxygen dissolved in the water thus by purging the water with molecular nitrogen reduces the amount of reactive oxygen species. Ablation in nitrogen-purged water leads to the production of mostly Mo suboxides and only very few MoS2.

Nanoparticle Surface Coating Laser ablation of the target material can take place in a solution of a chemical precursor which undergoes thermally induced decomposition reactions onto the surfaces of the just formed NPs which are still at a high temperature immediately after formation, resulting in the formation of a core/shell type of NPs. Thus silica-coated Au NPs were obtained by laser ablation (515 nm, 10 ns, 20 kHz) of a Au target in a solution of 2-propanol with tetraethyl orthosilicate (TEOS) (0.5 mM) and ammonia (0.7 M) [26]. In this case due to the high temperature of the formed Au NPs, decomposition of the TEOS precursor occurs on their surfaces, with the ammonia acting as the catalyst for the chemical reaction, resulting in the formation of silica shells on the NPs (Fig. 5c).

Nanoparticle–Laser Beam Interaction Because of the hemispherical symmetry of the laser ablation plasma plume and the cooling of the plume during its adiabatic expansion in the liquid, which can also reach very high rates, the temperature, pressure, density of the plume and density of the liquid species are neither uniform in space nor constant Page 9 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

in time. This is the reason for not obtaining, by laser ablation of bulk target materials in liquids, NPs which have a monodisperse size distribution but a rather wide-size distribution which usually follows lognormal function. Thus a NP ensemble can consist of NPs with diameters from 1–2 nm up to 200–300 nm. In the most simple experimental configuration of laser ablation in liquids, the NPs which are produced in the solution lie in the path of the ablating laser beam and thus they interact with the beam. This interaction is stronger if the wavelength of the laser beam coincides or lies close to the plasmon resonance absorption of the NPs. This effect in turn results in the modification of the sizes of the NPs and of their size distribution. On a few occasions, tuning of the NP sizes and size distribution is achieved by re-irradiating the solution after formation. In order to achieve homogeneity and reproducibility in the irradiation conditions, the solution is being irradiated while flowing through a capillary tube with diameter close to the extent of the tip of the Gaussian laser beam. Both fs and ns laser beams lead to the reshaping of metallic NPs in the solution depending on the excitation intensity via photothermal effects, with the fs lasers better suited for this purpose because due to their high intensity, the rate of absorption and heating of the lattice is extremely rapid and thus the energy threshold for complete melting of the NP is reduced by a large factor. It was found that surface melting of Au NPs occurs at temperatures much lower than the melting point of bulk gold due to the large surface-tovolume ratio, leading to reshaping. Three basic mechanisms were proposed to explain size reduction of NPs by laser irradiation based, on photothermal surface evaporation, Coulomb explosion, or a near-field laser ablation, but the last mechanism still lacks convincing experimental verification [27]. A combination of experiments of laser irradiation of Au NPs and computer simulations of the temporal evolution of the electron, lattice, and surrounding water temperatures have shown that there is a difference in the mechanisms of laser-induced size reduction of NPs in the case of ns and fs laser irradiation which originates from the well-known difference in the ablation mechanism of a material between the two cases, characterized by the laser pulse duration in relation to the electron–phonon coupling time constant of the material. Mathematically this is characterized by the so-called fragmentation temperature (Tfrg) which is defined as the minimum temperature at which sufficiently energetic electrons in the tail of the Fermi distribution can overcome the work function of the metal and escape from the surface. In the case of a fs pulse, because there is a clear difference between electron temperature (Te) and lattice temperature (TL), it is possible that Te becomes greater than Tfrg (due to the absence of energy dissipation to the lattice before the end of the pulse), while in the case of a ns pulse, because TL = Te, extremely high Te which exceeds Tfrg cannot occur (due to the energy dissipation to the lattice during the pulse absorption), but instead the TL increases steadily with the laser power intensities. Thus in the case of ns pulses (Fig. 6a), the experimental data could be explained by the photothermal surface evaporation mechanism. Due to the loss to the surrounding water of the thermal energy from the laser heating of the NPs, when the temperature reaches the spinodal temperature of 573 K, explosive evaporation of water occurs. A hot high-pressure bubble is formed around the NP which expands rapidly and results in the depression of the absorption cross section of the NPs through the reduction of the refractive index in the region of the plasmon resonance. If the laser intensity is high enough to heat the thermally insulated NP to the boiling point (3,129 K), surface evaporation occurs resulting to a size reduction of the original Au NP. The generated fragments can coagulate and coalesce inside the nanobubble due to the low permittivity. Finally after the nanobubble collapses and the NPs cool down to room temperature, the original NPs with now reduced size can coexist together with the aggregates. In the case of fs pulses (Fig. 6b), the experimental data could be explained by the Coulomb explosion mechanism. Thus if, for high enough laser intensity, Te becomes greater than Tfrg (for instance, for 60 nm diameter particles, Tfrg is estimated to 7,300 K), electrons are emitted from the NPs by thermionic emission leaving them positive multiply ionized. At the same time the increase of the lattice temperature above the melting point of bulk gold (TL > 1,337 K) results in surface melting and reshaping of the NP Page 10 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015 nanobubble generation and expansion

a

explosive vaporization

Pulsed laser- heat heating dissipation

bubble collapse and cooling

coagulation and coalescence inside nanobubble

surface evaporation at boiling point

b

coexistence of reduced NP and small snake-like structures

time scale of size-reduciton process~100 ps

3 – 10 ps e–

e–

e– e– e– e– – – – – e e– e e e ~700 K 1337 K

e–

e–

e– e–

e–

e– e–

e–

aggregates

isolated particles

e– e–

surface melting liquid NP & reshaping Rayleigh instability

Fragmentation by Coulomb explosion

separation

Fig. 6 Mechanisms of laser-induced size reduction of Au NPs in the case of (a) ns (Reprinted from Hashimoto et al. [27], Copyright (2012), with permission from Elsevier) and (b) fs, laser irradiation (Reprinted with permission from Werner et al. [28]. Copyright (2011) American Chemical Society)

transforming it into the liquid state. This phase transformation greatly decreases the surface tension (surface energy) of the NP. When the repulsion energy caused by the critical charge of the liquid NP exceeds the Rayleigh instability threshold (Coulomb energy > surface energy), the liquid droplet splits (fragmented) into many smaller nanodroplets which eventually separate into individual NPs [28]. If the laser beam wavelength does not coincide with or lies close to the plasmon resonance absorption of the NPs, such as at 800 nm, the direct absorption of the laser pulse by the NPs is very weak in order to produce fragmentation of the NPs, but it was shown that in the case of fs pulses (160 fs, 1 kHz, and in general pulses with width below 1 ps), an effective control of the size characteristics of Au NP colloidal solution can still be achieved by the interaction with the NPs of the white light broad supercontinuum spectrum (400–1,200 nm) which is produced by the nonlinear optical interaction of the fs pulses with the aqueous medium below the optical breakdown of the liquid via again the above mechanisms and in particular Coulomb explosion [29]. This method can be applied in any case independently on the size, size dispersion, or type of the NPs in the solution since it does not rely on the relation of the wavelength of the laser beam with the plasmon resonance absorption of the NPs. The fragmented species then re-coalesce to form smaller, less disperse, and much more stable NPs in solution. Thus it was shown that upon 2 h of irradiation, the mean size and dispersion are reduced from 54  36 to 20  4 nm in pure water or to 6  2 nm in the presence of dextran.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Nanoparticle Alloying Binary alloy NPs can be synthesized by laser ablating suitable binary alloy targets [30–32]. Alternatively bulk targets for laser ablation can be prepared with different compositions by mixing powders of the two metals in the appropriate ratio and using compression molding to form a compact target [33]. However this procedure many times requires the use of heat during compression (calcination) of the powders which might change the crystalline properties of the starting powder materials and often leads to the formation of irregular shape NPs by laser ablation. Alternatively bimetallic NPs can be prepared by laser ablating each metallic target separately in liquid, mixing the colloidal solutions in different ratios, and re-irradiating the mixed solution by the laser beam. Depending on the proximity of the wavelength of the laser beam to the plasmon resonance absorption of the NPs, on the melting point of the NP element, and on the laser fluence, selective laser heating and melting of the NPs of one of the two elements can occur which leads to the attachment of the NPs of the other element onto it (“nanosoldering” effect) [34]. For high enough fluence or longer irradiation times, melting of both elements of the composite NP can occur leading to the formation of single-phased alloy NPs (“nanoalloying” effect) [35]. Increasing further the fluence or the irradiation time leads to photofragmentation of the alloyed NPs. A good example is the system of Au–Ag NPs [35, 36]. In the UV–vis optical absorption spectra of the mixed solution just before irradiation, plasmon resonances from both elements appear. When the solution is irradiated by using a laser beam at 532 nm, initially there is melting of the Ag NPs and attachment onto the Au NPs with the formation of Au/Ag core/shell NPs. In this case, if the shell is not thick and dense enough, still plasmon resonances from both elements appear. For longer irradiation times or higher fluences, there is melting of both elements, accompanied by the diffusion of Ag atoms from the shell into the Au core due to the higher atomic mobility of Ag atoms as compared to Au because of its lower atomic mass indicating the onset of alloy formation. Au and Ag form nearly ideal solid solutions at all compositions, and therefore mixing the two metals is a thermodynamically favorable process. This time-dependent composition of the core results in the shift of the Au plasmon resonance to lower wavelengths, while the Ag plasmon resonance position remains unchanged. The formation of alloy NPs is indicated by the disappearance of the double plasmon resonance and appearance of single plasmon resonance with a maximum between those of pure Ag and pure Au. Fragmentation of the alloy NPs results also in a single plasmon band, but the maximum intensity decreases and shifts to smaller wavelengths.

Nanoparticle Productivity Scaling Up A characteristic of the method of synthesis of NPs by laser ablation of bulk target materials in liquids is the relatively low amount of NPs produced, a drawback which has limited the applicability of the method in large-scale industrial applications. The problem of the large fluctuations of the ablation rate of the target as the ablation proceeds for NP generation due to the thermal distortion, scattering, and shielding of the laser beam by vapor bubbles, which are formed onto the target surface, as well as of the relatively long resident time of the NPs within the ablation zone which seriously affect the reproducibility of the experiments was overcome by carrying out the ablation in a specially designed chamber in which the liquid flows (flow cell) rather than being stationary [37]. The liquid flow aims to the rapid dispersion of the NPs into the whole liquid volume. This also results in the increase of the NP production rate (up to 8.6 mg/s extrapolated to 34 mg/h for 50 kHz, 110 mJ, 10 ps, 1,064 nm, a factor of 4 increase as compared to stationary liquid) due to the absence of redeposition of the ablated material onto the target surface and generation of micro-size fragments. By further optimizing the interpulse distance in relation to the cavitation bubble lifetime, dispersed NP interaction with the following laser pulse and temperature Page 12 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

gradient in the target lattice, as well as height of the liquid above the target [38], it was shown that a productivity of 1,265 mg/h of corundum NPs can be achieved, about 300 % higher than in the non-optimized scan speed (18.5 W, 4 kHz, 20–60 ns, 1,047 nm) [39]. Lately, an increase of the NPs productivity as well as of the continuity of the production process was achieved by making use of a target for ablation in the form of a continuously fed thin wire instead of a bulk material inside an ablation chamber in which there is a continuous liquid flow [40]. Because the wire acts as one-dimensional heat conductor, the energy loss due to heat conduction is reduced, and thus for high enough fluence, the metal is superheated near the spinodal leading to its ablation via phase explosion. Also in the case of wire, the induced cavitation bubble grows spherically, enwrapping the wire, and then it is expelled from the wire during the rebound phase, pushing the ablated material more efficiently away from the target. These effects result in an increase of the ablation rate as compared to bulk material ablation. The ablation efficiency (NP mass per laser pulse) increases with the wire diameter d reaching a maximum at d = 750 mm for a Ag wire (attaining an ablation efficiency higher by almost 15 times as compared to the bulk material), but further decreases for thicker wires. This is partially due to the optimization of the ablation by phase explosion in relation to the heat dissipation rate which depends on the wire diameter. The ablation efficiency also is higher for metals with higher thermal diffusivity (Pt, W, Ag). The NP productivity (mass per sec) increases linearly with the pulse repetition rate, and it can reach a value of >25 g/h for rates at the kHz regime.

Nanoparticle Synthesis Out of Different Materials The reports in the literature of material combinations, liquids, and type of laser sources used for ablation are numerous ranging from single-element metals, binary metallic alloys to single-element semiconductors or binary semiconducting alloys, graphite, and lanthanide-doped transition metal oxides by laser ablating them while they are immersed in water, organic solvents to aqueous solutions of surfactants and polymers. Laser ablation of metals such as Ag [41, 42], Pd [43], Pt [44], Ti [7], Zn [45], Cu [16], Al [46, 47], Sn [48, 49], W [50], Ta [51] (Fig. 7(a)), Zr [52], Pb [53], Fe [6, 22], Cr [54, 55], Co [23] (Fig. 7(b)), Mn [56] or Mg [57] with the exception of Au or Pd, in water or in some organic solvents, gives in most cases spherical NPs of one or the different oxides of the metal which on some occasions have core–shell structure with the oxide as a shell. Laser ablation in organic solvents leads most of the times to the formation of carbides of the metal or to the formation of metal NPs which are imbedded into a matrix of graphitic carbon which is produced by the pyrolysis of the organic solvent by the plume extreme temperature or by the still hot NPs after generation. Laser ablation of binary metal alloys such as PtIr [31], NiFe [32, 58], SmCo [32], PtAu [33], FePt [59] or AuFe [60] gives NPs which retain or not the stoichiometry of the bulk target material depending on the difference in the heat of evaporation between the alloy target elements or the degree of their reactivity with the oxygen molecules present in the solvent. Laser ablation of Si in water gives Si/SiO2 NPs with the oxide usually forming a shell surrounding the Si core [61]. Laser ablation of Si-doped GaAs in water or ethanol gives nearly stoichiometric NPs which are surface passivated by a Ga-rich oxidized amorphous compound [62]. Laser ablation of doped sesquioxides, oxysulfides, silicates, and tantalates such as Y2O3:Eu3+, Lu2O2S: Eu3+, Gd2SiO5:Ce3+, Lu3TaO7:Gd3+, and Tb3+ in water gives NPs with a mean diameter of roughly 7 nm which preserve the stoichiometry and the phase of the bulk material [63]. Similarly laser ablation of the doped oxides of Y2O3:Eu3+, Gd2O3:Eu3+, and Y3Al5O12:Ce3+ in aqueous solution of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid results in the coordination of the produced NPs by the carboxylate group (COO) of the molecule via the bridging bidentate mode which limits their size and narrows their size distribution, while the polyether chain of the molecule ensures their stability. The Page 13 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

a

c

b

TaxO/Ta2O5 core/shell NPs

d

e

Ge NPs (0 V)

hollow Fe19Ni81 MPs

Co3C nano-onions

g

f

GeO2 nanocubes (14.5 V)

GeO2 nanospindles (32 V)

β-Zn(OH)2/DS nanoflowers

Fig. 7 Examples of NMs produced by laser ablation of bulk targets in liquids: (a) TaxO crystalline core-Ta2O5 amorphous shell NPs by ns, 1,064 nm laser ablation of Ta in ethanol [51] (Reproduced from Li et al. [51] with permission of The Royal Society of Chemistry). (b) Onion-like carbon-encapsulated Co3C core–shell NPs by ns laser ablation of Co in acetone [23] (Reprinted from Zhang et al. [23], Copyright (2013), with permission from Elsevier). (c) Hollow Fe19Ni81 permalloy MPs by 30 ns, 248 nm laser ablation of the target in aqueous solution of SDS [58] (Reprinted with permission from Yan et al. [58]. Copyright (2010) American Chemical Society). (d) Ge NPs. (e) GeO2 nanocubes. (f) GeO2 nanospindles, by 10 ns, 532 nm laser ablation of Ge under 0, 14.5, and 32 V electric field, respectively [67] (Reprinted with permission from Liu et al. [67]. Copyright (2008) American Chemical Society). (g) b Zn(OH)2/DS nanoflowers by 30 ns, 248 nm laser ablation of Zn in ethanol–water solution of SDS [73] (Reprinted from Yan et al. [73], Copyright (2010) with permission from Elsevier)

NPs produced from the Y2O3:Eu3+ are in the cubic disordered phase, while ablation of the Y3Al5O12:Ce3+ leads to a majority of a-Al2O3 and Y3Al5O12:Ce3+ NPs and a minority of YAlO3 NPs [64]. Similarly laser ablation of Tb3Al5O12:Ce3+ in aqueous solution of the amphoteric surfactant lauryl dimethylaminoacetic acid betaine (LDA) produces NPs which retain the stoichiometry and crystal structure of the bulk target material and also exhibit blue-shifted enhanced luminescence as compared to NPs made in just water as the liquid [65]. Examples of NPs or NMs synthesized by laser ablation of bulk target materials in liquids are summarized in Table 1.

Nanomaterials Other than Spherical Nanoparticles. Except from spherical shape NPs, NMs with different shapes and morphology can be synthesized by laser ablation of bulk target materials in liquids. Thus CuO nanospindles were synthesized by laser ablating a Cu target in water under the application of an electric field [66]. The polar CuO nanocrystals which are synthesized by the target laser ablation are aligned by the electric field and are subsequently attached and coalesced in an oriented way forming the nanospindles. The control of the shape of the synthesized NMs by the applied electric field was demonstrated in the case of the synthesis of GeO2 NMs [67]. Without the application of an electric field, spherical Ge NPs are synthesized (Fig. 7d), but when an electric field is applied, GeO2 nanocubes enclosed by high-index planes ({1011}) are obtained for low fields (14.5 V) (Fig. 7e) and nanospindles at higher fields (32 V) (Fig. 7f). In this case, due to the strong dependence on the crystallite facet of the magnitude of the electrostatic potential which is induced on the crystallites by the external electric field [68], there is a preferred orientation for particle–particle interaction during the growth of the embryonic nuclei which leads to an anisotropic growth of the agglomerates. Similarly, copper vanadate nanoflake-assembled Page 14 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Table 1 Examples of NPs or NMs synthesized by laser ablation of bulk target materials in liquids Target Au

NPs or NMs1 Au [14], Au [15], Au/ Au@graphite/carbon NMsa, Au@TPyP2−-Au3+-Cl−(b) [18], Au@silica [26]

Liquid2 SDS [14], Dextran, PEG, chitosan, SH-PNIPAM-SH [15], chloroforma, chloroform/ TPyP(b) [18], TEOS/ammonia/ 2-propanol [26]

Ag

Aga, carbon coated or impeded Agb [41], Ag/Ag2O3 [42], Ag/ Ag2O [71]

Acetonitrilea, DMFa, THFb, DMSOb [41], DI water [42], polysorbate [71]

Pd

Pda, PdHxb [43]

Pt

Pt/PtOx [44]

DI watera, acetoneb, ethanolb [43] DI water [44]

Ti

TiO [7]

DI water [7]

Zn

Zn/ZnO [45], Zn(OH)2/DS [73]

SDS [45], SDS/distilled water/ ethanol [73]

Cu

Cu [16], CuO [66]

Al

Al, AlHx [46], Al@Al2O3 [47]

Sn

SnO2-x [48], Sn6O4(OH)4 [49]

Acetone, distilled water, 1,10phenanthroline, 4,4″bipyridine [16], DI water [66] Ethanol, n-propanol, hydrogen, deuterium saturated ethanol [46], hydrogen saturated ethanol [47] DI water, SDS [48], DI water [49]

W

WO3 [50]

DI water [50]

Ta

TaxO@Ta2O5 [51]

Ethanol [51]

Zr

ZrO2 [52]

Ammonia, water [52]

Pb

Pb/PbS [53]

Fe

FeO [6], Fe@Fe3O4 or γ-Fe2O3a, carbon impeded Fe3O4/γ-Fe2O3b, carbon impeded Fec, Fe or Fe3C@graphited, Fe3C/Fe3O4e [22] Cr3O4/α-Cr2O3 [54], Cr3O4/ Cr2O3/CrO3a, Cr3O4/Cr7C3/ Cr3C2-xb, Cr3C2-xc [55] Co3C@carbon [23]

Dodecyl mercaptan, n-hexane, mercaptoacetic acid, mercaptoethanol [53] PVP [6], THFa, acetonitrileb, DMFb, DMSOc, toluened, ethanole [22]

Cr

Co

DI water [54], DI watera, ethanolb, acetonec, toluenec [55] Acetone [23]

Laser parameters Nd:YAG laser/1,064, 532 nm/10 Hz/20–80 mJ [14], 110 fs/800 nm/1 kHz/0.2–1.10 J.cm−2 [15], 6 ns/1,064 nm/10 Hz/70–270 mJ [18], 10 ns/515, 1,030 nm/20 kHz/10 J.cm−2 [26] 9 ns/1,064 nm/10 Hz/10 J.cm−2 [41], 10.4 ps/1,064 nm/50 kHz/ 4.2 J.cm−2 [42], 30 ns/248 nm/ 10 Hz/8.8 J.cm−2 [71] 12 ps/532 nm/80 kHz/32.5 μJ [43] 7 ns/355 nm/10 Hz/1–110 J. cm−2 [44] 10.4 ps/1,064 nm/50 kHz/2.1 J. cm−2 [7] 10 ns/1,064 nm/10 Hz/70 mJ [45], 30 ns/248 nm/10 Hz/4.3 J. cm−2 [73] 10 ns/1,064, 532 nm/10 Hz/2.5 J.cm−2 [16], 10 ns/532 nm/5 Hz/ 100 mJ [66] 70 ns/1,064 nm/2 kHz, 180 fs/ 800 nm/1 kHz [46], 30 ps/1.06 μm/10 Hz/4 J.cm−2 [47] Nd:YAG laser/355 nm/10 Hz/ 100 mJ [48], 10 ns/532 nm/10 Hz/700 mJ [49] 10 ns/1,064 nm/10 Hz/80 mJ [50] Nd:YAG laser/1,064 nm/10 Hz/ 90 mJ [51] 120 fs/800 nm/1 kHz/0.1–0.36 mJ [52] 1 ms/1,064 nm/1–20 Hz/106 W. cm−2 [53] 10 ns/1,064 nm/10 Hz/80 mJ [6], 9 ns/1,064 nm/10 Hz/5 J.cm−2 [22]

240 μs/1,064 nm/10 Hz/1,100 mJ [54], 90 fs/800 nm/1 kHz/ 110 μJ [55] Nd:YAG laser [23] (continued)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Table 1 (continued) Target Mn Mg

NPs or NMs1 Mn3O4 [56] Mg(OH)2a, MgO/Mgb [57], MgO/Mg(OH)2a, MgOb [72]

V PtIr

CuxVyOn [69] PtIr [31]

NiFe

NiFe [32], NiFe [58]

Cyclopentanone [32], SDS [58]

SmCo

SmCo [32]

Cyclopentanone [32]

PtAu

PtAu [33]

Water [33]

FePt

FePt [59]

DI water, hexane [59]

AuFe Si

AuFe [60] Si/SiOx [61]

Ethanol [60] DI water [61]

Ge GaAs:Si

GeO2 [67] Amorphous Asa,b, amorphous GaAsa,b, crystalline GaAsa,b, As2S3b [62] MoS2/MoO3 [25]

DI water [67] Ethanola, ammonium sulfideb [62]

Y2O3:Eu3+(a), Lu2O2S:Eu3+(b), Gd2SiO5:Ce3+(c), Lu3TaO7:Gd3+(d), Tb3+(e) Y2O3:Eu3+(a), Gd2O3:Eu3+(b), Y3Al5O12:Ce3+(c) Tb3Al5O12:Ce3+

Y2O3:Eu3+(a), Lu2O2S:Eu3+/ Lu2O3(b), Gd2SiO5:Ce3+(c), Lu3TaO7:Gd3+(d), Tb3+(e) [63]

DI water [63]

Y2O3:Eu3+(a), Gd2O3:Eu3+(b), α-Al2O3/Y3Al5O12:Ce3+/ YAlO3(c) [64] Tb3Al5O12:Ce3+ [65]

2-[2-(2-methoxyethoxy) ethoxy]acetic acid [64]

5 ns/355 nm/10 Hz/2–69 mJ [64]

C

C [70]

Graphite

α-C3N4 [24]

Lauryl dimethylaminoacetic acid betaine [65] Ethanol/acetone/KCl or NaCl [70] Liquid ammonia [24]

5–7 ns/355 nm/30 Hz/60 mW [65] 10 ns/532 nm/10 Hz/1010 W. cm−2 [70] 15 ns/532 nm/10 Hz/15 J.cm−2 [24]

MoS2

Liquid2 DI water [56] DI watera, SDSa, acetoneb, 2-propanolb [57], watera, SDSb, citrateb [72] DI water [69] Acetone [31]

Water [25]

Laser parameters 10 ns/1,064 nm/80 mJ [56] 5.5 ns/1,064 nm/10 Hz/75 mJ [57], 30 ns/248 nm/10 Hz/ 3.2–15 J.cm−2 [72] 10 ns/532 nm/5 Hz/150 mJ [69] 120 fs/800 nm/5 kHz/300 μJ [31] 120 fs/800 nm/5 kHz/300 μJ [32], 30 ns/248 nm/20 Hz/7 J. cm−2 [58] 120 fs/800 nm/5 kHz/300 μJ [32] KrF excimer laser/248 nm/20 Hz/4–150 J.cm−2 [33] Nd:YAG laser/532 nm/10 Hz/ 100 mJ [59] 9 ns/1,064 nm/10 Hz/30 mJ [60] 110 fs/800 nm/1 kHz/0.15–0.40 mJ [61] 10 ns/532 nm/5 Hz/150 mJ [67] 20 ps/1,060 nm/1 MHz/1.6 μJ [62] 5 ns/532 nm/10 Hz/1–10 J.cm−2 [25] 5 ns/355 nm/10 Hz/1.77–20.7 GW.cm−2 [63]

1

The symbol / indicates that NPs or NMs of all kinds are found to be present in the same ensemble. The symbol @ indicates core-shell type of NPs or NMs 2 The symbol / indicates that the liquid is a mixture of all liquids

flowerlike, nanoplate-stacked, or nanoparticle-grown nanostructures were produced by laser ablating a vanadium target in DI water under the application of an electric field produced by two copper electrodes, at different values [69]. Carbon micro- and nanocubes with C8-like structures and blue luminescence have been synthesized by laser ablating an amorphous carbon film on silicon substrate in a mixed solution of twice-distilled water, Page 16 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

ethanol, acetone, and a low concentration (
4 mM) of inorganic salts such as KCl and NaCl, due to the selective adsorption of the inorganic salt ions onto a certain crystallographic plane of the embryonic nuclei, which lowers the surface energy of the bound plane and thus hinders the crystallite growth perpendicular to that plane resulting in a cubic morphology of the synthesized products [70]. Ag2O micro-/nanostructures including a mixture of cubes, pyramids, triangular plates, pentagonal rods, and bars have been produced by laser ablation (KrF excimer laser, 248 nm, 30 ns, 10 Hz) of a Ag target in aqueous solution of polysorbate surfactants, and it was proposed that the formation of Ag2O was due to the fact that the polysorbate micelles in water promote the dissociation of the water molecule into OH and H with the subsequent combination of the hydroxyls with the Ag+ which are formed by the target ablation while at the same time providing an environment for the crystallization of the formed Ag2O into the different morphologies based on the thermodynamic principle of the surface free energy minimization [71]. Hollow micro-/nanoparticles (M/NPs) were produced by the excimer laser ablation of bulk Pt, Ag, Cu, Zn, Al, Si, Fe–Ni alloy (Fig. 7c), TiO2, Nb2O5, and Mg targets in water [72], and this was explained by assuming a preferential condensation and nucleation of the vaporized plume species on the interfaces between water and gas bubbles in order to minimize the interfacial free energy followed by the bonding of the nanoclusters by capillary attraction. These bubbles are formed at the laser focal spot because of the ionization or evaporation of the water at the plume–water interface due to the extreme temperature of the plasma plume. Collapse of the bubble results in the trapping of gas within the formed NPs and thus formation of a cavity in its interior. Complex three-dimensional nanostructures assembled by nanolayers which resemble “nanoflowers” were formed by excimer laser ablation of a Zn target in ethanol–water solution of SDS [73] (Fig. 7g). The ethanol facilitates the formation of ZnO clusters that immerse in the Zn(OH)2 lamellae because of defects which are formed at the hydroxyl groups due to the local reduction of water molecules. The extra free energy of the Zn(OH)2 layers due to their lattice distortion caused by the ZnO clusters will provide the thermodynamic driving force for the heterogeneous nucleation of Zn(OH)2 species to secondary nanolayers and resulting in three-dimensional nanostructures. Laser ablation (1,064 nm, 10 ns, 10 Hz) of a W target in DI water [50] produces isopolyanions of tungsten oxide from the reaction with the H2O molecules of the W clusters which are formed by the target ablation. After the aging treatment of this precursor solution under well-defined conditions of temperature (25  C), aging time (48 h), and pH value (~3.0) followed by subsequent annealing (500  C, 2 h), leaflike tungsten oxide nanoplatelets were produced due to the polymerization and aggregation of the isopolyanions by nucleation and growth. Laser ablation of metal targets in superfluid 4He (He II) results in the formation of nanowires with extremely large ratio due to the pressure-gradient-driven coalescence of the metal clusters and nanofragments produced by the ablation onto quantized vortex lines and/or normal fluid eddy currents [74]. By ablating metal targets using a long-pulse millisecond laser in different liquids, NMs with different shapes ranging from pure spherical metal NPs to core/shell spherical NPs and cubes were produced [53]. This is because in the case of the long-pulse laser ablation at low fluences, the target material is ablated in the form of nanodroplets due to melting by the laser beam rather than vaporization and plasma plume formation as in the case of short-pulse laser ablation; thus chemical reactions with the liquid which take place on the surfaces of the nanodroplets control the structure and elemental composition of the formed NMs. Thus the ablation of Pb in dodecyl mercaptan/n-hexane (1:5 v/v) solution leads to the production of Pb/PbS core/shell NPs due to the reaction of sulfur on the surface of the high-temperature Pb NP, but ablation in progressively more reactive liquids such as mercaptoacetic acid and dodecyl mercaptan resulted in the chemical reactions to proceed faster and deeper into the Pb NP producing PbS hallow NPs due to the Kirkendall voiding effect and PbS nanocubes, respectively. Page 17 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

Conclusion The method of generation/synthesis of NPs or NMs in general, by laser ablation of bulk target materials in liquids can be applied with an almost unlimited combination of materials, liquids, and laser sources/ ablation conditions, and the results in terms of the morphological, physical, structural, chemical, and other properties of the products are usually unpredictable a priori. This, in combination with the overall simplicity of the method, makes this field of research fascinating and attractive. Furthermore, the products and the production methodology adaptation are ideally suited for utilization in a wide variety of applications, and they may lead to the fabrication and manufacturing of materials, composites, components, or devices with advanced and superior properties while at the same time offering a reduction of production cost, processing time and utilization of resources.

References 1. G.W. Yang, Laser ablation in liquids: applications in the synthesis of nanocrystals. Prog. Mater. Sci. 52, 648 (2007) 2. P. Lorazo, L.J. Lewis, M. Meunier, Short-pulse laser ablation of solids: from phase explosion to fragmentation. Phys. Rev. Lett. 91, 225502 (2003) 3. T. Tsuji, D.-H. Thang, Y. Okazaki, M. Nakanishi, Y. Tsuboi, M. Tsuji, Preparation of silver nanoparticles by laser ablation in polyvinylpyrrolidone solutions. Appl. Surf. Sci. 254, 5224 (2008) 4. T. Tsuji, Y. Okazaki, Y. Tsuboi, M. Tsuji, Nanosecond time-resolved observations of laser ablation of silver in water. Jpn. J. Appl. Phys. 46, 1533 (2007) 5. A. De Giacomo, M. Dell’Aglio, A. Santagata, R. Gaudiuso, O. De Pascale, P. Wagener, G.C. Messina, G. Compagnini, S. Barcikowski, Cavitation dynamics of laser ablation of bulk and wireshaped metals in water during nanoparticles production. Phys. Chem. Chem. Phys. 15, 3083 (2013) 6. P. Liu, W. Cai, H. Zeng, Fabrication and size-dependent optical properties of FeO nanoparticles induced by laser ablation in a liquid medium. J. Phys. Chem. C 112, 3261 (2008) 7. N.G. Semaltianos et al., Laser ablation of a bulk titanium target in water: a route to synthesize nanoparticles of titanium monoxide. Chem. Phys. Lett. 496, 113 (2010) 8. D. Amans, A.-C. Chenus, G. Ledoux, C. Dujardin, C. Reynaud, O. Sublemontier, K. MasenelliVarlot, O. Guillois, Nanodiamond synthesis by pulsed laser ablation in liquids. Diam. Rela. Mater. 18, 177 (2009) 9. J.-P. Sylvestre, S. Poulin, A.V. Kabashin, E. Sacher, M. Meunier, J.H.T. Luong, Surface chemistry of gold nanoparticles produced by laser ablation in aqueous media. J. Phys. Chem. B 108, 16864 (2004) 10. H. Muto, K. Yamada, K. Miyajima, F. Mafuné, Estimation of surface oxide on surfactant-free gold nanoparticles laser-ablated in water. J. Phys. Chem. C 111, 17221 (2007) 11. S.A. Al-Mamun, R. Nakajima, T. Ishigaki, Tuning the size of aluminium oxide nanoparticles synthesized by laser ablation in water using physical and chemical approaches. J. Coll. Interf. Sci. 392, 172 (2013) 12. C. Rehbock, V. Merk, L. Gamrad, R. Streubel, S. Barcikowski, Size control of laser-fabricated surfactant-free gold nanoparticles with highly diluted electrolytes and their subsequent bioconjugation. Phys. Chem. Chem. Phys. 15, 3057 (2013) 13. O.M. Magnussen, B.M. Ocko, J.X. Wang, R.R. Adzic, In-situ X-ray diffraction and STM studies of bromide adsorption on Au(111) electrodes. J. Phys. Chem. 100, 5500 (1996) 14. F. Mafuné, J.Y. Kohno, Y. Takeda, T. Kondow, H. Sawabe, Formation of gold nanoparticles by laser ablation in aqueous solution of surfactant. J. Phys. Chem. B 105, 5114 (2001) Page 18 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

15. S. Besner, A.V. Kabashin, F.M. Winnik, M. Meunier, Synthesis of size-tunable polymer-protected gold nanoparticles by femtosecond laser-based ablation and seed growth. J. Phys. Chem. C 113, 9526 (2009) 16. M. Muniz-Miranda, C. Gellini, E. Giorgetti, Surface-enhanced Raman scattering from copper nanoparticles obtained by laser ablation. J. Phys. Chem. C 115, 5021 (2011) 17. R. Zamiri, B.Z. Azmi, H.A. Ahangar, G. Zamiri, M.S. Husin, Z.A. Wahab, Preparation and characterization of silver nanoparticles in natural polymers using laser ablation. Bull. Mater. Sci. 35, 727 (2012) 18. K. Šišková, J. Pfleger, M. Procházka, Stabilization of Au nanoparticles prepared by laser ablation in chloroform with free-base porphyrin molecules. Appl. Surf. Sci. 256, 2979 (2010) 19. P. Wagener, A. Schwenke, S. Barcikowski, How citrate ligands affect nanoparticle adsorption to microparticle supports. Langmuir 28, 6132 (2012) 20. S. Petersen, S. Barcikowski, In situ bioconjugation: single step approach to tailored nanoparticlebioconjugates by ultrashort pulsed laser ablation. Adv. Funct. Mater. 19, 1167 (2009) 21. S. Petersen, S. Barcikowski, Conjugation efficiency of laser-based bioconjugation of gold nanoparticles with nucleic acids. J. Phys. Chem. C 113, 19830 (2009) 22. V. Amendola, P. Riello, M. Meneghetti, Magnetic nanoparticles of iron carbide, iron oxide, iron@iron oxide, and metal iron synthesized by laser ablation in organic solvents. J. Phys. Chem. C 115, 5140 (2011) 23. H. Zhang, C. Liang, J. Liu, Z. Tian, G. Shao, The formation of onion-like-encapsulated cobalt carbide core/shell nanoparticles by the laser ablation of metallic cobalt in acetone. Carbon 55, 108 (2013) 24. L. Yang, P.W. May, L. Yin, J.A. Smith, K.N. Rosser, Ultra fine carbon nitride nanocrystals synthesized by laser ablation in liquid solution. J. Nanopart. Res. 9, 1181 (2007) 25. G. Compagnini, M.G. Sinatra, G.C. Messina, G. Patanè, S. Scalese, O. Puglisi, Monitoring the formation of inorganic fullerene-like MoS2 nanostructures by laser ablation in liquid environments. Appl. Surf. Sci. 258, 5672 (2012) 26. T. Salminen, M. Honkanen, T. Niemi, Coating of gold nanoparticles made by pulsed laser ablation in liquids with silica shells by simultaneous chemical synthesis. Phys. Chem. Chem. Phys. 15, 3047 (2013) 27. S. Hashimoto, D. Werner, T. Uwada, Studies on the interaction of pulsed lasers with plasmonic gold nanoparticles toward light manipulation, heat management, and nanofabrication. J. Photochem. Photobiol. C Photochem. Rev. 13, 28 (2012) 28. D. Werner, A. Furube, T. Okamato, S. Hashimoto, Femtosecond laser-induced size reduction of aqueous gold nanoparticles: in situ and pump-probe spectroscopy investigations revealing coulomb explosion. J. Phys. Chem. C 115, 8503 (2011) 29. S. Besner, A.V. Kabashin, M. Meunier, Fragmentation of colloidal nanoparticles by femtosecond laser-induced supercontinuum generation. Appl. Phys. Lett. 89, 233122 (2006) 30. R. Mahfouz, F.J.C.S. Aires, A. Brenier, E. Ehret, M. Roumié, B. Nsouli, B. Jacquier, J.C. Bertolini, Elaboration and characterization of bimetallic nanoparticles obtained by laser ablation of Ni75Pd25 and Au75Ag25 targets in water. J. Nanopart. Res. 12, 3123 (2010) 31. J. Jakobi, A. Menéndez-Manjon, V.S.K. Chakravadhanula, L. Kienle, P. Wagener, S. Barcikowski, Stoichiometry of alloy nanoparticles from laser ablation of PtIr in acetone and their electrophoretic deposition on PtIr electrodes. Nanotechnology 22, 145601 (2011) 32. J. Jakobi, S. Petersen, A. Menéndez-Manjon, P. Wagener, S. Barcikowski, Magnetic alloy nanoparticles from laser ablation in cyclopentanone and their embedding into a photoresist. Langmuir 26, 6892–6897 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

33. J. Zhang, D. Nii Oko, S. Garbarino, R. Imbeault, M. Chaker, A.C. Tavares, D. Guay, D. Ma, Preparation of PtAu alloy colloids by laser ablation in solution and their characterization. J. Phys. Chem. C 116, 13413 (2012) 34. F. Mafuné, J. Kohno, Y. Takeda, T. Kondow, Nanoscale soldering of metal nanoparticles for construction of higher-order structures. J. Am. Chem. Soc. 125, 1686 (2003) 35. S. Besner, M. Meunier, Femtosecond laser synthesis of AuAg nanoalloys: photoinduced oxidation and ions release. J. Phys. Chem. C 114, 10403 (2010) 36. G. Compagnini, E. Messina, O. Puglisi, R.S. Cataliotti, V. Nicolosi, Spectroscopic evidence of a coreshell structure in the earlier formation stages of Au–Ag nanoparticles by pulsed laser ablation in water. Chem. Phys. Lett. 457, 386 (2008) 37. S. Barcikowski, A. Menéndez-Manjón, B. Chichkov, M. Brikas, G. Račiukaitis, Generation of nanoparticle colloids by picosecond and femtosecond laser ablations in liquid flow. Appl. Phys. Lett. 91, 083113 (2007) 38. Y. Jiang, P. Liu, Y. Liang, H.B. Li, G.W. Yang, Promoting the yield of nanoparticles from laser ablation in liquid. Appl. Phys. A 105, 903 (2011) 39. C.L. Sajti, R. Sattari, B.N. Chichkov, S. Barcikowski, Gram scale synthesis of pure ceramic nanoparticles by laser ablation in liquid. J. Phys. Chem. B 114, 2421 (2010) 40. G.C. Messina, P. Wagener, R. Streubel, A. De Giacomo, A. Santagata, G. Compagnini, S. Barcikowski, Pulsed laser ablation of a continuously-fed wire in liquid flow for high-yield production of silver nanoparticles. Phys. Chem. Chem. Phys. 15, 3093 (2013) 41. V. Amendola, S. Polizzi, M. Meneghetti, Free silver nanoparticles synthesized by laser ablation in organic solvents and their easy functionalization. Langmuir 23, 6766 (2007) 42. N.G. Semaltianos et al., Polymer-nanoparticle composites composed of PEDOT:PSS and nanoparticles of Ag synthesized by laser ablation. Coll. Polym. Sci. 290, 213 (2012) 43. N.G. Semaltianos et al., Palladium or palladium hydride nanoparticles synthesized by laser ablation of a bulk palladium target in liquids. J. Coll. Interf. Sci. 402, 307 (2013) 44. W.T. Nichols, T. Sasaki, N. Koshozaki, Laser ablation of a platinum target in water. III. Laser-induced reactions. J. Appl. Phys. 100, 114913 (2006) 45. H. Zheng, W. Cai, Y. Li, J. Hu, P. Liu, Composition/structural evolution and optical properties of ZnO/Zn nanoparticles by laser ablation in liquid media. J. Phys. Chem. B 109, 18260 (2005) 46. P.G. Kuzmin, G.A. Shafeev, G. Viau, B. Warot-Fonrose, M. Barberoglou, E. Stratakis, C. Fotakis, Porous nanoparticles of Al and Ti generated by laser ablation in liquids. Appl. Surf. Sci. 258, 9283 (2012) 47. G. Viau, V. Collière, L.-M. Lacroix, G.A. Shafeev, Internal structure of Al hollow nanoparticles generated by laser ablation in liquid ethanol. Chem. Phys. Lett. 501, 419 (2011) 48. C. Liang, Y. Shimizu, T. Sasaki, N. Koshizaki, Synthesis of ultrafine SnO2-x nanocrystals by pulsed laser-induced reactive quenching in liquid medium. J. Phys. Chem. B 107, 9220 (2003) 49. J. Xiao, Q.L. Wu, P. Liu, Y. Liang, H.B. Li, M.M. Wu, G.W. Yang, Highly stable sub-5 nm Sn6O4(OH)4 nanocrystals with ultrahigh activity as advanced photocatalytic materials for photodegradation of methyl orange. Nanotechnology 25, 135702 (2014) 50. H. Zhang, G. Duan, Y. Li, X. Xu, Z. Dai, W. Cai, Leaf-like tungsten oxide nanoplatelets induced by laser ablation in liquid and subsequent aging. Cryst. Growth Des. 12, 2646 (2012) 51. Q. Li, C. Liang, Z. Tian, J. Zhang, H. Zhang, W. Cai, Core-shell TaxO@Ta2O5 structured nanoparticles: laser ablation synthesis in liquid, structure and photocatalytic property. CrystEngComm 14, 3236 (2012) 52. D. Tan, G. Lin, Y. Liu, Y. Teng, Y. Zhuang, B. Zhu, Q. Zhao, J. Qiu, Synthesis of nanocrystalline cubic zirconia using femtosecond laser ablation. J. Nanopart. Res. 13, 1183 (2011) Page 20 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

53. K.Y. Niu, J. Yang, S.A. Kulinich, J. Sun, H. Li, X.W. Du, Morphology control of nanostructures via surface reaction of metal nanodroplets. J. Am. Chem. Soc. 132, 9814 (2010) 54. C.H. Lin, S.Y. Chen, P. Shen, Defects, lattice correspondence, and optical properties of spinel-like Cr3O4 condensates by pulsed laser ablation in water. J. Phys. Chem. C 113, 16356 (2009) 55. N.G. Semaltianos et al., Laser ablation of a bulk Cr target in liquids for nanoparticles synthesis. RSC Adv. 4, 50406 (2014) 56. H. Zhang, C. Liang, Z. Tian, G. Wang, W. Cai, Single phase Mn3O4 nanoparticles obtained by pulsed laser ablation in liquid and their application in rapid removal of trace pentachlorophenol. J. Phys. Chem. C 114, 12524 (2010) 57. T.X. Phuoc, B.H. Howard, D.V. Martello, Y. Soong, M.K. Chyu, Synthesis of Mg(OH)2, MgO and Mg nanoparticles using laser ablation of magnesium in water and solvents. Opt. Lase Eng. 46, 829 (2008) 58. Z. Yan, R. Bao, Y. Huang, A.N. Caruso, S.B. Qadri, C.Z. Dinu, D.B. Chrisey, Excimer laser production, assembly, sintering and fragmentation of novel fullerene-like permalloy particles in liquid. J. Phys. Chem. C 114, 3869 (2010) 59. Y. Ishikawa, K. Kawaguchi, Y. Shimizu, T. Sasaki, N. Koshizaki, Preparation of Fe-Pt alloy particles by pulsed laser ablation in liquid medium. Chem. Phys. Lett. 428, 426 (2006) 60. V. Amendola, M. Meneghetti, O.M. Bakr, P. Riello, S. Polizzi, D.H. Anjum, S. Fiameni, P. Arosio, T. Orlando, C. de J. Fernandez, F. Pineider, C. Sangregorio, A. Lascialfari, Coexistence of plasmonic and magnetic properties in Au89Fe11 nanoalloys. Nanoscale 5, 5611 (2013) 61. R. Intartaglia, K. Bagga, M. Scotto, A. Diaspro, F. Brandi, Luminescent silicon nanoparticles prepared by ultra short pulsed laser ablation in liquid for imaging applications. Opt. Mater. Express 2, 510 (2012) 62. T. Salminen, J. Dahl, M. Tuominen, P. Laukkanen, E. Arola, T. Niemi, Single-step fabrication of luminescent GaAs nanocrystals by pulsed laser ablation in liquids. Opt. Mater. Express 2, 799 (2012) 63. G. Ledoux, D. Amans, C. Dujardin, K. Masenelli-Varlot, Facile and rapid synthesis of highly luminescent nanoparticles via pulsed laser ablation in liquid. Nanotechnology 20, 445605 (2009) 64. D. Amans, C. Malaterre, M. Diouf, C. Mancini, F. Chaput, G. Ledoux, G. Breton, Y. Guillin, C. Dujardin, K. Masenelli-Varlot, P. Perriat, Synthesis of oxide nanoparticles by pulsed laser ablation in liquids containing a complexing molecule: impact on size distributions and prepared phases. J. Phys. Chem. C 115, 5131 (2011) 65. S.W. Mhin, J.H. Ryu, K.M. Kim, G.S. Park, H.W. Ryu, K.B. Shim, T. Sasaki, N. Koshizaki, Pulsedlaser-induced simple synthetic route for Tb3Al5O12:Ce3+ colloidal nanocrystals and their luminescent properties. Nanosci. Res. Lett. 4, 888 (2009) 66. X.Z. Lin, P. Liu, J.M. Yu, G.W. Wang, Synthesis of CuO nanocrystals and sequential assembly of nanostructures with shape-dependent optical absorption upon laser ablation in liquid. J. Phys. Chem. C 113, 17543 (2009) 67. P. Liu, C.X. Wang, X.Y. Chen, G.W. Yang, Controllable fabrication and cathodoluminescence performance of high-index facets GeO2 micro- and nanocubes and spindles upon electrical-field assisted laser ablation in liquid. J. Phys. Chem. C 112, 13450 (2008) 68. A.S. Barnard, M. Sternberg, Crystallinity and surface electrostatics of diamond nanocrystals. J. Mater. Chem. 17, 4811 (2007) 69. Y. Liang, P. Liu, H.B. Li, G.W. Yang, Synthesis and characterization of copper vanadate nanostructures via electrochemistry assisted laser ablation in liquid and the optical multi-absorptions performance. CrystEngComm 14, 3291 (2012) 70. P. Liu, Y.L. Cao, C.X. Wang, X.Y. Chen, G.W. Yang, Micro- and nanocubes of carbon with C8-like and blue luminescence. Nano Lett. 8, 2570 (2008) Page 21 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_1-1 # Springer International Publishing Switzerland 2015

71. Z. Yan, R. Bao, D.B. Chrisey, Generation of Ag2O micro-/nanostructures by pulsed excimer laser ablation of Ag in aqueous solutions of polysorbate 80. Langmuir 27, 851 (2011) 72. Z. Yan, R. Bao, C.M. Busta, D.B. Chrisey, Fabrication and formation mechanism of hollow MgO particles by pulsed excimer laser ablation of Mg in liquid. Nanotechnology 22, 265610 (2011) and references there in 73. Z. Yan, R. Bao, D.B. Chrisey, Self-assembly of zinc hydroxide/dodecyl sulfate nanolayers into complex three-dimensional nanostructures by laser ablation in liquid. Chem. Phys. Lett. 497, 205 (2010) 74. P. Moroshkin, V. Lebedev, B. Grobety, C. Neururer, E.B. Gordon, A. Weis, Nanowire formation by gold nano-fragment coalescence on quantized vortices in He II. Europhys. Lett. 90, 34002 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Nano-Emulsions Nicolas Anton* and Thierry Vandamme Faculty of Pharmacy, CNRS 7199 Laboratoire de Conception et Application de Molécules Bioactives (CAMB), équipe de Pharmacie Biogalénique, University of Strasbourg, Strasbourg, France

Abstract Nano-emulsion systems consist of a suspension of liquid nanodroplets stabilized by surfactants. Nanoemulsions are very powerful and promising systems for numerous applications, since there are very stable systems and their formulation and characterization are not only very simple but also simply transposable for industrial scale-up. Owing to a liquid core (mainly oily core), nano-emulsions have appeared as an efficient solution to disperse and stabilize poorly water-soluble compounds in aqueous media, through their nano-encapsulation. The main emerging applications of nano-emulsions include the formulation of innovative drug delivery systems and/or contrast agents. In this chapter, we will present a state of the art of the different aspects of the nano-emulsion formulation: processes of fabrication, optimization of the processes, impact of the chemical nature of the compounds on the processes, stability, strategies for optimizing the stability, and characterization. Likewise, we will discuss the emerging technologies aiming the surface treatment of nano-emulsions, including polymer coating (e.g., for inducing stealth properties in vivo) or ligand grafting for active targeting.

Introduction Nano-emulsions constitute a very particular class of emulsions, typically due to their size range, exhibiting hydrodynamic diameters from 10 to 20 nm up to 200–300 nm. Nano-emulsions are also frequently known as miniemulsions, fine-dispersed emulsions, submicron emulsions, and so forth but are all characterized by a great stability in suspension due to their very small size, essentially the consequence of significant steric stabilization between droplets, which goes to explain why the Ostwald ripening is the only adapted droplet destabilization process. In general, emulsions and also nano-emulsions are not at the thermodynamic equilibrium. That means that at infinite time, all these emulsions will give a phase separation. However, compared to classical emulsions, this destabilization time is very slow and typically lasts several months. Actually, this kinetic stability is the main typical characteristic of nano-emulsions, making them prime candidates for numerous applications from nano-medicine, pharmaceutics, to agrifood industries. In short, emulsions are thermodynamically unstable systems because the free energy DGf is greater than zero. Considering the global expression DGf = gDA – TDSf (with g the water-oil interfacial tension, DA the water-oil interfacial area gained with emulsification, TDSf the entropy of droplet formation), the emulsion instability only comes from DA, and DGf can be reduced with playing on the interfacial tension g. The physical destabilization of emulsions is related to the spontaneous trend towards a minimal interfacial area between the two immiscible phases. Therefore, a minimization of interfacial area is attained by two mechanisms: (i) flocculation followed mostly by coalescence and (ii) Ostwald ripening. In nano-emulsion systems, the very small size of droplets will prevent the droplets from undergoing reversible processes like flocculation and creaming (or sedimentation), thus preventing the coalescence. *Email: [email protected] Page 1 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Table 1 Main publications of our research group on nano-emulsions, presented by type of publication and applications Type of article/application Fundamental on formulation and process Drug delivery systems Contrast agent Reviews

References [1–7] [8–12] [13–18] [19–22]

Eventually, Ostwald ripening remains as the only destabilization process of nano-emulsions. On the other hand, it is to keep in mind that the stability of nano-emulsions is actually a paradox since, due to the very small droplet size, DA of nano-emulsions is definitively higher than the one of macro-emulsions, thus resulting in even more increasing DGf. However, stability of nano-emulsions is an experimental fact, almost a general rule, and very easily obtained with simple formulation procedures. Origins of this stability were studied by many authors and found several plausible explanations (summarized shortly below), but the most important ideas are that (1) stability is linked to the droplet submicron size, (2) the droplets always slowly grow with time due to Ostwald ripening, and (3) some formulation strategies can be followed to reduce the destabilization rate. Nano-emulsions are thermodynamically unstable systems, but kinetically stable, and stable against fluctuations of thermodynamic variables like temperature fluctuations or dilution, giving them compatibility with a number of industrial applications. To sum up, nano-emulsions are rather robust. As a consequence, nano-emulsions naturally find numerous applications in various fields, notably, since they can be fabricated with nontoxic compounds, in nano-medicines as lipid nano-carriers. Nanoemulsions allow highly stable dispersion of lipid active ingredients, drugs, and contrast agents, in aqueous medium. The main fundamental and applied works based on nano-emulsions, published by our group, are reported in Table 1.

Nano-Emulsion Stability Principles

Nano-emulsion flocculation is naturally prevented by steric stabilization due to the sub-micrometric size of droplets. When interfacial layers of two different droplet layers overlap, steric repulsion arises. It comes from two main origins [23, 24]: the first one is the unfavorable mixing of the stabilizing chain of the adsorbed layer, depending on the interfacial density, interfacial layer thickness d, and Flory-Huggins parameter w1,2, reflecting the interactions between the interfacial layer and solvent. The second one is the reduction of the configurational entropy, due to the bending stress of the chains, which occurs when interdroplet distance h becomes lower than d. As well, the small droplet size reduces their deformability and the potential formation of a thin film between two droplets (i.e., a permanent contact occurring in the flocculation process). The sum of these contributions, i.e., energies of interactions noted UT, can be represented in the function of the inter-droplet distance h as shown in Fig. 1. This profile typically adopts a weak minimum around h = 2d, for which the depth of value |U0| depends on the particle radius r, the Hamaker constant A, and the thickness of the adsorbed layer d, with the result that the smaller the droplet size, the lower the value of |U0| and thus the ability for the nano-emulsion droplets to flocculate. As well, it is worth noting that the small droplet sizes also induce stabilization against sedimentation or creaming, insofar as the droplets are solely under the influence of the Brownian motion. To summarize, nanoemulsion droplets cannot have direct interaction or contact for physical reasons, and their behavior in suspension trends towards a homogeneous and stable repartition in the whole volume.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 1 Schematic illustration of the influence of the nano-emulsion droplet size on their steric stabilization (Reprinted adapted with permission from Ref. [19])

To sum up the destabilization of nano-emulsions is due only to a mass transfer phenomenon between the droplets through the bulk phase, well described in the literature the so-called Ostwald ripening in emulsions [25]. In order to understand the different existing strategies for even improving the nanoemulsion stability, it is important to know the physical phenomena related to Ostwald ripening. At the origin of this destabilization process, the differences, however slight, of the droplet radius induce differences in chemical potential of the material within the drops. The reduction of free energy in the emulsion will result in the decrease in the interfacial area and therefore in the growth of the bigger emulsion droplets at the expense of the smaller ones. The dispersed phase migrates through the bulk from the smaller droplets to the bigger ones, owing to the higher solubility in the bulk of the smaller droplets. Ostwald ripening is initiated and will increase throughout the process. The literature provides a number of theories dealing with calculations of the rate of ripening, such as the most famous and complete given by Lifshitz, Slyozov, and Wagner, the so-called LSW theory [26–28]. The diffusion of dispersed materials through the continuous medium is assumed to be diffusion-controlled, i.e., crossing the interface with ease. Details on LSW theories are fully developed and discussed in the literature [24, 29] leading to the commonly used expression of the ageing rate, o, defined as o¼

dr3c dt

where rc is the critical radius of the system at any given time, at the frontier between the growth and decrease in the droplets. Consequently, Ostwald ripening is reflected by a linear relationship between the cube radius and time. The important idea to be used in working out nano-emulsion stability studies is that if plotting (radius)3 = f(time) is a linear function, the destabilization process is effectively Ostwald ripening, and the slope o allows to quantify it. This is very useful in order to quantitatively evaluate the impact of the different strategies undertaken to reduce the nano-emulsion destabilization rate. As an illustration, Fig. 2 (from Ref. [30]) presents the temporal evolution of oil-in-water nano-emulsion

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 2 Illustration of Ostwald ripening as a function of time and storage temperature: (a) size evolution; (b) Ostwald ripening rates o (Reprinted adapted with permission from Ref. [30]. Copyright (2013) American Chemical Society)

droplets’ hydrodynamic diameter as a function of time for different temperatures (Fig. 2a), as well as the evolution of the ripening rate (Fig. 2b). This simple system is an illustration of a non-stabilized system, solely composed of medium-chain triglycerides (oil core), nonionic surfactant (stabilizing agent), and water + NaCl (as continuous phase). One can note that the ripening rates can be affected by the storage temperature, but nevertheless remain suitable up to 40  C, and relatively constant at room temperature. Moreover, this example is relatively simple (only composed of oil + surfactant + water) and not further stabilized. Eventually, this illustrates the huge potentials of nano-emulsions.

Methods for Improving the Stability of Nano-Emulsions From the understanding of the processes driving the destabilization of nano-emulsions (summed up in Ostwald ripening), various strategies were imagined and studied [24, 30], in order to reduce or inhibit the destabilization kinetics. Actually, Oswald ripening is due to the diffusion of the dispersed phase through the continuous one, between two drops of different sizes. However, Ostwald ripening can be significantly reduced both when a second compound is solubilized in the dispersed phase and when this additive is significantly less soluble in the bulk phase than the dispersed phase itself. The diffusion of such additive limits the kinetics of the one of the dispersed phase, trending towards keeping constant the chemical potential over the droplet population. However, as it is done elsewhere [24], we will not describe in detail, here, the physical related principles. The main idea to keep in mind is that the kinetics of the diffusion between the droplets will be driven by the one of the additive, which should be slower than the one of the continuous phase since it is chosen much less soluble in the bulk one. In industrial processes using nano-emulsions, the formulations commonly include numerous additives like polymers, thickener, stabilizing agent, conservative agents, electrolyte, etc. They can also play the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

droplet r3 (nm3).10–5

a 45 40 35 30 25 20 15 10 5 0

Decane Dodecane Tetradecane Hexadecane Isohexadecane 0

50

100

150

200

250

300

Time (h)

r3•10–5 (nm3)

b 25 20 15

Isohex. / Sq. = 100/0 Isohex. / Sq. = 98/2 Isohex. / Sq. = 96/4 Isohex. / Sq. = 94/6 Isohex. / Sq. = 92/8 Isohex. / Sq. = 80/20

10 5 0 0

25

50 Time (h)

75

100

droplet r3(nm3).10–5

c 20 15

10

S: 4.0 wt% S: 5.0 wt% S: 6.0 wt% S: 7.0 wt% S: 8.0 wt%

5 0 0

50

100 Time (h)

150

200

Fig. 3 Influence of various experimental parameters on the Ostwald ripening rate of o/w nano-emulsions: (a) nature of oil; (b) addition of insoluble oil in the dispersed phase; (c) concentration of surfactant in the continuous phase (Adapted from Ref. [24])

role of Ostwald inhibitors. In the case of o/w nano-emulsions, various examples can be found in literature, such as the influence of the nature of oil on the Ostwald ripening rate (reported in Fig. 3a) or the impact of the concentration of additive (e.g., squalene) mixed with the dispersed phase (Fig. 3b). On the other hand, it is important to note that Ostwald ripening can be also affected by the composition of the continuous phase and notably by the presence of surfactant micelles, which will promote the diffusion of the dispersed phase (Fig. 3c). This is why, as we will see below, the amount of emulsifier has a crucial role in the control of the size and size distribution, but too much sufactants will also induce destabilization. As a last remark, the structure and the density of the interface stabilizing layer have also an influence on the Ostwald ripening rate. The diffusion of dispersed phase can be decreased in function of the density and compactness of the surfactant layer adsorbed at the water/oil interface of the droplets [31].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Table 2 Summary of the accessible sizes in function of the emulsification apparatuses (in blue, the ones compatible with the formulation of nano-emulsions) (Adapted from Ref. [32]) Emulsification method Mechanical stirring Colloidal mills High-pressure homogenization Membrane Microfluidizer ® Ultrasonication Low-energy methods

Typical size 1 mm–15 mm 10 mm–50 mm 50 nm–5 mm 0.2 mm–100 mm 10 nm–1 mm 20 nm–1 mm 10 nm–200 nm

Nano-Emulsion Formulation Processes Generalities on Emulsification

Emulsification consists of dispersing one fluid into another nonmiscible one, as seen above, creating interface (i.e., increasing DA). The physicochemical properties of the resulting emulsion, like size distribution and stability, are not only closely linked to the composition, surfactant properties, and ratio of viscosities of the dispersed and bulk phases but also on the formulation protocol, temperature and time of processing, shear rate, cooling time, and type of emulsification apparatus. On the other hand, once the emulsion is fabricated (beside temperature and composition), the monodispersity of emulsions is an important criterion influencing their stability. In the case of nano-emulsion, monodispersity will have a direct impact on the inhibition of Ostwald ripening, since the difference of the pressure between the bigger and smaller droplets will be reduced. In view of the expression of DGf above (DGf = gDA – TDS), the formulation of emulsions sizing below 100 nm is conditioned by the energy supplied by the formulation device. Actually, most of the apparatuses currently used for the fabrication of macro-emulsions do not allow decreasing the droplet size below 1 mm, because of low emulsification yields due to the dissipation of the mechanical energy in heat. It is the case of rotor/stator apparatuses like ULTRA-TURRAX ® and colloidal mills. Only several methods allow the fabrication of nano-emulsions. Table 2 (adapted from Ref. [32]) gathers the main methods for the formulation of emulsions along with the range of the generated droplet sizes (with limiting fvd < 30% to avoid droplet recombination during processing). In view of the possibilities offered by the emulsification devices (Table 2), we have three possibilities for the formulation of nano-emulsions: (1) high-pressure homogenization, (2) ultrasonication, and (3) low-energy emulsification. In the following sections, these processes will be presented and the conditions to reach nanometric-sized droplets will be discussed. However, the industrial production of emulsions follows several well-defined steps. After the preparation of the phase and all components like emulsifiers (e.g., weighting and heating for decreasing the viscosities), (i) the first mechanical step consists in the mixing or dispersing of the phases. This process is performed using stirring (rotor/stator) devices and gives rise to a premix emulsion sizing around 100 mm. (ii) The second step is the homogenization step, and this is an essential step that will give rise to fine and stable monodispersed emulsions. In industrial practice, the formulation of stable emulsions generally passes by these two steps, giving rise to nano-emulsions. One most famous and widespread example is the stabilization of milk by high-pressure homogenization, allowing to decrease the size below the micrometer. On the other hand, the low-energy methods can also be found in industrial processes especially in cosmetic applications, but overall not as widespread as high-pressure homogenizers.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 4 Schematic of high-pressure homogenizer chamber

High-Pressure Methods

High-pressure homogenization (also called microfluidization) is a very common process in the field of agri-food liquids or semiliquid products. For instance, it allows the stabilization of fatty emulsion (e.g., milk) by reducing the droplet sizes and narrowing the size distribution. High-pressure homogenization is a physical treatment during which a liquid or semiliquid system is projected under high pressure (30–1’000 bar) through a homogenization head of particular geometry (see Fig. 4). The premix emulsion undergoes a combination of elongation and shear flows, impacts, and cavitations. Despite the complexity of the mechanisms involved, the size distributions are usually reproducible with a mean size ranging from 50 nm to 5 mm. Emulsification by high-pressure homogenization results from a dynamic equilibrium between droplet breakup (promoted by drop deformation resulting from the high-speed flow) and recombination due to coalescence (promoted by collisions). Numerous studies were performed in order to determine the effect on the droplet size and emulsion stability, stabilizing agent concentration (protein or surfactant), applied pressure, and number of passages in the homogenizer (cycles). Conceptually, two processing regimes can be distinguished, depending on the surfactant concentration C. (i) The first one corresponds to low surfactant concentration, for C < (critical micelle concentration)/10. The applied pressure does almost not influence the size of the homogenized droplets. Even if, during processing, drops are efficiently fragmented, they undergo a strong coalescence owing to the inefficient surface stabilization by surfactant due to their low concentration. As a result, the droplet size cannot be decreased below 300 nm. (ii) The second regime occurs at higher surfactant concentration, typically for C > (critical micelle concentration)  10. This time, the newly fragmented droplets are largely stabilized by surfactant before coalescence, allowing decreasing the size up to 50 nm. This is due to the surfactant interfacial adsorption time being shorter than the recombination and coalescence time. One can understand that above a certain surfactant concentration, the interface of the newly formed droplets is totally saturated, and thus, further increasing C will not have an impact on the droplet size. Accordingly, in contrast with the case (i) above, here, the value of the applied pressure P significantly impacts on the droplet size, following a power law in the form (droplet size) / Pa, with the power exponent a typically varying between 0.6 and 0.9 [33]. As surfactants are adsorbed onto the droplet interface, the surface tension is globally gradually decreased, thus favoring further rupturing. To summarize, (i) for low surfactant concentration, the droplet size cannot be decreased enough to generate nano-emulsions, and (ii) for higher surfactant concentration, the droplet size can be lowered in the nanometric range, with the size depending on the pressure applied. It is to be noted that this behavior is Page 7 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 5 High-pressure device for the formulation of nano-emulsion: influence various experimental parameters on the droplet size. (a, b) The effects on the number of passages on the droplet size, (c) the effects of the value of ’vd, and (d) the effects of the pressure applied (Adapted from Ref. [34])

transposable to many surface-active compounds and macromolecules like protein or polymer. Furthermore, several other parameters can significantly impact on the nano-emulsion droplet size and distribution width, like (1) the number of passages in the homogenizer reduces the distribution width; (2) the volume fraction fvd can influence the mean droplet size, i.e., when fvd > 30 %, the number of droplet collisions and recombinations during the emulsification step is increased; thus, the mean droplet size is higher than the emulsion fabricated at low fvd values, and above fvd < 30 %, this effect becomes negligible; (3) a second chamber (with the pressure = 1/3 of the first one) is preferable, allowing a better control of the cavitation process and of the quality and monodispersity of the emulsion; (4) finally, it is to keep in mind that if the energy supplied is too high, it can induce the degradation of the principles composing the emulsion, e.g., protein denaturation. These different points are gathered in Fig. 5 (adapted from Ref. [34]): Fig. 5a, b presents the effects on the number of passages on the droplet size, Fig. 5c the effects of the value of fvd, and Fig. 5d the effects of the pressure applied.

Ultrasound-Based Methods Power ultrasounds are acoustic waves of frequencies from 16 kHz (upper limit of human acuteness) to 1 MHz. They are generally produced by a plane surface that vibrates in a sinusoidal way. The amplitude is generally between 1 and 200 mm. Cavitation bubbles alternatively undergo contraction and dilatations. However, their diameters gradually increase up to a very fast implosion. It is to be noted that such mechanical effects are favored at low frequencies (e.g., 20 kHz), at high acoustic intensity, at high pressure, and at low temperature. The main mechanisms that allow explaining the emulsification induced by ultrasounds consider that the implosion of the cavitation bubble gives rise to the fragmentation of the droplets, gradually decreasing their average diameter. It is to be noted that the ultrasonic emulsification is only efficient in a small volume around the sonotrode (see Fig. 6, left). That means that the fluid circulation in the sample is still necessary for optimizing the process and involves a minimum time to be reached before stabilization of the droplet sizes.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015 Sonication time

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Fig. 6 Left: schematic of a sonication-based nano-emulsification process. Right: evolution of droplet size distribution along the sonication process: particle mean diameter (black disks) and polydispersity index (open triangles). Schematic representation of a nano-emulsion droplet (Reprinted adapted with permission from Ref. [30]. Copyright (2013) American Chemical Society)

Furthermore, when ultrasound-based technologies are compared with high-pressure homogenizers, the properties of the resulting emulsions are generally similar. However, high-pressure homogenizers are widely used in industrial processes, whereas ultrasonifiers are more adapted for the laboratory scale, research, and development stages. Once a premix emulsion is ultrasonified, the suspension undergoes a decrease in the droplet size with the sonification time, up to a limit size. The visual aspect of the flack along the nano-emulsification process is presented in Fig. 6 (right). One can see the macro-emulsion or premix having a turbid aspect, and when the droplet size decreases, a milky aspect appears and decreases with the droplet size. The suspension becomes transparent for the smaller droplets. The quantification of this behavior gives the nano-emulsion mean size that describes an exponential decay up to stabilization. This is as well illustrated in Fig. 6 (right) above, for a simple system composed of medium-chain triglycerides (oily core), nonionic surfactant (stabilizing agent), and water as continuous phase. The figure shows the follow-up of the mean size and polydispersity indexes (PDI). PDI reflects the quality and monodispersity of the dispersion, such that a suspension is considered of good monodispersity (good quality) if the value of the PDI is below 0.2–0.15 and of very good monodispersity (very good quality) if the PDI is below 0.1. Actually, as a general rule for ultrasound-based nano-emulsification processes, this behavior follows an exponential decay. Literature has highlighted several key points impacting on the characteristic time of the exponential (i.e., time to reach the stabilization (in the example of Fig. 6, it is ~10 min)) and impacting on the final droplet size: the characteristic time is actually only due to the energy supplied. That is to say, the higher the power of the ultrasonifier (selected in the process by the operator), the faster the nanoemulsification. This is illustrated in Fig. 7 below, showing (left) the droplet size decrease in function of the sonication time, for the same system in Fig. 6 (triglycerides/nonionic surfactant/water) at different

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

200 180 P20% P25% P40%

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Fig. 7 Left: size monitoring for different sonication powers. Right: size monitoring as a function of the global energy supplied (Reprinted adapted with permission from Ref. [30]. Copyright (2013) American Chemical Society)

powers. Now, since the global energy supplied is given by the power of sonication  time of sonication, the right part of this figure shows the droplet diameter in function (this time) of the total energy supplied. The curves appear exactly similar. This result is actually important for understanding the process, as well as its design and optimization. The second key parameter emphasized by the literature is the influence of the surface-active agents used: both their chemical nature and concentration impact on the final size of the nano-emulsion droplets (after the size stabilization time shown above). The higher the surfactant amount, the lower the resulting nano-emulsion size (as illustrated for instance in Fig. 8 (left) below). However, high and low surfactant concentrations have to be avoided in order to formulate stable nano-emulsions. The reason is simple and illustrated in Fig. 8 (right): (i) for the higher surfactant concentrations (i.e., smaller sizes), there is the concomitant presence of droplets and micelles. This will decrease the suspension stability due to the enhancement of Ostwald ripening (due to the inter-droplet transport of dispersed phase induced by the micelles). (ii) On the other hand, along the nano-emulsification process, the interfacial area increases in a dramatic manner, so that for low surfactant concentrations, emulsion instability can come from the low interface covering by surfactants. There are not enough molecules to cover the entire available interface, and thus, the surface tension at the oil-water interface increases. This remark is a general remark for the nano-emulsions formulated by the high-energy method and may also be valuable for the nano-emulsions formulated by high-pressure homogenization.

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Diameter / nm

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

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Fig. 8 Left: size as a function of the emulsifier amount. Right: impact of the surfactant amount on the coverage of the nanoemulsion droplet interface (Adapted from Ref. [35])

Likewise, the surface-active properties of the emulsifiers play a significant role in the resulting size of nano-emulsion droplets. To summarize, the ultrasonification process applied to a premix emulsion induces a size decrease following an exponential decay (see Figs. 6 and 7). The time necessary to reach the final stabilized size only relies on the energy supplied (i.e., similar results will be obtained between low power and long time, or high power and short time). Secondly, the size of the droplet size after stabilization depends on the nature and concentration of the surfactant(s) used. Too high or too low concentrations of surfactants have to be avoided, since these cases induce instabilities in the nano-emulsion suspension. Finally, this sonication process must be associated with a circulation of the liquid within the emulsification vessel.

Low-Energy Methods Low-energy methods allow generating nano-emulsion droplets without energy input, as it is the case for mechanical high-energy emulsification described above (high pressure and sonication). In low-energy methods, the increase in DA is not due to the supplied energy but rather is only obtained by taking benefit of the intrinsic physicochemical properties of the different compounds. The slight energy supplied is dedicated to mixing the sample and/or heating for optimizing the spontaneous emulsification process. In the facts, important fundamental research efforts are led to understand and control these low-energy formulation methods. Such simple and cost-effective formulation processes are very attractive; however, the low-energy methods are very much studied but almost only on the fundamental point of view and much less used in industrial processes than high-energy ones. This is likely due to several points, like the fact (1) that these methods only allow nano-emulsification and not homogenization of premix (e.g., not suitable for homogenizing milk), (2) that the physicochemical properties of the dispersion cannot always be finely controlled, and finally (3) that they involve a non-negligible amount of surfactants that is not Page 11 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 9 Schematic representation of the mechanism driving the spontaneous emulsification (Adapted from Ref. [3])

always compatible with all the specifications (impact on the taste in agri-food industries, induce a toxicity, etc.). Spontaneous Emulsification Spontaneous emulsification, or self-emulsification, is a process that occurs without the need of an external energy supply when two immiscible fluids are brought in contact and mixed. As a result, metastable nanoemulsion droplets are formed. When, as seen above, increasing the interfacial area requires a significant energy input, the spontaneous emulsification gives rise to similar gain in DA without energy. Actually, the phenomena driving the spontaneous emulsification take benefit of the physicochemical properties of the water, oil, and surfactant (plus potentially other compounds like solvent, etc.), for creating the emulsion droplets. However, in order to optimize the spontaneous process and emulsification kinetics, the samples will be homogenized and/or heated during emulsification. Of course, this still requires certain energy, but with no comparisons with the one supplied for high-energy emulsifications. Actually, although spontaneous emulsification was reported for more than 100 years, this phenomenon is still not fully understood. The literature has proposed a plethora of explanation; however, it is only recently that a universal and simple mechanism was proposed [3], explaining globally the spontaneous emulsification of all the low-energy methods. The main mechanism is simple, as illustrated in Fig. 9, and has been attributed to the penetration of the water phase in the oily one, inducing the creation of nanodroplets by breaking up the oil phase at the molecular level.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 10 Nano-emulsions formulated with oil and surfactant freely soluble at room temperature (25  C). Surfactant = Cremophor ELP ®, oil = Labrafil M1944 CS ®. The hydrodynamic diameter (filled circles) and PDI (open squares) are plotted against the surfactant-to-oil weight ratio. The hatched parts indicate that the criteria of PDI quality are not met; the suspension cannot be considered as a nano-emulsion. Inset presents the number of droplets as a function of SOR (Adapted from Ref. [3])

The first step is the homogeneous mixing of surfactant in oil (i.e., solubilized or dispersed) (Fig. 9a). Next, this surfactant/oil phase is mixed with the aqueous phase (e.g., pure water) (Fig. 9b). Very rapidly, the water phase penetrates the former in order to solubilize the surfactant molecules (Fig. 9c). Small nanometric oily drops with a very narrow size distribution are immediately generated and stabilized with surfactants (Fig. 9d). Actually, it appears that the mechanism is governed by the physicochemical properties and solubility of the surfactant for the two oily and aqueous phases. The first condition is a total solubilization of the surfactants in the oily phase, and then, they must be also soluble in water. Actually, for an optimal fractionation of the oil, during the water penetration step (Fig. 9c), surfactant molecules must present significantly more affinities for water than for oil. Logically, the size of the nano-emulsion droplets depends on the concentration of oil in the first surfactant/oil mixture (i.e., proportion of oil compared to surfactant). The smaller is the oil amount, the higher is the size of the resulting droplets. Besides, the amount of continuous phase in the process has been shown to not influence the droplet size. In literature, as above described in emulsification mechanism, the compound inducing the diffusion of water is generally a surfactant, but it can also be a hydrophilic solvent like ethanol (even if the presence of surfactants is in all cases required for stabilizing the newly formed droplets). Therefore, the whole process is based on the physicochemical properties of the compound inducing the diffusion of water and thus on its affinities for the oil and water. An example is presented in Fig. 10, showing the influence of the proportion of surfactant in the oil plus surfactant mixture (noted SOR in the figure, surfactant-to-oil weight ratio), on the properties of the w/o nano-emulsion generated, i.e., size (filled circles) and polydispersity (open squares). Two main results emerge from this graph: (i) first, the sizes of the emulsions are very finely controllable from all over the nano-emulsion size range, i.e., from 200 nm up to 15 nm (for this example), and (ii) second, the polydispersity indexes are very low, typically lower than 0.1, signifying that nano-emulsions prepared by spontaneous emulsification are extremely monodispersed. As a comparison with the example shown in Figs. 6 and 7 with a very similar

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

system, where the values of the PDI stabilize between 0.10 and 0.15, here, the spontaneous method allows reducing the PDI below 0.05. To summarize, the spontaneous emulsification process is due to the fractionation of the phase to be dispersed by the continuous one. The success of the process comes (i) from a good solubilization of the compound inducing the diffusion (surfactant) into the phase to be dispersed (oil) and (ii) from an even higher affinity of the surfactant with the continuous phase (water), therefore ensuring a very rapid penetration of water in the surfactant/oil phase once mixed. On the other hand, nonionic surfactants constitute the class of surfactants predominantly used in spontaneous emulsification methods. This is actually due to their particular physicochemical properties very compatible with the above-described process, for the following reasons. The hydrophilic part of nonionic surfactants is a hydrophilic polymer, generally a polyethylene glycol (PEG). This polymer is sensitive to temperature and precisely will see its solubility changing with the temperature. That is to say, the temperature modifies the surfactant affinities for water and oil. Basically, at low temperature, the surfactants are hydrosoluble. Upon a temperature increase, their solubility in water decreases, and it becomes more soluble in oil (see general description of such affinities in [21]). We saw above that the mechanism on which the spontaneous emulsification is based is precisely linked to surfactant affinities for oil and water, needing first a good solubilization in oil and then (when the surfactant/oil phase is mixed with water) an even better affinity for water. This is actually often performed and/or enhanced by the temperature. Indeed, if the surfactant/oil phase is heated, the surfactant solubility in oil will be increased, resulting in a better homogeneous dispersion of surfactant in oil. Then, when the hot surfactant/oil phase is mixed with room-temperature water (i.e., colder water), the surfactant affinity will immediately change towards the water, thus promoting the water penetration in the surfactant/oil phase and promoting as well the nano-emulsification process. This is a basic overview on the method, of course depending on the chemical nature of each compound, predominantly on the transition temperature of the nonionic surfactant (i.e., cloud point). Phase Inversion Temperature Method In literature, emulsification through “phase inversion” is also often considered as a spontaneous emulsification process because it requires low energy input with similar results than for spontaneous emulsification presented above. A second advantage of this method is the possibility of producing concentrated emulsions. Emulsification through phase inversion is often used industrially, especially in cosmetics. The literature reports a large number of fundamental studies dealing with the potential mechanisms governing the phase inversion emulsification methods and actually providing as well a number of different theories explaining these mechanisms. In order to understand how this emulsification process is worked out, and what the influence of the formulation parameters on the process is, the two following questions should be addressed: (i) what is emulsion phase inversion and (ii) how can phase inversion induce nanoemulsification? (i) What is emulsion phase inversion? In contrast with the spontaneous emulsification described above, oil, surfactant, and water are mixed right from the start, forming a macroscopic emulsion. When we speak of emulsion phase inversion, it is referred to the inversion of such macroscopic emulsions (and not to nano-emulsions). However, the inversion process can be used for the generation of nanoemulsions, and once nano-emulsions are generated, the emulsion phase inversion process is over and cannot occur any more: the whole system is converted to stable nano-emulsions. Emulsion inversion is produced when an oil-in-water (o/w) emulsion becomes a water-in-oil (w/o) one, that is to say, the continuous phase changes.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

Fig. 11 Schematic emulsion inversion map, in dynamic conditions and at fixed surfactant concentration (simplified to the effect of temperature) (Adapted from Ref. [19])

Beforehand, we have to notice that the nature of the continuous phase (if it is oily of aqueous) is linked to the difference of the surfactant solubility for oil and water. If the surfactants exhibit a higher solubility in one phase, the latter will be the continuous phase of the emulsion (i.e., following the empirical Bancroft’s rule). Thus, according to these principles, a general map of the emulsion inversion can be drawn, as illustrated in Fig. 11. The phase inversion temperature (PIT) is the temperature for which the surfactant presents the same affinity for water and oil (horizontal gray line in the figure). In this domain, the ternary system does not present anymore the structure of an emulsion but becomes a bicontinuous (at the nanometric scale) system called microemulsion. However, far from the PIT, the nonionic surfactant is hydrophilic or lipophilic, respectively, forming and stabilizing o/w or w/o emulsions. It must be noted that the inversion process can occur only for a roughly comparable amount of water and oil, at the region corresponding to the horizontal gray line in the figure. For higher proportions of oil, or water, the continuous phase will not invert but will rather give instable double emulsions. (ii) How can phase inversion induce nano-emulsification? The emulsion inversion is a reversible process, that is to say, o/w emulsion can invert to give w/o upon a temperature rise and vice versa upon a temperature decrease. In contrast, the nano-emulsification based on the PIT method is an irreversible process, i.e., once the nano-emulsions are generated, the ternary system has reached a thermodynamic metastable state. The nano-emulsification process is actually very simple and performed as follows: (1) the water/surfactant/oil system is emulsified by a gentle stirring and heated above the PIT. The o/w emulsion formed at T < PIT undergoes a phase inversion when T > PIT, giving rise to a w/o emulsion. (2) The second step is an irreversible step consisting in a rapid cooling of this emulsion. The system is broken up into nano-droplets, forming the kinetically stable nano-emulsion. In view of the literature that provides a plethora of explanations regarding the potential emulsification mechanism, it seems not fully understood. However, actually, the simple emulsification mechanism explaining the spontaneous emulsification presented above in section “Spontaneous Emulsification” can be totally transposable to understand the PIT method. Indeed, at T > PIT, the surfactant is lipophilic, and up to now, we considered that such surfactant properties had only an impact on the nature of the continuous phase (according to the Bancroft’s rule), stating that lipophilic surfactants induce the oil is the continuous phase. Moreover, in addition, at this temperature, the majority of free surfactant (i.e., not adsorbed at the interface) is also lipophilic and will be solubilized within the oily phase. This means that the so-called rapid cooling step will induce a sudden change of the surfactant solubility, making them

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015 Spontaneous emulsification

PIT method

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Fig. 12 A comparison between nano-emulsions generated by the PIT method and spontaneous emulsification. Surfactant = Solutol HS 15 ®, oil = Labrafil M1944 CS ®, aqueous phase = ultrapure Milli-Q water. The hydrodynamic diameter plotted against the WOR (water-to-oil weight ratio) and the SOR (surfactant-to-oil weight ratio). One star = 0.1 < PDI < 0.2, no star = PDI < 0.1 (Adapted from Ref. [3])

hydrophilic. Finally, exactly like for spontaneous emulsification, this sudden change in the surfactant affinities will result in the immediate penetration of water within the oily phase (as illustrated in Fig. 9c), creating the nano-emulsion droplets. This universality in the mechanisms has been proposed by comparing the properties of different nano-emulsions, made with the same composition, but formed with two different methods: spontaneous emulsification described in section “Spontaneous Emulsification” and the PIT method. The results are presented in Fig. 12 and show clearly comparable sizes whatever the formulation method, suggesting that the mechanism of formation of the nano-emulsion droplets is likely similar. As well, this confirms the mechanism proposed to govern the spontaneous emulsification, eventually extended to low-energy methods in general.

Characterization of Nano-Emulsions When macroscopic emulsions can be characterized according to numerous methods, from optical microscopy, optical counter, to static light scattering, all these characterization methods are inapplicable with the nanoscaled emulsions. Overall, the characterization techniques applied for characterizing emulsions sizing > 1 mm are totally different than the ones sizing < 1 mm. In that way, the characterization of nano-emulsions is mainly performed by dynamic light scattering (DLS) and sometimes by transmission electron microscopy (TEM). Representative examples we did with iodinated nanoemulsions are reported in Fig. 13, showing the size distribution of nano-emulsions centered in 85 nm and performed with a NanoSZ Malvern apparatus (left) and a picture of electron microscopy of the same nano-emulsion droplets using a Philips Morgagni 268D electron microscope (right).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

11 nm

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Fig. 13 Characterization of nano-emulsions. (Left) Size distribution performed by dynamic light scattering and (right) pictures done by transmission electron microscopy (Adapted from Ref. [16])

Dynamic Light Scattering The matter here is not to present the theory of autocorrelation giving size distribution of nano-dispersion, on which the method is based, but rather to describe the experimental aspect of the characterization. Briefly, the sample is placed on a thermostatic cell, crossed by a laser light. A photodetector (photomultiplier) at a fixed angle, with respect to the light pathway, records the fluctuations of scattered intensities over time (that are very slight). After a complex calculation, the apparatus gives the distribution of the diffusion coefficients. This step involves knowing the refractive indexes of the bulk and continuous phases. As the particles are very small, we consider them only moving because of the Brownian motion, and this is precisely why this method is valid in this case and not with bigger particles (for which the gravitational component is not negligible). These diffusion coefficients allow providing the size distribution according to the Stokes-Einstein relationship. It is as well to be noticed that the Stokes-Einstein equation contains the temperature and viscosity of the continuous phase. To conclude, the method is not complicated for the operator since the apparatuses are generally built to automatically adapt the operating conditions to the samples (e.g., by attenuating the incident light); the related software are very simple to use; however, the measurements are valid, only if we know the values of the refractive indexes of the bulk and continuous phases and the viscosity of the continuous phase.

Electron Microscopy Various electron microscopy technologies were developed, but only some of them can be used for observing the structure of the nano-emulsion droplets. For the study of liquid nano-droplets, only transmission electron microscopy, potentially cryo-transmission microscopy, could be compatible. The liquid samples are placed on a carbon grid and then dried. The dilution must be adapted in order to avoid droplet aggregation. Measurements are performed under a strong vacuum. In contrast, the cryomicroscopy will freeze the samples in a liquid state, allowing them to keep their native structure (not affected by the evaporation stage). Actually, it is clear that the more simple and appropriate routine characterization of nano-emulsions is only dynamic light scattering.

Conclusion Nano-emulsions constitute a very particular class of emulsions, with unique physicochemical properties, high stability, and homogeneity. These features make nano-emulsion a powerful and simple system for numerous domains and applications. In this chapter, we proposed an overview of the main principles related to the nano-emulsions and its main features, stability properties, and formulation methods. For Page 17 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

each experimental approach, high-energy methods (high-pressure and ultrasound-based emulsification) and low-energy methods (spontaneous emulsification and PIT methods) were detailed, and the impacts of the experimental parameters on the resulting emulsification properties were discussed.

References 1. A. Béduneau et al., Pegylated nanocapsules produced by an organic solvent-free method: evaluation of their stealth properties. Pharm. Res. 23, 2190–2199 (2006) 2. N. Anton et al., Nano-emulsions and nanocapsules by the PIT method: an investigation on the role of the temperature cycling on the emulsion phase inversion. Int. J. Pharm. 344, 44–52 (2007) 3. N. Anton, T.F. Vandamme, The universality of low-energy emulsification. Int. J. Pharm. 377, 142–147 (2009) 4. X. Li et al., Microencapsulation of nano-emulsions: novel Trojan particles for lipid bioactive molecule delivery. Int. J. Nanomed. 6, 1313–1325 (2011) 5. N. Anton et al., A new application of lipid nano-emulsions as coating agent, providing zero order hydrophilic drug release from tablets. J. Drug Deliv 2012, 1–9 (2012) 6. I. Souilem et al., A novel low pressure device for the production of nano-emulsions. Chem. Eng. Tech. 35, 1692–1698 (2012) 7. N. Anton, P. Saulnier, Adhesive water-in-oil nano-emulsions generated by the phase inversion temperature method. Soft Mat. 9, 6465–6474 (2013) 8. N. Anton et al., Aqueous-core lipid nanocapsules encapsulating fragile hydrophilic and/or lipophilic molecules. Langmuir 25, 11413–11419 (2009) 9. N. Anton et al., Reverse micelles-loaded lipid nano-emulsions: a new technology for the nanoencapsulation of hydrophilic materials. Int. J. Pharm. 398, 204–209 (2010) 10. T.F. Vandamme, N. Anton, Low-energy nano-emulsification to design veterinary controlled drug delivery devices. Int. J. Nanomed. 5, 867–873 (2010) 11. S. Vrignaud et al., Reverse micelle-loaded lipid nanocarriers: a novel drug delivery system for the sustained release of doxorubicin hydrochloride. Eur. J. Pharm. Biopharm. 79, 197–204 (2011) 12. S. Vrignaud et al., Aqueous core nanocapsules: a new solution for encapsulating doxorubicin hydrochloride. Drug Dev. Ind. Pharm. 39, 1706–1711 (2013) 13. F. Hallouard et al., Radiopaque iodinated nano-emulsions for preclinical X-ray imaging. RSC Adv. 1, 792–801 (2011) 14. A. Klymchenko et al., Highly lipophilic fluorescent dyes in nano-emulsions: towards bright non-leaking nano-droplets. RSC Adv. 2, 11876–11886 (2012) 15. F. Hallouard et al., Iodinated nano-emulsions as contrast agents for preclinical X-ray imaging, impact of the free surfactants on the pharmacokinetics. Eur. J. Pharm. Biopharm. 83, 54–62 (2013) 16. X. Li et al., Iodinated alpha-tocopherol nano-emulsions as non-toxic contrast agent for preclinical X-ray imaging. Biomaterials 34, 481–491 (2013) 17. F. Hallouard et al., Poly(ethylene glycol)-poly(epsilon-caprolactone) iodinated nanocapsules as contrast agents for X-ray imaging. Pharm. Res. 30, 2023–2035 (2013) 18. N. Anton et al., Do iodinated nano-emulsions designed for preclinical vascular imaging alter the vascular reactivity in rat aorta? Int. J. Pharm. 454, 143–148 (2013) 19. N. Anton, J.P. Benoit, P. Saulnier, Design and production of nanoparticles formulated from nanoemulsion templates – a review. J. Control. Release 128, 185–199 (2008) 20. F. Hallouard et al., Iodinated blood pool contrast media for preclinical X-ray imaging applications – a review. Biomaterials 31, 6249–6268 (2010) Page 18 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_2-1 # Springer International Publishing Switzerland 2015

21. N. Anton, T.F. Vandamme, Nano-emulsions and microemulsions: clarifications of the critical differences. Pharm. Res. 28, 978–985 (2011) 22. N. Anton, T.F. Vandamme, Nanotechnology for computed tomography: a real potential recently disclosed. Pharm. Res. 31, 20–34 (2014) 23. D.H. Napper, Polymeric Stabilization of Colloidal Dispersion (Academic, London, 1983) 24. T.F. Tadros et al., Formation and stability of nano-emulsions. Adv. Colloid Interface Sci. 108–109, 303–318 (2004) 25. P. Taylor, Ostwald ripening in emulsions. Adv. Colloid Interface Sci. 75, 107–163 (1998) 26. I.M. Lifshitz, V.V. Slezov, The kinetics of precipitation from supersaturated solid solution. J. Phys. Chem Solids 19, 35 (1961) 27. I.M. Lifshitz, V.V. Slezov, Kinetics of diffuse decomposition of supersaturated solid solutions. Soviet Phys J. E. T. P. 35, 331 (1959) 28. C. Wagner, Theorie der alterung von niederschl€agen durch umlösen (ostwald reifund). Z. Elektrochem 65, 581–591 (1961) 29. M. Kahlweit, Ostwald ripening of precipitates. Adv. Colloid Interface Sci. 5, 1–35 (1975) 30. T. Delmas et al., How to prepare and stabilize very small nanoemulsions. Langmuir 27, 1683–1692 (2011) 31. W.I. Higuchi, A.H. Goldberg, Mechanism of interphase transport. ii. Theoretical considerations and experimental evaluation of interfacially controlled transport in solubilized systems. J. Pharm. Sci. 58, 1342–1352 (1969) 32. F. Leal-Calderon, V. Schmitt, J. Bibette, Emulsion Science Basic Principles, 2nd edn. (Springer, New York, 2007) 33. L. Taisne, P. Walstra, B. Cabane, Transfer of oil between emulsion droplets. J. Colloid Interface Sci. 184, 378–390 (1996) 34. K. Meleson, S. Graves, T.G. Mason, Formation of concentrated nano-emulsions by extreme shear. Soft Mat. 2(2-3), 109–123 (2004) 35. M. Antonietti, K. Landfester, Polyreactions in miniemulsions. Prog. Polym. Sci. 27, 689–757 (2002)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Characterization and Imaging of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers Melike Üner* Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Turkey

Keywords Atomic force microscopy; Differential scanning calorimetry; Dynamic light scattering; Fourier transform infrared spectroscopy; Low angle laser light scattering; Nanostructured lipid carriers; Proton nuclear magnetic resonance spectroscopy; Raman spectroscopy; Scanning electron microscopy; Solid lipid nanoparticles; Transmission electron microscopy; X-ray scattering Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), the second generation of SLN, are colloidal drug carrier systems that can be used for controlled drug delivery via various administration routes. They introduce various advantages over traditional dosage forms and their colloidal counterparts. SLN and NLC products are available in the market of the European community, and lipid nanotechnology has been increasingly attracted by the industry. Moreover, studies on lipid nanoparticles have been focused on targeting of drugs to the specific sites of the body, thus surface modification and treatment of SLN and NLC in the last decades. Naturally, several parameters must be taken into consideration for design of well-performing formulations, which have a long-term stability. A lot of analytical methods, which give scientists extensive informations, are essential for characterization of SLN and NLC. Investigation of factors affecting their physicochemical properties and common techniques used for their characterization will be introduced in this chapter. Determination methods of particle size, particle charge, and surface characteristics, crystallographic and structural investigations, and imaging of SLN and NLC will be discussed. In vivo and in vitro experiments will also be summarized to describe future direction of researches.

Introduction SLN and NLC are colloidal drug carrier systems, composed of middle-chain-length triglycerides and/or waxes [1–3]. Their composition provides controlled delivery of actives. SLN and NLC are sophisticated systems suitable to administer actives including parenteral [4], oral [5], ocular [6], nasal [7], pulmonary [8], topical [9], and transdermal routes [10]. They improve tissue distribution leading to enhancement of bioavailability of entrapped actives [11]. Researchers have reported that targeting of drugs to specific organs can be possible with SLN and NLC [12–14]. SLN and NLC are safe and compatible colloidal drug carriers, which can be produced by environmentcompatible techniques including high-pressure homogenization, membrane contactor method, liquidflow focusing using microchannels or microtubes, and supercritical fluid technology. The use of organic solvents and surface active agents at high concentrations can be avoided for the production of SLN and NLC by these cost-effective techniques, which have excellent reproducibility for scaling-up [15,

*Email: [email protected] Page 1 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Table 1 Exemplary studies on SLN and NLC in the literature Method High-pressure homogenization

Product/drug SLN/tamoxifen

Solid lipid/liquid lipid Softisan ® 154

Surfactant Phospholipon ® 90 H

1-Hexadecanol/ Miglyol ® 812 Gelucire® 44/14

TegoCare ® 450

Membrane contactor method

SLN and NLC/loratadine SLN/–

Tween ® 20

SLN/–

Softisan ® 100

Poloxamer ® 188

SLN/caffeine

Lumulse ® GMS

–

SLN/insulin

Tristearin phosphatidylcholine Beeswax and carnauba wax Gelucire® 44/14/ Capmul ® MCM Dynasan ® 114 Dynasan ® 118 Hydrogenated castor oil Glyceryl monostearate

Tween ® 80

Pluronic ® F68

Glyceryl monostearate

Tween ® 80

SLN/etoposide

Softisan ®601

SLN/ropinirole HLC SLN/dibenzoyl peroxide Erythromycin Triamcinolone acetonide SLN and NLC/sildenafil citrate SLN/itraconazole

Stearylamine

Tween ® 80 and Lutrol ® F127 Pluronic ® F68

Liquid-flow focusing using microchannels or microtubes Supercritical fluid technology

Microemulsion

SLN/flurbiprofen NLC/celecoxib

Double emulsion (w/o/w) method

Solvent emulsificationevaporation

Solvent emulsification-diffusion

High-shear homogenization

Ultrasonication

SLN/5-flurouracil (5-FU) SLN/yak interferon-alpha SLN/ syringopicroside SLN/efavirenz

NLC/–

Tween ® 80 and egg lecithin Cremophor ® RH 40 Soya lecithin and polyvinyl alcohol Polyvinyl alcohol

References AL-Haj et al. [17] Üner et al. (2014) Charcosset et al. [18] Yun et al. [16] De Sousa et al. [19] Salmaso et al. [20] Baviskar et al. [21] Joshi and Patravale [22] Yassin et al. [23] Li et al. [24]

Glyceryl monostearate

Tween ® 20 Tween ® 80

Zhang et al. [25] Madhusudhan et al. [26] Fernandes et al. [27] Pardeshi et al. [28] Gardouh et al. [29]

Cetyl palmitate/ Maisine ® 35-1

Cremophor ® RH 40 and Span ® 85

Elnaggar et al. [30]

Stearic acid Palmitic acid Apifil ® Compritol ® 888ATO Cutina ® CP Berry wax/Myritol ® 312 and Cetiol ®V

Polyvinyl alcohol

Mohanty et al. [31] Lasoń et al. [32]

Plantacare ® 2000UP Poloxamer ® 188 TegoCare ® CG-90 Crodesta ® SL40LQ Tween ® 80

16]. Various production methods else have also been reported in the literature. All techniques are listed in Table 1 with exemplary studies. Several methods are used for characterization of SLN and NLC. Thus, informations can be obtained to reach desired formulations and to evaluate parameters affecting long-term stability of nanoparticles.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Table 2 Characterization methods of SLN and NLC Method Laser diffractometry Photon correlation spectroscopy Zeta potential Transmission electron microscopy Scanning electron microscopy Atomic force microscopy Differential scanning calorimetry X-ray diffraction Photon nuclear magnetic resonance spectroscopy Fourier transform infrared spectroscopy Raman spectroscopy

Data Particle size distribution Average particle size and particle size distribution Particle charge Particle size and imaging Particle size and imaging Particle size and imaging Thermal and crystallization behaviors of solid lipid in nanoparticles and druglipid interaction Crystallographic analysis, crystal order of lipid and drug in nanoparticles Nanoparticle structure and drug-lipid interaction Nanoparticle structure and drug-lipid interaction Nanoparticle structure and drug-lipid interaction

These methods are based on characterization of particle size and distribution, thermal behaviors and crystallinity properties, structural properties of nanoparticles, and surface morphology (Table 2). Factors affecting parameters and common methods used for characterization of SLN and NLC will be discussed in upcoming sections.

Particle Size of SLN and NLC SLN and NLC have been explained that they are produced in the 50–1,000 nm size range with low microparticle content [33]. Particle sizes of nanoparticles are usually expected in a 50–300 nm range in the case of site-specific delivery including anticancer therapy by antineoplastic agents and genes and central nervous system disorders [34]. Then, nanoparticles must accumulate onto specific sites to provide drug delivery. Meanwhile, they are mostly required to cross several anatomic barriers. The particle size and charge with surface properties are important for site-specific delivery. For instance, nanoparticles have been proclaimed to be in an optimum size range for their accumulation in a tumor and internalization by tumor cells in the case of nanoparticles designed for targeting according to one of the strategies of sitespecific delivery in cancer treatment. It is because the cutoff size of pores in tumor vessels is as large as 200 nm–1.2 mm in general. A decrease in the size of nanoparticles provides easier uptake and leads to a significant increase in the rate of cellular uptake [34]. A particle size higher than 300 nm provides sustained drug delivery in this case when the 50–300 nm size range displays rapid action. Moreover, particle size is one of the important parameters for having information on SLN and NLC stability [35]. The particle size of lipid nanoparticles should stay in a limited size range during storage. Therefore, investigation on the change in particle size and particle size distribution in long-term stability experiments provides strict information about agglomeration and physical stability of formulations. Various parameters affect the particle size of SLN and NLC such as composition of formulation (such as surfactant and mixture of surfactants and structural properties of the lipids and drug incorporated) and preparation process (such as choice of the preparation method, equipment, temperature, number of the cycles and pressure in the case of high-pressure homogenization, sterilization, lyophilization, and spray drying) [3, 36]. These parameters must be optimized to achieve well-formulated nanoparticles. An increase in the concentration of surfactant(s) usually causes a decrease in particle size of lipid nanoparticles, i.e., if a higher/lipid surfactant ratio is chosen, a smaller particle size is obtained [37, 38]. Page 3 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

The use of relatively lower-melting-point solid lipids and the increase in the oil content in the lipophilic phase of nanoparticle dispersion reduce the viscosity of the melted droplets during homogenization; thus nanoparticles form in smaller sizes. Entrapment of drug into nanoparticles may increase the particle size [39]. Drug concentration lower than 1 % does not affect the particle size of lipid nanoparticles in general. Processing temperature is also one of the most important parameters affecting particle size. Homogenization temperature, which is lower than the melting point of solid lipid or equal to it, results in heterogeneous particle size distribution with high microparticle content in the case of hot homogenization process. This situation is related to the viscosity of the lipophilic phase of nanoparticle dispersion during homogenization. Therefore, at least 10–15
C higher than the melting point of a solid lipid should be preferred in hot homogenization techniques. Homogenization efficiency increases with higher homogenization pressure. An increase in homogenization pressure up to 1,500 bar and in the number of cycles (three to seven cycles) decreases the particle size of nanoparticles [40, 41]. In general, SLN and NLC are resistant colloidal systems to lyophilization in the case of addition of proper cryoprotectant at proper concentrations. Spray drying can be used as an alternative method to lyophilization in the case of hydrolyzable drug content or a need for suitable product for per-oral administration. However, spray drying can destabilize the system due to the elevated temperature and shear forces, which increase the kinetic energy leading to frequent particle collisions [42]. Partial melting of the lipid phase during spraying is also one of the reasons for particle growth. Besides these procedures, sterilization is required for parenteral application of nanoparticles. Thus, proper sterilization (filtration, autoclaving, or gamma irradiation) technique should be chosen. Surface modifiers to reduce phagocytic uptake of SLN and NLC for parenteral administration, such as polyethylene oxide and PEG, may increase the particle size. Various particle size measurement techniques are used to obtain information on qualification and physical stability of SLN and NLC during storage. Theoretically, the shape of a particle makes particle size analysis more complicated than it appears since shapes of particles vary, which makes it complicated to obtain one unique mean size [43]. One unique mean size can be obtained with perfect spherical particles which cannot be possible to obtain in practice. If the shape or size of a single nanoparticle changes, its volume/weight will also change. Therefore, it will be possible to say that nanoparticles have gotten smaller/larger with an equivalent sphere model which is required for the approximation of certain values. The equivalent volume to each nanoparticle should be calculated to reach a mean number. Techniques like laser diffractometry (LD) measure proportional particle size distribution in order to provide the mean result. It should not be forgotten that different techniques give different means. LD and photon correlation spectroscopy (PCS) are commonly used for characterizing particle size of lipid nanoparticles and their particle size distribution.

Laser Diffractometry (LD) This technique, which is used for obtaining information on particle size distribution and microparticle content of SLN and NLC, is also called low-angle laser light scattering (LALLS) [44]. In a laser diffractometer, a laser beam passes through the sample in a laser scattering cell (Fig. 1). The laser is scattered with a diffraction angle inversely proportional to particle size when it interacts to the nanoparticles. The intensity of scattering is detected by a suitable detector. Then, data gives information on the volume distribution of the sample. LALLS is used for the characterization of particles for the range of 0.05–3,500 mm typically. He-Ne gas lasers (l = 0.63 mm) are one of the most commonly used lasers since they display the best stability, Page 4 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Obscuration Detector

Particles

Laser Beam Source Unscattered Light

Fourier Transform Lens

Multi-element Detector Computer

Volume (%)

20 15 10 5 0 0.01

0.1

1 10 Particle Size (μm)

100

1000 3000

Fig. 1 Illustration and working principle of low-angle laser light scattering (LALLS)

especially in respect to temperature. They give better and more reliable signals to noise than the higherwavelength laser diodes. Using the Mie theory introduces advantages over the Fraunhofer approximation since it provides the volume of the particle as opposed to the Fraunhofer approximation, which gives a projected area prediction. It is also capable to solve the equations for the interaction of light with matter through LALLS instruments. Nanoparticle dispersions and powders can be measured directly with LALLS within 1 min. 4–10 g and 1–2 g samples are required for dry powders and dispersions in the measurements, respectively. LALLS is a nondestructive and nonintrusive method. Therefore, samples can be recovered if it is required.

Photon Correlation Spectroscopy (PCS) PCS is also called dynamic light scattering (DLS) and quasi-elastic light scattering (QELS). DLS is used to measure particle size in submicron range using their Brownian motion in aqueous media [44]. In this technique, a laser beam is sent through the nanoparticle dispersion and scattering light is detected by a photomultiplier, which is positioned at a scattering angle of 90
(Fig. 2). Therefore, nonlinearity of the light can be avoided with the scattering angle. The scattered light causes a signal, which is received by a photomultiplier. The photomultiplier transforms intensity variations into a variation of voltage evaluating the signal with a correlation function. It is because small particles diffuse faster and lead to more rapid fluctuation of the intensity of the light scattered compared to larger particles. DLS measurements also provide polydispersity index (PI), the width of particle size distribution of samples in the area of light scattering [45]. PI is calculated via an intensity autocorrelation function using a cumulant analysis of DLS.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Sample Objective

Dichroic Mirror

Laser Beam Source

Filter Intensity Control

Computer

Size Distribution by Intensity

Intensity (%)

Detector

14 12 10 8 6 4 2 0 0.1

1

10 100 Size (r.nm)

1000

10000

Fig. 2 Illustration of dynamic light scattering (DLS) and its working principle

Several advantages of DLS have been reported in the literature [44, 46]. One of them is that a minimum number of particles are needed, i.e., around 100 particles are sufficient for the measurements. The measurement results can be obtained within 1 min. DLS is also a nondestructive and nonintrusive method. Therefore, samples can be recovered if it is required. Although DLS is the most powerful technique for particle size measurements of SLN and NLC, it has various limitations like problems that occurred in the cases of a sample with broad particle size distribution, multimodal distribution, and nonspherical particles. Additionally, it must be paid attention to measurement conditions and related details such as temperature, refractive index, and/or viscosity.

Particle Charge (Zeta Potential) of SLN and NLC The nature of the electrostatic potential near the surface of a particle is called the zeta potential (ZP). The amount of charge on the particle surface is one of the important characteristics giving information on the tendency of nanoparticles to agglomerate and on their long-term stability [3, 40]. SLN and NLC may have a surface charge, which attracts a thin layer of ions of opposite charge to the nanoparticle surface. This double layer of ions travels with the nanoparticle as it diffuses throughout the solution [47]. ZP is the electric potential at the boundary of the double layer. ZP has values that typically range from +100 to 100 mV. There are several reasons for increasing ZP of lipid nanoparticles. The surface of nanoparticles containing chemical groups may ionize to produce a charged surface. Or ZP increases with ionic surfactant. If ionic lipids or drugs are used for the preparation of SLN and NLC, nanoparticles give higher ZP values. Sometimes the surface itself preferentially adsorbs ions. In general, a ZP greater than 60 mV is known to require for excellent physical stability of nanoparticles when greater than 30 mV indicates good electrostatic stabilization and good physical stability [48]. Nevertheless, this rule cannot be applied strictly for every colloidal drug carrier system which contains steric stabilizers because the adsorption of nonionic steric stabilizers usually decreases ZP due to the shift in the shear plane of the particle [49]. An increase in the kinetic energy caused by light and temperature decreases ZP and leads to frequent particle collisions.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Changes in the crystalline structure of lipid in nanoparticles may also lead to a change in the particle charge [48]. In a coherent manner, the ZP of dispersions may decrease after autoclaving, particularly for nanoparticles composed of fatty acids [50]. ZP is an important parameter for systemic half-life and biodistribution of nanoparticles when it is critical for the long-term stability of SLN and NLC. Besides the nature of lipids and surface actives used for the preparation of SLN and NLC, coating materials contribute to the surface charge of nanoparticles [51, 52]. Negatively charged nanoparticles usually have longer systemic half-life compared to positively charged nanoparticles when strongly negative and strongly positive charges usually lead to phagocytic uptake of nanoparticles more rapidly than weak-medium negative charge. ZP is determined by measuring the velocity of the particles in an electric field. For this purpose, a DLS apparatus or a zetasizer may be used. The laser beam, which is sent to pass through the center of the sample cell is scattered at an angle of 17
. Scattered light is detected and the type of ZP of the sample is recognized by the system configuration.

Imaging of SLN and NLC Particle size measurements and imaging of nanoparticles can be made by electron microscopy [53]. Structural details of SLN and NLC can be visualized with this technique since the spatial resolution can be usually achieved at around 0.2 nm. Electrons are used instead of light for the imaging of objects in electron microscopy [54]. The resolving power of an electron microscope is a linear function of the wavelength. Therefore, electrons with wavelengths about 100,000 times shorter than the photons of visible light provide for a resolution better than 50 pm [55]. Electrons, which are sent through the sample, interact with the constituent atoms via electrostatic forces (Coulomb forces) in an electron microscope. Thus, some electrons are scattered. Electrons are focused, collected, and processed to acquire a two-dimensional projected image of the three-dimensional sample structure. Atomic force microscopy (AFM), which is based on scanning sample surface, is also commonly used for the imaging of SLN and NLC.

Transmission Electron Microscopy (TEM) A transmission electron microscope contains an illumination system, which takes the electron from a gun and transfers them to the sample (Fig. 3). Then, the sample can be screened by a computer using several consecutive lenses. A TEM imaging system contains objective, condenser, intermediate, and projector lenses. If the system is adjusted to the diffraction mode, the back focus plane is taken as the objective plane of the intermediate and projector lenses. Thus, the diffraction pattern is obtained on the screen. Alternatively, if the system is adjusted to the image mode, the image plane of the objective lens is used as the objective plane of the intermediate and projector lenses. Then, the image forms on the screen. The second system mode is more commonly used for imaging and surface characterization of SLN and NLC [56]. Images of lipid nanoparticles obtained by TEM are seen in Fig. 4 as an example [57].

Scanning Electron Microscopy (SEM) A focused electron beam scans across the surface of a solid sample point by point to acquire the image in SEM [54]. Electrons, which are sent through the sample, are deflected by a large number of elastic scattering processes (Fig. 5). The energy spectrum emerged by the deflection of electrons is collected by the detector. The system configures the data in different types of contrast. Large areas of samples can be investigated with a high depth of focus. The depth of focus allows a special image formation since

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Electron Gun Anode

Condenser Lenses Condenser Aperture

Sample Objective Lens

Objective Aperture

Projector Lense

Select Area Aperture

Intermediate Lenses

Screen

Fig. 3 Illustration and working principle of transmission electron microscopy (TEM)

Fig. 4 TEM images of molecular sunscreen nanoparticles based on n-hexadecyl palmitate and glyceryl stearate (Reproduced from Lacatusu et al. [57] with the Permission of Springer)

projecting areas cast shadows when recessed areas appear dark. Therefore, the image enables the human eye to interpret and readily comprehend the obtained information (Fig. 6) [58].

Atomic Force Microscopy (AFM) Atomic force microscopy (AFM), which is a three-dimensional topographic technique with a high atomic resolution, is based on scanning a sample surface with a probe and on imaging surface properties of the Page 8 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Electron Gun

Anode

Condenser Lenses

Projector Aperture

Stigmator Scan Coils

Scanning Unit

Detector

Objective Lens

Sample

Computer

Sample Stage

Fig. 5 Illustration and working principle of scanning electron microscopy (SEM)

Fig. 6 SEM images of SLN derived from 2,3-di-o-alkanoyl-b-cyclodextrin, scale bar: (a) 1 mm, (b) 0.5 mm, and (c) 0.2 mm (Reproduced from Dubes et al. [58] with the Permission of Elsevier)

sample [59]. An atomic force microscope is operated to measure force between the probe and the sample (Fig. 7). A tip is attached to the probe of a cantilever. AFM tips and cantilevers are microfabricated from Si or Si3N4. The tip is designed typically as a pyramidal sharp tip.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Fig. 7 Illustration and working principle of atomic force microscopy (AFM)

AFM relies on the forces between the tip and sample. Thus, these forces must be correctly measured to provide a proper imaging of the sample. The force is not measured directly; it must be calculated by measuring the deflection of the lever considering the stiffness of the cantilever. The optical lever operates by reflecting a laser beam off the cantilever. A four-segment photodetector, which is position sensitive, detects the reflected laser beam striking. The differences between the signals produced by the segments of the photodetector of signals display the position of the laser spot on the detector and the angular deflections of the cantilever. An atomic force microscope can generally measure the vertical and lateral deflections of the cantilever by using the optical lever for obtaining the image resolution. In general, lateral and vertical resolution of AFM can be up to 30 and 0.1 nm, respectively. AFM is a versatile technique for imaging since it can be applied to samples in a wide range of characteristics and a microscope can be modified (lateral force microscopy and force modulation) or operated in different modes (dynamic force tapping, contact, noncontact, and phase modes) suitable for different samples. Tapping, contact, and noncontact modes are commonly used for the imaging of SLN and NLC [60–63]. In the case of the contact mode of the microscope, the system uses feedback to regulate the force on the sample. It measures the force on the sample regulating it, thus allowing acquisition of images at very low forces. The feedback loop controls the height of the tip attached to the cantilever and optical lever. Microscope performance depends on appropriate construction and operation of the feedback loop. Dynamic force mode (intermittent contact) is commonly referred as the tapping mode. It is an advantageous method since an improved lateral resolution on soft samples can be obtained. This technique is preferable for poorly adsorbed samples on a substrate surface. In this mode, very stiff cantilevers are required and the cantilever is oscillated close to the sample but not touching it. A repulsive regime is applied to the oscillation, and then the tip is allowed to intermittently touch or tap the sample surface (Fig. 8) [60]. In the noncontact mode, a stiff cantilever is adjusted to a close position to the sample without touching it and is given oscillation in the attractive regime. The detection is based on measuring changes to the resonant frequency or amplitude of the cantilever (Fig. 9) [63].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Fig. 8 Tapping mode AFM image of podophyllotoxin-loaded SLN (Reproduced from Chen et al. [60] with the Permission of Elsevier)

E 3.44 nm 4002 nm

4002 nm

2001 nm

2001 nm

0 nm 0 nm

Fig. 9 Noncontact mode AFM image of para-acyl-calix-arene-based SLN (Reproduced from Shahgaldian et al. [63] with the Permission of Elsevier)

Crystal Properties of SLN and NLC (Crystallographic Analysis) The crystallization and solidification properties of solid lipids are fundamental behaviors to understanding and optimizing SLN and NLC dispersions to obtain stable formulations. Subsequently, polymorphic transition, crystallization temperature, and crystallization degree of the solid lipid in nanoparticles must be paid special attention. Hot nanoemulsion obtained using a solid lipid in the lipophilic phase of the dispersion must be cooled down below the critical crystallization temperature of the lipid to crystallize and to acquire nanoparticles after the homogenization process. If the critical temperature is not reached, particles remain in the liquid state. Hence, a supercooled emulsion is obtained instead of the desired product containing lipid nanoparticles in the solid state. The polymorphic transition to a more stable lipid polymorph is attended by the rearrangement of the lipid molecules with an increase in lattice density [3, 40, 64]. The melting process requires lower energy in amorphous crystal or a less ordered state of the lipid compared to the perfect crystalline substance to Page 11 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

overcome lattice forces. Therefore, a higher-ordered lattice arrangement gives a higher melting enthalpy. Although the lipid nanoparticles are produced from solid bulk lipids in the crystalline state, the lipid in SLN and NLC occurs in a less ordered arrangement [65, 66]. The crystallization behavior (degree of crystallinity and formation of crystal modifications) of a solid lipid in nanoparticles is affected by some factors including production method, concentration of solid lipid and surfactant(s), melting point of the lipid, incorporation of a liquid lipid, drug incorporation, and particle size of the resulting system [67]: – The polymorphic transition process of the lipid in nanoparticles is defined by the type of homogenization. Lipid is provided in the solid state in the cold homogenization technique that the lipid melt is solidified in liquid nitrogen and homogenization is performed at room temperature or below. However, recrystallization of solid lipid delays in the hot homogenization technique [36]. – Lipid concentration lower than 5 % w/w disturbs the formation of crystals when crystallization is delayed with an increase in surfactant concentration [68]. – There is a converse relationship between the melting point of the lipid and the rate of the polymorphic transition. – The type of surfactant(s) is critical for the kinetics of polymorphic transition of lipids and the crystallization temperature of the dispersed phase. The stabilizers not only influence the colloidal state of the dispersion (e.g., with respect to particle size and stability) but may also have pronounced effects on the internal structure of the particles, which is also an important parameter for the development of drug carriers based on lipid nanosuspensions [37]. – Incorporation of a liquid lipid into the solid lipid matrix of nanoparticles disturbs crystal formation and creates amorphous regions in the structure. Hence, recrystallization behavior and transformation to the more stable forms of the solid lipid are delayed during storage. – Incorporation of drug usually prevents the formation of unstable modifications and accelerates the transformation to the stable polymorph [35, 69]. – Crystalline structures are distorted by the high surface-to-volume ratio of lipid nanoparticles. This distortion induces depression of the melting point and recrystallization point of lipid nanoparticles. A small particle size may cause formation of liquid, amorphous, or only partially crystallized metastable systems [70]. Polymorphic transition to the stable form of the lipid may lead to drug expulsion from nanoparticles during storage [37]. Additionally, drug payload and drug release rate are relevant to crystallinity characteristics of the lipid [71]. A less ordered arrangement of the lipid crystals increases the drugloading capacity [64]. The incorporation of a liquid into nanoparticles provides several benefits in order to overcome some limitations occurred along with SLN [51]. Drug loss during storage may be possible due to the lipid crystallization in SLN to the stable b-modification. However, NLCs, which have special structures, provide an increase in drug payload and prevent drug expulsion with better drug accommodation. The liquid lipid inside nanoparticles provides different types of NLC with large distances between fatty acid chains (imperfect type), structureless solid amorphous matrix (amorphous type), or liquid regions (oily nanocompartments) (multiple type) (Fig. 10). Differential scanning calorimetry (DSC), X-ray diffraction, and high-resolution proton nuclear magnetic resonance (H1 NMR) spectroscopy are commonly used to investigate thermodynamic behaviors and state of lipid in SLN and NLC. Additionally, structural analyses like Fourier transform infrared (FT-IR) spectroscopy and Raman spectroscopy may also help to understand supramolecular characteristics.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Fig. 10 Types of SLN and NLC

Differential Scanning Calorimetry (DSC) DSC experiments are used for investigation of the melting and crystallization behavior of lipid nanoparticles. Internal polymorphism and crystal ordering of solid lipid and breakdown or fusion of crystal lattice can be defined by heating or cooling a sample [72]. DSC is also useful to obtain information about simple eutectic mixtures, solid dispersions like solid solutions, drug-lipid interactions, and the mixture behavior of solid and liquid lipids [3, 40]. DSC experiments are based on the fact that different lipid modifications possess different melting points and enthalpies [15]. The principle of DSC is based on the measurement of the difference in the amount of heat required to increase the temperature of a sample and reference (typically an empty pan) as a function of temperature (Fig. 11). When the sample undergoes a polymorphic transition, more or less heat will need to flow to it than to the reference to maintain both at the same temperature. When solid lipid melts, it requires more heat flowing to increase its temperature at the same rate as the reference. The lipid absorbs heat and undergoes the endothermic phase transition from solid to liquid. More or less heat flow to the sample depends on whether the process is exothermic or endothermic. As the sample undergoes exothermic processes such as crystallization, less heat is required to raise the sample temperature. Therefore, the difference in heat flow between the sample and reference can be measured observing the amount of heat absorbed or released during such transitions. DSC can also be used for determination of more subtle phase changes like glass transitions.

X-Ray Diffraction A solid lipid in SLN and NLC exhibits different crystalline species during storage. The polymorphism of the solid lipid is observed because alkane chains are locally organized in a, b0 , and b packing [73–75]. The hexagonal a packing is the most disordered, the orthorhombic b0 is less disordered, and the well-organized b exhibits a triclinic packing. When thermodynamic stability increases with crystal order, it is decreased by crystallization kinetics. Lipid chains exhibit tilts and molecular conformation in the layers. X-ray Page 13 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Oven

Reference Pan

Sample Pan

Gas Inlet

Flux Plate

Purge Gas

Heating Cooling

Cooling Gas Inlet

Thermocouples

Computer

40 Heat Flow (mW)

Purge Gas Inlet

30 20 10 20

30

40 50 60 Temperature (ºC)

70

Fig. 11 Illustration and working principle of differential scanning calorimetry (DSC)

diffraction experiments provide information on the length of the long and short spacings of the lipid lattice (Fig. 12). Packings in the range of 3–5 Å can be characterized by wide-angle X-ray scattering (WAXS) [76, 77]. However, layer thickness in the range of 20–50 Å can be characterized by small-angle X-ray scattering (SAXS) [78, 79].

Structural Analysis of SLN and NLC Proton Nuclear Magnetic Resonance (H1-NMR) Spectroscopy

H1-NMR spectroscopy is based on the fact that the energy required to cause a nuclear spin flip is a function of the magnetic environment experienced by the nucleus [80]. An atomic nucleus possesses a nuclear spin and thus a permanent magnetic dipole moment. A charged particle like a nucleus or an electron in motion generates a magnetic field. In the case of an external magnetic field, the magnetic moment (spin) of 1H nucleus, which represents a proton in resonance, becomes aligned with the external field of lower energy or against it at the higher energy. The number, position, relative intensity, and splitting of signals are detected in H1-NMR spectroscopy in order to obtain information on the molecular structure of the sample. H1-NMR spectroscopy is commonly used for the characterization of lipid nanoparticles, presenting the statement of the liquid lipid contained in SLN (i.e., NLC) and the drug [81, 82]. The arrangement and mobility of molecules of the liquid lipid can be defined by H1-NMR measurements. Moreover, H1-NMR spectroscopy is also suitable to deduce drug distribution and to obtain information on the mobility of the drug molecules within nanoparticles [82, 83].

Fourier Transform Infrared Spectroscopy (FT-IR) and Raman Spectroscopy Fourier transform infrared (FT-IR) spectroscopy is developed to overcome some limitations related to traditional IR. Thus, a number of advantages have been provided such as increased sensitivity and improved data processing and scanning speed. In this method, a broadband of different wavelengths of infrared radiation is emitted by an IR source and it is sent through an interferometer that modulates the Page 14 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

Liquid Sample Computer

Detector

X-Ray Beam Source

Beam Stop

Computer

Intensity (a.u.)

Powder Sample

10

20

30 2θ (degree)

40

50

Fig. 12 Illustration and working principle of wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS)

infrared radiation. The modulated IR beam passes through the sample and it is absorbed to various extents at different wavelengths by the various molecules present. The intensity of the IR beam passed is detected by a detector, and data is configurated by the system software to obtain an FT-IR graph. Raman spectroscopy is a vibrational spectroscopy technique. Its working principle is based on the emission and absorption of infrared and visible light. This technique differs than IR since it can detect changes that do not involve dipole moment. Raman spectroscopy requires a change in dipole moment and polarizability of a molecule according to its vibration. Both of the methods are employed to obtain conformational information about lipid molecules (solid and liquid lipids or their mixture) in a dispersion [84, 85]. Thus, information on physicochemical changes, drug-excipient interaction, and chemical compatibility of ingredients in SLN and NLC dispersions can be obtained during storage [26, 29].

Conclusion Besides physicochemical experiments, SLN and NLC may also be evaluated considering their drug release characteristics, biodistribution properties, and movement capability through tissues by researchers. The drug release characteristics of SLN and NLC are important parameters, which are required to investigate by in vitro experiments and to evaluate by considering mathematical models. They are strongly affected by the drug incorporation model, crystallization behaviors, and particle size of nanoparticles. The capability of nanoparticles for controlled drug delivery may define pharmaceutical quality of SLN and NLC dispersion. For an instance, drug release with burst effect within 10 min is an undesirable situation for parenteral application of SLN and NLC. A well-formulated system should Page 15 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

protect most of its drug content until it reaches the targeted organ or tissues in the case of site-specific delivery. The site-specific delivery of nanoparticles is investigated by cell culture, ex vivo, and in vivo experiments. For site-specific delivery of nanoparticles, their several biological properties must be known. Information on efficiency of surface treatment of nanoparticles; their stability in the systemic circulation, phagocytosis, opsonization, and endocytosis; and then their activity in tissues/cells can be acquired by cell culture experiments. The cytotoxicity of nanoparticles loaded with antineoplastics is also observed. In the case of well-formulated nanoparticles, drugs or genes can be delivered with maximal efficacy and potency and minimal side effects. Ex vivo studies with organic materials obtained from human and experiment animals and in vivo studies give the most reliable and definite results. SLN and NLC are sophisticated colloidal drug carrier systems, which have unique properties and a lot of advantages over traditional dosage forms and their colloidal counterparts. They are promising for the treatment of genetical disorders and deadly illnesses like cancer. Various research groups and pharmaceutical companies are increasingly attracted with SLN and NLC. Successful results obtained from physicochemical experiments and in vivo, ex vivo, and in vitro studies indicate SLN and NLC as promising colloidal drug carrier systems for the selective delivery of actives in the near future.

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12. N. Chattopadhyay, J. Zastre, H.L. Wong et al., Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharm. Res. 25, 2262–2271 (2008) 13. L. Reddy, R. Sharma, K. Chuttani et al., Etoposide-incorporated tripalmitin nanoparticles with different surface charge: formulation, characterization, radiolabeling, and biodistribution studies. AAPS J. 6, 55–64 (2004) 14. Y.H. Yu, E. Kim, D.E. Park et al., Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA. Eur. J. Pharm. Biopharm. 80, 268–273 (2012) 15. R.H. M€uller, K. M€ader, S. Gohla, Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur. J. Pharm. Biopharm. 50, 161–177 (2000) 16. J. Yun, S. Zhang, S. Shen et al., Continuous production of solid lipid nanoparticles by liquid flowfocusing and gas displacing method in microchannels. Chem. Eng. Sci. 64, 4115–4122 (2009) 17. N.A. Al-Haj, R. Abdullah, S. Ibrahim et al., Tamoxifen drug loading solid lipid nanoparticles prepared by hot high pressure homogenization techniques. Am. J. Pharmacol. Toxicol. 3, 219–224 (2008) 18. C. Charcosset, A. El-Harati, H. Fessi, Preparation of solid lipid nanoparticles using a membrane contactor. J. Control. Release 108, 112–120 (2005) 19. A.R.S. De Sousa, A.L. Simplício, H.C. De Sousa et al., Preparation of glyceryl monostearate-based particles by PGSS ®-Application to caffeine. J. Supercrit. Fluids 43, 120–125 (2007) 20. S. Salmaso, N. Elvassore, A. Bertucco et al., Production of solid lipid submicron particles for protein delivery using a novel supercritical gas-assisted melting atomization process. J. Pharm. Sci. 98, 640–650 (2009) 21. D.T. Baviskar, A.S. Amritkar, H.S. Chaudhari et al., Modulation of drug release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising natural waxes. Pharmazie 67, 701–705 (2012) 22. M. Joshi, V. Patravale, Nanostructured lipid carrier (NLC) based gel of celecoxib. Int. J. Pharm. 346, 124–132 (2008) 23. A.E. Yassin, M.K. Anwer, H.A. Mowafy et al., Optimization of 5-flurouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer. Int. J. Med. Sci. 7, 398–408 (2010) 24. S. Li, B. Zhao, F. Wang et al., Yak interferon-alpha loaded solid lipid nanoparticles for controlled release. Res. Vet. Sci. 88, 148–153 (2010) 25. X. Zhang, S. L€ u, J. Han et al., Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with syringopicroside. Pharmazie 66, 404–407 (2011) 26. A. Madhusudhan, G.B. Reddy, M. Venkatesham et al., Design and evaluation of efavirenz loaded solid lipid nanoparticles to improve the oral bioavailability. Int. J. Pharm. Pharm. Sci. Res. 2, 84–89 (2012) 27. C.B. Fernandes, S. Mandawgade, V.B. Patravale, Solid lipid nanoparticles of etoposide using solvent emulsification diffusion technique for parenteral administration. Int. J. Pharm. Biosci. Technol. 1, 27–33 (2013) 28. C.V. Pardeshi, P.V. Rajput, V.S. Belgamwar et al., Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial design approach. Drug Deliv. 20, 47–56 (2013) 29. A.R. Gardouh, S. Gad, H.M. Ghonaim et al., Design and characterization of glyceryl monostearate solid lipid nanoparticles prepared by high shear homogenization. Br. J. Pharm. Res. 3, 326–346 (2013)

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30. Y.S.R. Elnaggar, M.A. El-Massik, O.Y. Abdallah, Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles. Int. J. Nanomed. 6, 3195–3205 (2011) 31. B. Mohanty, D.K. Majumdar, S.K. Mishra et al., Development and characterization of itraconazoleloaded solid lipid nanoparticles for ocular delivery. Pharm. Dev. Technol 20, 458–464 (2015) 32. E. Lasoń, E. Sikora, J. Ogonowski, Influence of process parameters on properties of nanostructured lipid carriers (NLC) formulation. Acta Biochim. Pol. 60, 773–777 (2013) 33. S.S. Shidhaye, R. Vaidya, S. Sutar et al., Solid lipid nanoparticles and nanostructured lipid carriersinnovative generations of solid lipid carriers. Curr. Drug Deliv. 5, 324–331 (2008) 34. F. Wan, J. You, Y. Sun et al., Studies on PEG-modified SLNs loading vinorelbine bitartrate (I): preparation and evaluation in vitro. Int. J. Pharm. 359, 104–110 (2008) 35. K. Manjunath, V. Venkateswarlu, A. Hussain, Preparation and characterization of nitrendipine solid lipid nanoparticles. Pharmazie 66, 178–186 (2011) 36. M. Üner, Preparation, characterization and physicochemical properties of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC): their benefits as colloidal drug carrier systems. Pharmazie 61, 375–386 (2006) 37. H. Bunjes, M.H.J. Koch, K. Westesen, Influence of emulsifiers on the crystallization of solid lipid nanoparticles. J. Pharm. Sci. 92, 1509–1520 (2003) 38. A. Lippacher, R.H. M€ uller, K. M€ader, Semisolid SLNTM dispersions for topical application: influence of formulation and production parameters on viscoelastic properties. Eur. J. Pharm. Biopharm. 53, 155–160 (2002) 39. A. Dingler, R.P. Blum, H. Niehus et al., Solid lipid nanoparticles (SLNTM/LipopearlsTM) – a pharmaceutical and cosmetic carrier for the application of vitamin E in dermal products. J. Microencapsul. 16, 751–767 (1999) 40. W. Mehnert, K. M€ader, Solid lipid nanoparticles. Production, characterization and applications. Adv. Drug Deliv. Rev. 47, 165–196 (2001) 41. V.B. Patravale, A.V. Ambarkhane, Study of solid lipid nanoparticles with respect to particle size distribution and drug loading. Pharmazie 58, 392–395 (2003) 42. C. Freitas, R.H. M€ uller, Spray-drying of solid lipid nanoparticles (SLNTM). Eur. J. Pharm. Biopharm. 46, 145–151 (1998) 43. A. Califice, F. Michel, G. Dislaire et al., Influence of particle shape on size distribution measurements by 3D and 2D image analyses and laser diffraction. Powder Technol. 237, 67–75 (2013) 44. R.H. M€ uller, W. Mehnert, Particle and Surface Characterisation Methods (Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997) 45. M. Üner, R.H. M€ uller, Sage extract entrapped in nanostructured lipid carriers for application into the mouth cavity for oral hygiene. Curr. Top. Nutraceutical Res. 10, 193–200 (2012) 46. M. Üner, Solid lipid nanoparticles and nanostructured lipid carriers for cancer therapy, in Handbook of Clinical Nanomedicine – From Bench to Bedside, ed. by R. Bawa, G.F. Audette, I. Rubinstein (Raj Bawa, Series Editor). Pan Stanford Series in Nanomedicine, vol. 1 (Pan Stanford Publishing, Singapore, 2015 in press) 47. http://nanocomposix.com 48. C. Freitas, R.H. M€ uller, Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLNTM) dispersions. Int. J. Pharm. 168, 221–229 (1998) 49. R.H. M€uller, Zetapotential und Partikelladung-Kurze Theorie, praktische Mesdurchfuhrung, Dateninterpretation (Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996) 50. R. Cavalli, O. Caputo, M.E. Carlotti et al., Sterilization and freeze-drying of drug-free and drugloaded solid lipid nanoparticles. Int. J. Pharm. 148, 47–54 (1997) Page 18 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

51. M. Üner, G. Yener, Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J. Nanomed. 2, 289–300 (2007) 52. X.-Y. Ying, D. Cui, L. Yu et al., Solid lipid nanoparticles modified with chitosan oligosaccharides for the controlled release of doxorubicin. Carbohydr. Polym. 84, 1357–1364 (2011) 53. C. Carrillo, N. Sánchez-Hernández, E. García-Montoya et al., DNA delivery via cationic solid lipid nanoparticles (SLNs). Eur. J. Pharm. Sci. 49, 157–165 (2013) 54. V. Klang, C. Valenta, N.B. Matsko, Electron microscopy of pharmaceutical systems. Micron 44, 45–74 (2013) 55. R. Erni, M.D. Rossell, C. Kisielowski et al., Atomic-resolution imaging with a sub-50-pm electron probe. Phys. Rev. Lett. 102, 96–101 (2009) 56. K. Jores, W. Mehnert, M. Drechsler et al., Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J. Control. Release 95, 217–227 (2004) 57. I. Lacatusu, N. Badea, A. Murariu et al., The encapsulation effect of UV molecular absorbers into biocompatible lipid nanoparticles. Nanoscale Res. Lett. 6, 73 (2011) 58. A. Dubes, H. Parrot-Lopez, W. Abdelwahed et al., Scanning electron microscopy and atomic force microscopy imaging of solid lipid nanoparticles derived from amphiphilic cyclodextrins. Eur. J. Pharm. Biopharm. 55, 279–282 (2003) 59. S. Vahabi, B.N. Salman, A. Javanmard, Atomic force microscopy application in biological research: a review study. Iran. J. Med. Sci. 38, 76–83 (2013) 60. H. Chen, X. Chang, D. Du et al., Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting. J. Control. Release 110, 296–306 (2006) 61. C. Olbrich, U. Bakowsky, C.M. Lehr et al., Cationic solid-lipid nanoparticles can efficiently bind and transfect plasmid DNA. J. Control. Release 77, 345–355 (2001) 62. P. Shahgaldian, L. Quattrocchi, J. Gualbert et al., AFM imaging of calixarene based solid lipid nanoparticles in gel matrices. Eur. J. Pharm. Biopharm. 55, 107–113 (2003) 63. P. Shahgaldian, E. Da Silva, A.W. Coleman et al., Para-acyl-calix-arene based solid lipid nanoparticles (SLNs): a detailed study of preparation and stability parameters. Int. J. Pharm. 253, 23–38 (2003) 64. H. Bunjes, M.H.J. Koch, K. Westesen, Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 129, 159–173 (1996) 65. J.S. Negi, P. Chattopadhyay, A.K. Sharma et al., Development and evaluation of glyceryl behenate based solid lipid nanoparticles (SLNs) using hot self-nanoemulsification (SNE) technique. Arch. Pharm. Res. 37, 361–370 (2014) 66. M. Üner, E.F. Karaman, Z. Aydoğmuş, Solid lipid nanoparticles and nanostructured lipid carriers of loratadine for topical application: physicochemical stability and drug penetration through rat skin. Trop. J. Pharm. Res. 13, 653–660 (2014) 67. K. Westesen, B. Siekmann, M.H.J. Koch, Investigations on the physical state of lipid nanoparticles by synchrotron radiation X-ray diffraction. Int. J. Pharm. 93, 189–199 (1993) 68. R.H. M€uller, W. Mehnert, J.S. Lucks et al., Solid lipid nanoparticles (SLN) – an alternative colloidal carrier system for controlled drug delivery. Eur. J. Pharm. Biopharm. 41, 62–69 (1995) 69. A. Zur M€ uhlen, C. Schwarz, W. Mehnert, Solid lipid nanoparticles (SLN) for controlled drug delivery-Drug release and release mechanism. Eur. J. Pharm. Biopharm. 45, 149–155 (1998) 70. B. Siekmann, K. Westesen, Thermoanalysis of recrystallisation process of melt-homogenized glyceride nanoparticles. Colloids Surf. B: Biointerfaces 3, 159–175 (1994) 71. V. Venkateswarlu, K. Manjunath, Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J. Control. Release 95, 627–638 (2004) Page 19 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_3-1 # Springer International Publishing Switzerland 2015

72. J.L. Ford, P. Timmins, Pharmaceutical Thermal Analysis (Ellis Horwood, Chichester, 1989) 73. C. Allais, G. Keller, P. Lesieur et al., X-ray diffraction/calorimetry coupling. A tool for polymorphism control. J. Therm. Anal. Calorim. 74, 723–728 (2003) 74. A.I. Kitaigorodskii, Organic Chemical Crystallography (Springer, New York, 1984) 75. D.M. Small, Handbook of Lipid Research. The Physical Chemistry of Lipids (Plenum Press, New York, 1986) 76. C.W. How, R. Abdullah, R. Abbasalipourkabir, Physicochemical properties of nanostructured lipid carriers as colloidal carrier system stabilized with polysorbate 20 and polysorbate 80. Afr. J. Biotechnol. 10, 1684–1689 (2011) 77. K. Jores, W. Mehnert, K. M€ader, Physicochemical investigations on solid lipid nanoparticles and on oil-loaded solid lipid nanoparticles: a nuclear magnetic resonance and electron spin resonance study. Pharm. Res. 20, 1274–1283 (2003) 78. B. Angelov, A. Angelova, R. Mutafchieva et al., SAXS investigation of a cubic to a sponge (L3) phase transition in self-assembled lipid nanocarriers. Phys. Chem. Chem. Phys. 13, 3073–3081 (2011) 79. A. Illing, T. Unruh, M.H.J. Koch, Investigation on particle self-assembly in solid lipid-based colloidal drug carrier systems. Pharm. Res. 21, 592–597 (2004) 80. C. R€ umenapp, B. Gleich, A. Haase, Magnetic nanoparticles in magnetic resonance imaging and diagnostics. Pharm. Res. 29, 1165–1179 (2012) 81. M.A. Schubert, M. Harms, C.C. M€ uller-Goymann, Structural investigations on lipid nanoparticles containing high amounts of lecithin. Eur. J. Pharm. Sci. 27, 226–236 (2006) 82. E. Zimmermann, E.B. Souto, R.H. M€ uller, Physicochemical investigations on the structure of drugfree and drug-loaded solid lipid nanoparticles (SLN) by means of DSC and 1H NMR. Pharmazie 60, 508–513 (2005) 83. M.S. Berkman, Y. Yazan, Solid lipid nanoparticles: a possible vehicle for zinc oxide and octocrylene. Pharmazie 67, 202–208 (2012) 84. K. Jores, A. Haberland, S. Wartewig et al., Solid lipid nanoparticles (SLN) and oil-loaded SLN studied by spectrofluorometry and Raman spectroscopy. Pharm. Res. 22, 1887–1897 (2005) 85. Y. Li, H.L. Wong, A.J. Shuhendler et al., Molecular interactions, internal structure and drug release kinetics of rationally developed polymer–lipid hybrid nanoparticles. J. Control. Release 128, 60–70 (2008)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Sonochemistry: A Greener Protocol for Nanoparticles Synthesis Aniruddha B. Patil and Bhalchandra M. Bhanage* Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, India

Abstract Current nanoparticles synthetic methodologies are focused on greener aspects which eliminate or minimize the use of hazardous chemicals or conventional energy sources. Typical greener techniques involve the use of sonochemical, microwave, electrochemical, hydrothermal, supercritical solvents, biosynthesis, and solar energy. Among this sonochemical route of nanoparticles synthesis is a welldeveloped and well-explored area due to its simplicity and diverse applicability. Sonochemistry arises from acoustic cavitation which involves the formation, growth, and implosive collapse of bubbles in a liquid which create high pressure and temperature followed by high rate of cooling. These properties are often responsible for shape and size selective nanoparticles synthesis. Present chapter mainly focused on the basic concept of ultrasound and its application toward the synthesis of inorganic nanocrystalline materials like nanoparticles of metal, metal oxides, and metal sulfides. In addition, it covers the USP system for nanosize material synthesis.

Introduction The area of nanoscience and nanotechnology is a center of current research activities that is growing with an enormous rate. The property of nanomaterials depends on the characteristics such as size distribution, grain size, grain boundaries, presence of free surface, heterophase interfaces, chemical composition of the constituent phases, and interactions among the constituent domains. These characteristics regulate the properties of nanomaterials, which are quite diverse from that of the bulk materials. Nanomaterials bridge the gap between the solid state and the molecular level that revels unique physicochemical properties showing novel technological applications. The area of nanostructured materials has opened up with new prospect in electronics, catalysis, energy, materials chemistry, and even biology [1] (Table 1). The properties and applications of nanostructured materials are mainly associated with preparation method, and hence the appropriate selection of synthesis route ultimately determines the performance of nanostructured materials. Definitely, this has escort scientists’ attention to the development of versatile synthesis techniques for the preparation of diverse nanomaterials. The synthetic protocols applied for nanoparticle preparation, including gas phase method (e.g., laser pyrolysis decomposition of volatile organometallics and molten metal evaporation), liquid phase methods (e.g., metal precursor reduction using diverse reductants), as well as mixed phase approaches (e.g., deposition of metal atom vapor into cryogenic fluids and synthesis of conventional heterogeneous catalysts on oxide supports). The above-stated protocol often entails the harsh reaction conditions like application of organic surfactants/solvents and strong reducing agents that results into generation of hazardous waste. In addition, the conventional nanoparticles synthesis methods found to be expensive. Hence, green and cost-effective alternative approach becomes more desirable for the preparation of nanomaterial that bypasses hazardous reagents. A typical greener technique involves the use of conventional energy sources like the use of sonochemical [2], microwaves *Email: [email protected] *Email: [email protected] Page 1 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Table 1 Available green methods for nanomaterial synthesis Method of synthesis Sonochemical Microwave

Electrochemical Solar energy

Nanomaterial Molybdenum carbide Zinc oxide Zinc oxide Mg(OH)2 and MgO Cuprous oxide Pd(0) nanoparticles Pd(0) nanoparticles ZnO Pd(0) nanoparticles

Shape of nanomaterial Face centered cubic (fcc) Polygonal Triangular Mg(OH)2 one-dimensional rod-like spherical Spherical Spherical Multiple twinned particles Triangular and hexagonal Decahedral

Size of nanomaterial 2 nm 40 nm 20 nm 77 nm 45 nm 38 nm 5.91  1 nm 30–45 nm 10–15 nm 30–45 nm

References [2] [3] [4] [5] [6] [7] [8] [9] [10]

Fig. 1 Schematic representation of sonochemistry as a green energy source for nanomaterial synthesis

[3–6], electrochemical [7], hydrothermal methods eliminating toxic reagents, supercritical CO2, biosynthesis, and solar energy [8–10]. In consideration to abovementioned conventional and nonconventional techniques, the ultrasound application for nanomaterial’s preparation has a well-developed and well-explored area; that is because of its simplicity and diverse applicability. The basic idea of sonochemistry arises from acoustic cavitation, which includes the formation of bubbles followed by growth, and implosive collapse that results high pressure as well as temperature followed by high cooling rate (Fig. 1). So far the variety of inorganic nanoparticles was reported by sonochemical route such as various metals, metal oxides, metal sulfides, metal selenides, alloys, bimetallic, etc. In 2007 review, Baranchikov et al. focus on the synthesis of diverse inorganic nanomaterials by application of sonochemical technique [11]. In this chapter, the ultrasound-assisted method as a most successful synthetic tool for the synthesis of nanosize material has been discussed that gives a primary understanding of their fundamental principles and to demonstrate application in the preparation of nanostructured materials. In addition to sonochemistry, the use of ultrasound for ultrasonic spray pyrolysis (USP) has also been discussed. Page 2 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

What Is Sonochemistry? Chemistry associates with the relations between matter and energy. Sometimes the chemical reaction needed driving force to proceed that is in the form of energy such as heat, radiation, light, electric potential, etc. [12]. In the case of nanostructured material synthesis, the control over chemical reactions is an important aspect, as it affects on morphology of the final product. At present, such control has obtained by manipulating different reaction parameters like time, energy input, and pressure. All types of energies have their own characteristic reaction conditions that are obtained by their typical reaction parameters. In this regard, ultrasonic irradiation offers unusual reaction conditions that cannot be realized by other traditional energy source methods. Robert Williams Wood was the first to report the influence of sonic waves traveling through liquids. At a molecular or atomic level, the interaction between acoustic waves and matter was not observed. Thus, interaction between the chemical species and ultrasound has absent at molecular level. Rather, acoustic cavitation accounts for the chemical effects (i.e., the generation, growth followed by implosive collapse of bubbles) [13]. In the process of cavitation, generated bubble collapse producing intense heat with high pressures in short time period, which drives high-energy chemical reactions [14]. In detail, acoustic waves (alternating expansive and compressive) by ultrasonic irradiation of liquid produce bubbles (cavities) and make them oscillate. These bubbles store ultrasonic energy very efficiently during their growth. A bubble can overgrow and subsequently collapse, releasing stored ultrasonic energy within short time period (heating and cooling rate of >1010 K s 1). This cavitational subsidence is extremely restricted and transient with a pressure of 1,000 bar and a temperature of 5,000 K [15]. The above conditions obtained during acoustic cavitation may result to raise light emission known as sonoluminescence, which was first observed by Frenzel and Schultes during the ultrasonic irradiation of water [16]. Different types of sonochemical apparatus are used for the production of ultrasonic waves like ultrasonic horns, ultrasonic cleaning baths, and flow reactors. For most of the applications, intensity of ultrasonic baths is inadequate, but is however suitable for liquid–solid reactions. In typical laboratoryscale reactions, high-intensity ultrasonic titanium horn with piezoelectric transducer is preferred (Fig. 2). The process of cavitation occurs over a wide array of frequencies (10 Hz–10 MHz).

Ultrasound-Assisted Nanostructured Material Synthesis The technique of sonochemistry has shown wide applications for the preparation of various inorganic materials. The core focus is on the preparation of nanosize material. Till date several processes had shown

Fig. 2 Schematic representation of ultrasonic horn Page 3 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

its application for the synthesis of various inorganic materials. In this regard, Suslick and co-workers have a good contribution for the synthesis of a variety of nanostructured metals, alloys, and carbides [17, 18]. Considering widespread applications to make systematic study and understanding of the said method, the chapter has been categorized into materials like metal nanoparticles, metal oxide nanoparticles, and so on (Table 2).

Metal Nanoparticles Synthesis by Sonochemical Rout Metal nanoparticles offer the latest research on the preparation, characterization, and application of nanoparticles. The structural, optical, electronic, and electrochemical properties of metal nanoparticles are the focus of current research activities. In addition, metal nanoparticles have shown application in cancer treatment, organic reactions, DNA detection, etc. Considering such a wide scope, different research groups synthesize metal nanoparticles by using sonochemical route; for example, Liu et al. reported synthesis of metal nanoparticles having excellent fluorescent properties. The study deals with the use of rapid sonochemical route for the preparation of water-soluble gold nanoclusters (AuNCs) and Au@AgNCs. The AuNCs were synthesized from HAuCl4 by one-step sonochemical route. The morphology of nanomaterial was obtained by HRTEM. The average size of AuNCs was about 1.8 nm with high crystallinity and monodispersity. This is a one-step synthesis of Au@AgNCs by using sonochemical method. The replacement of HAuCl4 by AgNO3 results in the enhancement of the size of the Au@AgNCs [19]. Dhas et al. reported palladium nanoclusters preparation using Pd(CH3CO2)2 as a metal precursor and myristyltrimethylammonium bromide as a reductant [CH3(CH2)13 N(CH3)3Br] (NR4X), in THF or methanol by sonochemical reduction technique at room temperature. Apart from stabilizing effect, NR4X acts as a reducing agent. The obtained nanocluster shows catalytic property toward carboncarbon coupling reaction, giving moderate extent of conversions without phosphine ligands [20]. As a follow-up to this work, the author reported sonochemical reduction of copper (II) hydrazine carboxylate [Cu(N2H3COO)2.2H2O] for the preparation of nanometallic copper clusters in an aqueous medium. The processes of reduction take place under an inert condition for a period of 2–3 h. The powder X-ray diffraction (XRD), FT-IR, and UV-visible studies used to check the ionic copper reduction. The powder XRD analysis of the product shows the formation of a mixture of metallic copper and copper oxide (Cu2O). Along with the synthesis of copper nanoparticles, the Cu2O formation can be ascribed to the partial oxidation of copper by in situ generated H2O2. However, use of Ar/H2 (95:5) mixture yields pure metallic copper nanoparticles that could be due to the scavenging action of OH* radicals formed during ultrasonic irradiation. The transmission electron microscopy (TEM) study shows the irregular networking of small particles having porous aggregates in size range of 50–70 nm. The synthesized nanoparticles are found catalytically active toward an “Ullmann reaction” for the aryl halides condensation [21]. Fujimoto et al. has reported synthesis of Pd and Pt nanoparticles by H2PtCl6 or K2PdCl4 precursors using sonochemical reduction method. In addition to the synthesis, study focuses on atmospheric gas effect on the particle size distribution. They used sonication reactor as shown in Fig. 3. The particle size of Pd was found to be 3.6  0.7 nm under Ar (Pd/Ar) and 2.0  0.3 nm in (Pd/N2) (Fig. 4). In the case of Pt, a smaller and sharper distribution of the particle size was observed under a Xe atm. This relation has been explained in terms of a hotspot temperature formed by acoustic cavitation [22]. In 2006 Nemamcha et al. reported palladium nanoparticles synthesis using ultrasonic irradiation technique. The stable palladium nanoparticle has been synthesized by ultrasonic irradiation of Pd (NO3)2 solution. Herein, precursor concentration effect on the particle size was studied with different concentrations of palladium (II) nitrate in ethylene glycol and poly (vinylpyrrolidone) (PVP) solutions. The synthesis was done in a glass vessel at 50 kHz ultrasonic waves for 180 min. The pH measurements Page 4 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Table 2 Nanomaterials synthesized using ultrasound Types of nanoparticles Metal nanoparticles

Metal sulfides Metal selenides and tellurides

Metal carbides and sulfides Bimetallic nanoparticles/metal alloys/ metal composites Metal oxides

Nanomaterial AuNCs and Au@AgNCs Palladium Copper and CuOnano Pd in argon atmosphere Pd in nitrogen atmosphere Palladium Ruthenium Fe nanoparticles Fe nanoparticles Gold nano Selenium nanowires CdS Hexagonal CdS Hollow spherical CdSe CdSe HgSe Ag2Se, CuSe, and PbSe ZnSe Palladium carbide Molybdenum carbide Composed of gold and palladium Fe and Co Co20Ni80 and Co50Ni50 Fe/Co alloy Pt-Ru Fe3O4@SiO2 SnO2 Fe2O3 TiO2 Rare earth metal (Y, Ce, La, Sm, Er) oxides MnO2 Zinc oxide Zinc oxide CuO, ZnO, and Co3O

Ultrasonic spray pyrolysis (USP)

Titania and ball-in-ball silica–titania composite decorated with Co oxide nanoparticles Nanostructured carbons

Size of nanomaterial 1.8 nm 2.4 nm Less than 100 50–70 nm 3.6  0.7 nm 2.0  0.3 nm Less than 10 nm 10–20 3 nm 3–8 nm ~40 nm (individual 3 nm) 40  7 nm 10–20 nm 40 nm 120 nm (individual 5 nm) Cluster size 30–40 nm having 7–10 nm crystal size 30–40 nm in ethylenediamine 18–25 ammonia ~70 nm, 30–150 nm and ~160 nm, respectively 3–5 nm Less than 100 nm 2 nm 8 nm Amorphous ferromagnetic less than 100 nm 10 nm ~40 nm 5 and 10 nm 4–8 nm 3–5 nm 100–200 nm diameter pore size of 3–5 nm Less than 10 nm Fe (3.8 nm); Cr (2.9 nm), Y (3.4 nm), La (4.3 nm), Ce(4.5 nm), Sm(4.2 nm), Er(3.8 nm) 10 nm 39 nm ZnO nanorods, nanocups, nanodisks, nanoflowers, and nanospheres CuO, ZnO, Co3O4, and Fe3O4 are 20 nm (length (L)) and 2 nm (width (W)), 340 nm (250), 30 nm, and 20 nm respectively Spherical shell

Spherical ball

References [19] [20] [21] [22] [23] [24] [25] [26] [27] [32] [34] [35] [38] [35] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57]

[64]

[65]

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Titanium hom

Stainless steel collar Gas/Vacuum line

O-ring

Sample solution

Water bath

Fig. 3 Schematics of the sonication reactor (Reprinted from Fujimoto et al. [22] with permission from American Chemical Society)

Fig. 4 (a, b) TEM and SAED pattern of Pd nanoparticles prepared under a N2 and Xe atmosphere, respectively (Reprinted from Fujimoto et al. [22] with permission from American Chemical Society)

and UV-visible spectroscopy revealed the reduction of Pd (II) to metallic Pd. The coordination between atomic palladium and carbonyl group of PVP helps for the stabilization of the nanoparticles. The concentration effect of the initial ionic Pd (II) on the morphology of Pd nanoparticle has been examined by TEM. It has been noticed that the increase of the Pd (II)/PVP molar ratio from 0.13  10 3 to 0.53  10 3 decreases palladium nanoparticles number with a slight increase in particle size [23]. He et al. applied ultrasound irradiation technique for the preparation of ruthenium nanoparticles. The sonochemical reduction of a ruthenium chloride solution was done by ultrasound frequencies in the range 20–1,056 kHz. The reduction process was checked by UV–vis spectrophotometry. The reduction proceeds sequentially from Ru(III) to Ru(II) to Ru(0) and in almost 13 h. The obtained Ru nanoparticles are in the range of 10–20 nm. In the typical synthesis procedure, 1 mM ruthenium chloride (RuCl3), 0.1 M perchloric acid, 80 mM propanol, and 8 mM sodium dodecyl sulfate (SDS) were used in argon atmosphere under ultrasonic irradiation. The reaction temperature was maintained at 21  2  C by water circulation through a jacket around the sonication cell. The reaction mass was sonicated at frequencies 213, 357, 647, and 1,056 kHz using different ultrasound transducers. An optimum reduction Page 6 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

rate was noticed at the frequency range of 213–355 kHz. The reduction rate of Ru (III) has been observed to be slower, and it may be because of the sequential one-electron reduction steps [24]. In 2004 Khalil et al. reported iron nanoparticles synthesis by ultrasonic irradiation protocol. Synthesis of encapsulated Fe nanoparticles in PEG-400 (FePEG) has been achieved by iron pentacarbonyl and poly (ethylene glycol)-400 (PEG-400) in hexadecane. The prepared material is in the range of 3 nm and is evenly spread in the PEG matrix. Considering the adverse effect of light on (Fe(CO)5), the reaction mixture was sonicated in the dark at 80 % pulsed cycle settings and 100 % intensity. The gas evolution with simultaneous appearance of a black slurry in the reaction vessel indicates Fe(CO)5 decomposition. The decomposited Fe(CO)5 amount was measured by monitoring the gas evolution with respect to time until the achievement of anticipated decomposition[25]. Suslick et al. reported silica-supported Fe nanoparticles by Fe(CO)5 in dry decane solution. The highintensity ultrasonic probe was used for the irradiation of reaction mixture. After 3 h irradiation at 20  C under argon, the obtained black powder was filtered and washed with dry pentane. The TEM analysis results showed that the formed iron particles were well dispersed on the SiO2 surface with 3–8 nm size. To check the catalytic response, the prepared nanoparticles were examined for the Fischer–Tropsch synthesis reaction [26]. Qui et al. reported gold nanoparticles synthesis in the presence of ascorbic acid from potassium dicyanoaurate (I) using sonochemical reduction method. The obtained results reveal the formation of aggregated gold particles with irregular shape in aqueous solution. The study also shows the preparation of needle-shaped gold nanoparticles having mean diameter ~40 nm using polyethylene glycol (PEG-400). The assumed synthesis mechanism of needle-shaped particle formation is because of the chain formation of individual 3 nm gold particles. The formation of gold nanoparticles in the redox reaction attributed to coordination by OH and C-O-C groups of the polymer solvent molecules. Then, these chains aggregate to form needle-shaped particles [27]. Nanowires are likely to play a significant action as active components in the nanoscale electronics and electrochemical, electromechanical, optical, and optoelectronic device fabrication [28–31]. Gates et al. paid a special attention for the preparation of selenium nanowires by cavitational route. The obtained result indicates the formation of nanometer size triangular selenium seeds in alcohol suspension. At room temperature in an aqueous medium, synthesis was carried out by the reduction of selenious acid with hydrazine. The acid reduction results into the formation of amorphous selenium followed by trigonal selenium nanowire formation. The final product obtained consists of nanowires of trigonal selenium with uniform diameter of 40  7 nm (Fig. 5) [32].

Metal Sulfides

Metal sulfides play a vital role because of their wide applications in the diverse fields like laser materials, optical filters, and solar cells [33]. The current research investigation proves that the nanocrystalline metal sulfides show superb performance due to their large volume to mass ratio than that of the bulk. In 2004, Gaoand Wang reported synthesis of cadmium sulfide (CdS) using sonochemical route. The report deals with the CdS nanoparticles deposition on the SnO2 surface. In a typical synthesis protocol, SnO2 nanobelts were used as a support. In distilled water, cadmium chloride and thiourea were added as a metal and sulfur source, respectively. Using horn sonicator, high-intensity ultrasonic frequency of 100 W was used to irradiate reaction mixture for different time intervals of 1–3 h. To expel dissolved oxygen from the reaction mixture, argon gas was bubbled prior to the sonication. The TEM result indicates the formation of nanoparticles in the range of 10–20 nm with nearly spherical shape [34]. Li et al. reported synthesis of hexagonal CdS nanoparticles from Cd(CH3CO)2 and elemental S as precursors. The nanoparticle formation was done under H2/Ar (5/95, V/V) atmosphere using ultrasound irradiation. The obtained product contains nanoclusters with an average size of about 40 nm. The control experiments were carried out to investigate the mechanism where hydrogen was acting as a reducing Page 7 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Fig. 5 (a–d) SEM images dealing with various stages of triangular selenium wire growth (Reprinted from Gates et al. [32] with permission from Wiley-VCH)

agent, whereas the extreme high temperature brought by the collapse of the bubble accelerates the reduction of elemental S [35].

Metal Selenides and Tellurides

Metal selenides show wide applications in thermoelectric cooling materials, optical filters, optical recording materials, solar cells, supersonic materials, and sensor and laser materials [36, 37]. The nanocrystalline CdSe has been found to be a very useful photoconducting semiconductor material. Zhu et al. reported nanosize CdSe synthesis via sonochemical route with proper mechanism (Fig. 6). This report shows the preparation of hollow spherical CdSe. For fabrication of CdSe hollow spherical assemblies, the ultrasonic waves play an important role. The TEM analysis result shows uniform and regular hollow spheres with 120 nm average diameter. These hollow spheres are the combination of spherical nanoparticles having the diameter of 5 nm (Fig. 7) [38]. Li et al. reported nanosize hexagonal CdSe synthesis by ultrasonic irradiation of Cd(Ac)2 and elemental Se in an H2/Ar (5/95, V/V) atmosphere. The observed products consist of aggregated nanoclusters with sizes in the range 30–40 nm having 7–10 nm crystal size. The control experiments govern that the hydrogen is acting as a reducing agent and the extreme high temperature developed by the bubble collapse accelerates the reduction of Se [35]. Mercury selenide having electrical properties possessing widespread applications in optoelectronic technology comprises photoconductive, photovoltaic, IR detector, IR emitter, tunable lasers, and thermoelectric coolers. In 2002, Wang et al. reported ultrasonic irradiation protocol for the preparation of mercury selenide from mercury acetate using sodium selenosulfate at room temperature in aqueous reaction medium. The control over particle size was achieved by screening variety of complexing agents. The results showed that the HgSe nanoparticles having different sizes could be obtained by the use of complexing agent like ethylenediamine (EDA), ammonia triethanolamine (TEA), etc. TEA has shown

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Se

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Synthesis of CdSe nanoparticles

Se Se

Se

Step.1

Se

Step.2 CdSe particles grow on the surface of the Cd(OH)2 Step.3.a

Growth of CdSe/Cd(OH)2 balls

Balls change to hollow spheres under the ultrasonic irradiation Step.3.b

Fig. 6 Proposed mechanism for synthesis of hollow CdSe spheres (Reprinted from Zhu et al. [38] with permission from Wiley-VCH)

Fig. 7 (a, b) TEM images of product. (c) HRTEM image of individual CdSe with SAED pattern in inset (Reprinted from Zhu et al. [38] with permission from Wiley-VCH)

effective control over the size of HgSe particle than that of other complexing agents. The experimental evidence indicates the high TEA concentrations lead to the formation of small particles [39]. Li et al. reported preparation of Ag2Se, CuSe, and PbSe using ultrasonic irradiation of AgNO3, CuI, and PbCl2, respectively. The metal precursor with selenium in ethylenediamine has been used for the Page 9 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

anticipated nanoparticles synthesis. The above reaction mass was irradiated at 18 kHz ultrasonic frequency for 10 h at room temperature. The synthesis was carried out using ultrasonic bath as an ultrasound generator. The synthesis was carried out in a 50 ml stoppered conical flask that was partially submerged in water in a commercial ultrasonic cleaner (Model-H66025, 220 V, 250 W) at room temperature. TEM image shows prepared Ag2Se nanoparticles are of ~70 nm size, CuSe is in the range of 30–150 nm, and PbSe is of ~160 nm [40]. Zhu et al. reported preparation of ZnSe nanoparticles. The nanosize material has been synthesized by the sonochemical irradiation of selenourea and zinc acetate in an aqueous medium. The reaction mixture was irradiated for 1 h at room temperature under argon atmosphere. The obtained nanomaterial has shown an average size of 3 nm. The time effect on particle size has been studied, and it has been observed that from 1 h to 3 h, the particle size increases from 3 to 5 nm and after 3 h it remains the same at 5 nm [41].

Metal Carbides and Sulfides Like various inorganic materials, nanosize metal carbides play a vital role in the current research activities such as catalysis. In this regard, Okitsu et al. reported sonochemical reduction technique for the preparation of palladium nanoparticles with interstitial carbon in aqueous medium. By reduction of tetrachloropalladate (II), metal particles of an interstitial solid solution of palladium carbide were prepared at room temperature. The carbon atom concentration in the Pd particles was controlled by varying the type and the concentration of organic additives. The PdC synthesis is proposed as follows: (1) An active Pd cluster was formed during the formation of palladium particles, (2) organic additives are then adsorbed on the surface of Pd cluster, and (3) finally, carbon atoms diffuse in the metal lattice of Pd. In practice, diverse organic sources are screened, and it has been observed that the increased carbon chain length (methanol < ethanol < hexanol) and the concentration of isopropyl alcohol result in large amount of carbon atoms in the Pd metal [42]. Nanostructured molybdenum carbide was prepared from molybdenum hexacarbonyl slurry in hexadecane. The reaction mixture was sonicated for 3 h at 90  C under argon environment to yield a black powder. The reason of selecting hexadecane as a solvent is due to its low vapor pressure at the sonication temperature. The obtained powder was filtered inside a dry box followed by several time washing with pentane. TEM showed the formation of 2 nm sized aggregated particles of the solids. The catalytic activity of the prepared nanomaterial was tested for the cyclohexane dehydrogenation [43].

Bimetallic Nanoparticles/Metal Alloys/Metal Composites Mizukoshi et al. reported sonochemical technique for bimetallic nanoparticles composed of gold and palladium. Ultrasonic irradiation helps for the reduction of Au (III) and Pd (II) ions from sodium tetrachloroaurate (III) dihydrate and sodium tetrachloropalladate (II), respectively, by (SDS) in an aqueous medium. Along with stabilizing effect, SDS remarkably enhances the reduction rate. A spherical particle with a mean diameter of about 8 nm has been obtained [44]. Amorphous ferromagnetic alloys consisting of Fe and Co have revealed excellent soft magnetic properties superior over conventional materials. Some applications comprise magnetic storage media and power transformers [45]. Considering such application, Shafi et al. reported preparation of nanosize amorphous alloy powders of Co20Ni80 and Co50Ni50 by sonochemical decomposition technique. The volatile organic precursors, Co(NO)(CO)3 and Ni(CO)4, in decalin were used at 273 K, under an argon pressure of 100–150 kPa. The obtained results by the analytical tools like SEM, TEM, SAED, and XRD reveal the amorphous nature of these particles. TEM result of the Co20Ni80 showed uniform particles with sizes less than 10 nm. The obtained material has shown the superparamagnetic characteristics [46]. Nanoparticles of the Fe/Co alloy were synthesized by a mixture of Fe(CO)5 and Co(NO)(CO)3 in diphenylmethane (DPhM) solution under argon atmosphere using ultrasonic irradiation method. The Page 10 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

obtained product is an amorphous material with 10 nm diameter size. By annealing in argon atmosphere at 600  C for 5 h, an air-stable Fe/Co alloy is obtained with ~40 nm particle size. The nanoparticles consist of a metal alloy core and a coated shell. The prepared nanoparticles demonstrate an excellent storage stability and magnetic performance [47]. Pt-Ru bimetallic system has great interest because of catalytic application for methanol oxidation in direct methanol fuel cells. In 2006, Vinodgopal et al. reported synthesis of colloidal Pt-Ru bimetallic nanoparticles by aqueous phase sonochemical reduction of Pt(II) and Ru(III). The synthesis was performed at the frequency of 213 kHz and at temperature of 20  C. The circulating water through a jacket around the sonication cell helps to retain constant temperature during the sonication. However, TEM result specifies the sequential reduction of the Pt(II) followed by the Ru(III) giving core shell (Pt@Ru) morphology. Application of SDS, as a stabilizer, helps for the formation of particles in the range of 5 and 10 nm. PVP enhances the rate of reduction giving ultrasmall bimetallic particles of up to 5 nm [48].

Metal Oxide Nanoparticles

Metal oxides show a crucial role in the field of physics, chemistry, and materials science. The elements form a diverse range of oxide compounds having a large number of structural geometries. In technological fields, metal oxides have application for the fabrication of various electronic gadgets such as piezoelectric devices, microelectronic circuits, sensors, and fuel cells. In addition, it proves application in coatings (passivation of surfaces against corrosion) and in catalysis. Nanoparticles of metal oxide displayed unique physical and chemical properties because of their restricted size and a high density at corner or edge sites. Considering their wide applicability, metal oxide nanoparticles have received attention from researchers toward the synthesis of such nanomaterials. Morel et al. reported a rapid synthesis of monodispersed non-aggregated Fe3O4@SiO2 nanoparticles by sonochemical technique (NPs) (Fig. 8). The coprecipitation of Fe(II) and Fe(III) under ultrasonic effect in aqueous solutions gives smaller Fe3O4 NPs with a size distribution of 4–8 nm. Sonication helps to control the thickness of the silica shell in the range of several nanometers. At 20 kHz ultrasonic field frequency, silica-coated Fe3O4 NPs have been obtained by alkaline hydrolysis of tetraethyl ortho-silicate in ethanol-water mixture. Core shell Fe NPs were synthesized by sonochemical route showing a high magnetization value than that of nanoparticles prepared under silent conditions, which is due to the high speed of sonochemical coating and better control over silica deposition [49].

Fig. 8 TEM images of Fe3O4@SiO2NPs after 1 h (a) and 3 h (b) of sonication. Zoomed image of a single core shell particle is shown in the inset of panel b (Reprinted from Morel et al. [49] with permission from American Chemical Society) Page 11 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Srivastava et al. prepared nanosize mesoporous SnO2 (tin oxide) by a sonochemical method. Synthesis was done by using tin ethoxide precursor and cetyltrimethylammonium bromide as the structure-directing agent. The mesoporous SnO2 formation was confirmed by comparing its wide-angle X-ray spectra with previously reported data. The pore size measurement by TEM analysis shows particle size in the range of 3–5 nm. The prepared porous SnO2 was used in dye-sensitized solar cells [50]. In continuation to above work, the same authors reported the preparation of mesoporous iron oxides using iron (III) ethoxide and cetyltrimethylammonium bromide (CTAB) as precursor and organic structure-directing agent, respectively. The synthesis was done by ultrasonic irradiation followed by calcination and solvent extraction for the removal of surfactant. The XRD, TEM, TGA, and BET surface area measurements of calcined material give detailed idea about the synthesized nanomaterial. The particles of Fe2O3 possess irregular shape having 100–200 nm diameter with a pore size of 3–5 nm. The as-prepared amorphous Fe2O3 has revealed paramagnetic properties, while it shows good magnetic properties after calcination at 350  C. The prepared mesoporous Fe2O3 shows high conversion with a high selectivity in the oxidation reaction of cyclohexane under mild reaction conditions [51]. Titanium oxide (TiO2) was used as a photocatalyst for treating environmental contaminants. Yu et al. focused on the mesoporous TiO2 synthesis. The reaction was carried under high-intensity ultrasound irradiation. The reaction was done in both the conditions as with and without use of copolymer. In the absence of thermal treatment, agglomerates of monodispersed TiO2 particles are formed. The obtained catalyst exhibited better activities for degradation of n-pentane than that of the commercially available photocatalyst P25. The rate of degradation by mesoporous TiO2 synthesized using triblock copolymer was about double than that of P25. The high catalytic activities of the TiO2 with a bicrystalline framework can be endorsed to the combined effect of high surface area and mesopores nature [52]. Wang et al. focused on the synthesis of rare earth metal (Y, Ce, La, Sm, Er) oxides by sonochemical method. The oxide synthesis was obtained by the use of SDS as the surfactant, urea as the precipitating agent, and the nitrate salts of metals as the precursors of metal ions, except ZrO(NO3)2 precursor for zirconium. The molar ratio of metal ion/SDS/urea was 1/2/30, respectively. The reaction mixture was sonicated for 3 h by a high-intensity ultrasonic probe (Misonix, XL sonifier, 1.13 cm diameter Ti horn, 20 kHz, 100 W/cm2) for the preparation of metal oxides. After sonication, the suspension was centrifuged, washed, and dried, which gives the desired material [53]. Zhu et al. reported synthesis of MnO2 nanoparticles confined in ordered mesoporous carbon using ultrasound irradiation technique. The MnO2 nanoparticles are synthesized in the pore channels of ordered mesoporous carbon CMK3. The TEM result shows obtained nanoparticles are in the range of 10 nm[54]. Bhatte et al. reported additives free nanocrystalline zinc oxide synthesis using zinc acetate and 1,4-butanediol. For the desired product, formation reaction was performed under ultrasonic waves. Ultrasonic horn was used as a source of sonic waves. The use of 1,4-butanediol gives double merits in the form of solvent and capping agent that eliminates addition of excess additives [55]. However Jung et al. reported shape-selective ZnO nanoparticles using sonochemical synthesis route. The core focus of this study allied with the shape-selective ZnO nanostructure preparation. The idea comprised synthesis of nanomaterials such as nanorods, nanocups, nanodisks, nanoflowers, and nanospheres (Fig. 9). The precursor concentration, type of hydroxide anion-producing agents, sonication time, and the type of capping agent are key factors in the shape-selective ZnO nanomaterial synthesis. Zinc nitrate hexahydrate (Zn(NO3)2
6H2O) and hexamethylenetetramine (HMT, (CH2)6 N4) were used for the synthesis.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Fig. 9 SEM (left) and TEM (right) images of ZnO nanostructures. (a, b) Nanorods. (c, d) Nanocups. (e, f) Nanodisks. (g, h) Nanoflowers. (i, j) Nanospheres. A corresponding electron diffraction pattern and a HRTEM image were inserted as an upper and a lower inset in TEM images, respectively (Reprinted from Jung et al. [56] with permission from American Chemical Society)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

The preparation of nanomaterial was achieved under ambient reaction conditions using sonochemical apparatus of 20 kHz frequency. In order to prepare ZnO nanorods, a 50 W ultrasonic wave power (intensity of 39.5 W/cm2) was introduced for 30 min. For ZnO nanocups synthesis, a mixture of 50 mL 0.2 M Zn(NO3)2
6H2O solution and 50 mL 0.2 M HMT solution was sonicated for 2 h with 39.5 W/cm2 intensity. However, ZnO nanodisk preparation was achieved by triethyl citrate, wherein 100 mL aqueous solution containing 0.01 M Zn(NO3)2
6H2O, 0.01 M HMT, and 0.1 M triethyl citrate was sonicated for 30 min with 39.5 W/cm2 intensity. In addition to this, Zn(CH3COO)2
2H2O as zinc cation precursors and ammonia–water (28–30 wt%,) combination as hydroxide anion supplier were used for the synthesis of ZnO nanoflowers and nanospheres. For ZnO nanoflowers, preparation mixture of 0.01 M zinc acetate dihydrate and 1.57 M ammonia concentrations was reported. However, ZnO nanosphere synthesis was achieved by addition of triethyl citrate in the mixture of 90 mL zinc acetate dihydrate and 10 mL ammonia–water solution. The reaction mixture was irradiated at an intensity of 39.5 W/cm2 for 30 min [56]. Vijaya Kumar et al. reported transition metal oxide nanoparticles like CuO, ZnO, and Co3O from metal acetates using sonochemical route. Solvent effect (water and 10 % water-N,N dimethylformamide (DMF)) on particle sizes, morphology, and yields of the products was investigated [57].

Ultrasonic Spray Pyrolysis (USP) In sonochemistry, ultrasound directly induces chemical reaction; however, in USP, ultrasound is not directly employed in chemical reactions. In USP, ultrasound is to offer the phase separation of one microdroplet reactor from another. The concept of sonochemistry is associated to a low frequency with highintensity ultrasound (typically 20 kHz), whereas USP usually utilize a high frequency with low-intensity ultrasound (e.g., 2 MHz). This technique utilizes ultrasound for nebulizing precursor solutions that help to produce the micron-sized droplets. The prepared droplets will work as individual micron-sized chemical reactors. The produced droplets by ultrasonic nebulization are heated in a gas flow and then subjected to chemical reaction. Technique proves wide applications in industry for the preparation of ultrafine particle and nanoparticle. In addition, it has applications for film deposition. Since it required simple and continuous setup, it can be applied simply for mass production. Overall, technique involves generation of aerosols by nebulizer followed by the thermal decomposition [58]. In accordance with traditional techniques, USP has several advantages like continuous operation technique, easy control, and high product purity. Methods work excellent for the synthesis of spherical particle [59, 60]. USP is a continuous flow process work in both small-scale and large-scale productions with superb reproducibility. In addition, USP showed main applications toward preparation of composite materials. In 1927, Wood and Loomis reported the process of droplet formation by low-frequency ultrasound application [61]. In 1962, Lang has experimentally shown the effect of ultrasonic frequency and droplet size [62]. In USP, the first step, that is, the formation of liquid droplets, was achieved by capillary waves from ultrasonic nebulization [63]. The prepared droplets were then carried into a heated zone by carrier gases like Ar, O2, and N2. The next step is solvent evaporation from the droplet surface where the droplets quickly shrink, and further heat supply results in supersaturation; this is the point where solute gets

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Fig. 10 Schematic illustration of typical USP apparatus

Fig. 11 (a) Macrophotograph of an ultrasonic fountain and mist. (b) TEM image of cobalt-doped porous silica nanosphere (Reprinted from Suh and Suslick [63] with permission from American Chemical Society)

precipitates on the surface of droplet. The decomposition may prepare intermediate in the form of porous or hollow particles, which may form solid particles due to densification. A typical USP apparatus consists of a vessel having transducer at the base fitted with a mist carrying gas stream to the tubular furnace; collected chambers are located at the furnace exit (Fig. 10). On close inspection, using USP method, cobalt nanoparticles embedded on the silica nanoparticles resulting in spherical porous material can be observed (Fig. 11). Suslick and co-workers reported titania nanomaterials using the USP synthesis protocol. The synthesis consists of different morphological forms like porous, hollow, and ball in ball. Aqueous solution consists of a mixture of silica nanoparticles and titanium complex; when subjected for USP process, it gives titania/silica nanocomposites (Fig. 12a). After selective etching of the silica by HF, it produces a porous

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Fig. 12 Electron micrographs of (a) silica–titania composite; (b) porous titania obtained by HF treatment; (c) SEM and (d) TEM image of ball-in-ball silica–titania composite decorated with Co oxide nanoparticles after partial etching with HF (Reprinted from Suh et al. [64] with permission from Wiley-VCH)

titania microsphere (Fig. 12b). Initial etching gives a ball-in-ball structure comprising silica core that is covered with porous titania shell outside (Fig. 12c, d). However, full etching results in the disappearance of core giving only porous spherical shells of titania [64]. The USP technique shows application for the formation of porous carbon. In this regard, Skrabalak and Suslick applied this technique for the preparation of several carbon nanostructures by alkali halocarboxylate decomposition (Fig. 13). When compared to tedious multistep traditional processes for porous carbon synthesis, this new one-step process approach eliminates expensive template materials. Depending on the type of alkali halocarboxylates, a diverse range of nanostructures have been prepared [65].

Conclusion In summary, this chapter focused on the use of ultrasound as an energy source by sonochemical technique or USP method. Along with the basic mechanism of sonochemistry, the chapter covers application of sonochemistry and USP for the synthesis of nanosize materials. Representative examples from different classes of inorganic materials like metal, metal oxide, sulfides, selenides, carbides, alloys, etc., have been discussed.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

Fig. 13 SEM images of USP porous carbons from various precursors: (a) lithium chloroacetate, (b) lithium dichloroacetate, and (c) sodium chloroacetate, (d) sodium dichloroacetate, (e) potassium chloroacetate, and (f) potassium dichloroacetate (Reprinted from Skrabalak and Suslick [65] with permission from American Chemical Society)

References 1. A. Roucoux, J. Schulz, H. Patin, Reduced transition metal colloids: a novel family of reusable catalysts? Chem. Rev. 102, 3757–3778 (2002) 2. T. Hyeon, M. Fang, K.S. Suslick, Nanostructured molybdenum carbide: sonochemical synthesis and catalytic properties. J. Am. Chem. Soc. 118, 5492–5493 (1996) Page 17 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_4-1 # Springer International Publishing Switzerland 2015

3. K. Bhatte, P. Tambade, S. Fujita, M. Arai, B. Bhanage, Microwave-assisted additive free synthesis of nanocrystalline zinc oxide. Powder Technol. 203, 415–418 (2010) 4. K. Bhatte, D. Sawant, R. Watile, B. Bhanage, A rapid, one step microwave assisted synthesis of nanosize zinc oxide. Mater. Lett. 69, 66–68 (2012) 5. K. Bhatte, D. Sawant, K. Deshmukh, B.M. Bhanage, Additive free microwave assisted synthesis of nanocrystalline Mg(OH)2 and MgO. Particuology 10, 384–387 (2012) 6. M. Bhosale, K. Bhatte, B.M. Bhanage, A rapid, one pot microwave assisted synthesis of nanosize cuprous oxide. Powder Technol. 235, 516–519 (2013) 7. K.M. Deshmukh, Z.S. Qureshi, K.D. Bhatte, K.A. Venkatesan, T.G. Srinivasan, P.R. Vasudeva Rao, B.M. Bhanage, One-pot electrochemical synthesis of palladium nanoparticles and their application in the Suzuki reaction. New J. Chem. 35, 2747–2751 (2011) 8. A. Patil, S. Lanke, K. Deshmukh, A. Pandit, B. Bhanage, Solar energy assisted palladium nanoparticles synthesis in aqueous medium. Mater. Lett. 79, 1–3 (2012) 9. A. Patil, D. Patil, B. Bhanage, ZnO nanoparticle by solar energy and their catalytic application for a-amino phosphonates synthesis. Mater. Lett. 86, 50–53 (2012) 10. A. Patil, D. Patil, B. Bhanage, Selective and efficient synthesis of decahedral palladium nanoparticles and its catalytic performance for Suzuki coupling reaction. J. Mol. Catal. A 365, 146–153 (2012) 11. A.Y. Baranchikov, V.K. Ivanov, Y.D. Tretyakov, Sonochemical synthesis of inorganic materials. Russ. Chem. Rev. 76, 133–151 (2007) 12. K.S. Suslick, Ultrasound: Its Chemical, Physical, and Biological Effects (Wiley-VCH, New York, 1988) 13. K.S. Suslick, S.J. Doktycz, The effects of ultrasound on solids. Adv. Sonochem. 1, 197–230 (1990) 14. E.B. Flint, K.S. Suslick, The temperature of cavitation. Science 253, 1397–1399 (1991) 15. S.J. Doktycz, K.S. Suslick, Interparticle collisions driven by ultrasound. Science 247, 1067–1069 (1990) 16. H. Frenzel, H. Schultes, Luminescenz im ultraschallbeschickten wasser (Luminescence in the ultrasound-fed water). Z. Phys. Chem. 27b, 421–424 (1934) 17. J.H. Bang, K.S. Suslick, Applications of ultrasound to the synthesis of nanostructured materials. Adv. Mater. 22, 1039–1059 (2010) 18. K.S. Suslick, S.B. Choe, A.A. Cichowlas, M.W. Grinstaff, Sonochemical synthesis of amorphous iron. Nature 353, 414–416 (1991) 19. H. Liu, X. Zhang, X. Wu, L. Jiang, C. Burda, J.-J. Zhu, Rapid sonochemical synthesis of highly luminescent non-toxic AuNCs and Au@AgNCs and Cu (II) sensing. Chem. Commun. 47, 4237–4239 (2011) 20. N.A. Dhas, A. Gedanken, Sonochemical preparation and properties of nanostructured palladium metallic clusters. J. Mater. Chem. 8, 445–450 (1998) 21. N.A. Dhas, C. Paul Raj, A. Gedanken, Synthesis, characterization, and properties of metallic copper nanoparticles. Chem. Mater. 10, 1446–1452 (1998) 22. T. Fujimoto, S. Terauchi, H. Umehara, I. Kojima, W. Henderson, Sonochemicalpreparation of singledispersion metal nanoparticles from metal salts. Chem. Mater. 13, 1057–1060 (2001) 23. A. Nemamcha, J.-L. Rehspringer, D. Khatmi, Synthesis of palladium nanoparticles by sonochemicalreduction of palladium(II) nitrate in aqueous solution. J. Phys. Chem. B 110, 383–387 (2006) 24. Y. He, K. Vinodgopal, M. Ashokkumar, F. Grieser, Sonochemical synthesis of ruthenium nanoparticles. Res. Chem. Intermed. 32, 709–715 (2006) 25. H. Khalil, D. Mahajan, M. Rafailovich, M. Gelfer, K. Pandya, Synthesis of zerovalentnanophase metal particles stabilized with poly(ethylene glycol). Langmuir 20, 6896–6903 (2004)

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26. K.S. Suslick, T. Hyeon, M. Fang, A.A. Cichowlas, Sonochemical synthesis of nanostructured catalysts. Mater. Sci. Eng. A204, 186–192 (1995) 27. X.F. Qui, J.J. Zhu, H.Y. Chen, Controllable synthesis of nanocrystalline gold assembled whiskery structures via sonochemical route. J. Cryst. Growth 257, 378–383 (2003) 28. Z.L. Wang, Characterizing the structure and properties of individual wire-like nanoentities. Adv. Mater. 12, 1295–1298 (2000) 29. X. Duan, Y. Huang, Y. Cui, J. Wang, C.M. Lieber, Indium phosphide nanowires as building blocks for nanoscale electronic and optoelectronic devices. Nature 409, 66–69 (2001) 30. C. Dekker, Carbon nanotubes as molecular quantum wires. Phys. Today May, 22–28 (1999) 31. S. Frank, P. Poncharal, Z.L. Wang, W.A. de Heer, Carbon nanotube quantum resistors. Science 280, 1744–1746 (1998) 32. B. Gates, B. Mayers, A. Grossmn, Y. Xia, A sonochemical approach to the synthesis of crystalline selenium nanowires in solutions and on solid supports. Adv. Mater. 14, 1749–1752 (2002) 33. S.T. Lakshmikvmar, A.C. Rastogi, Selenization of Cu and In thin films for the preparation of selenide photo-absorber layers in solar cells using Se vapour source. Sol. Energy Mater. Sol. Cells 32, 7–19 (1994) 34. T. Gao, T. Wang, Sonochemical synthesis of SnO2nanobelt/CdS nanoparticle core/shell heterostructures. Chem. Commun. 22, 2558–2559 (2004) 35. H.-l. Li, Y.-c. Zhu, S.-g. Chen, O. Palchik, J.-p. Xiong, Y. Koltypin, Y. Gofer, A. Gedanken: A novel ultrasound-assisted approach to the synthesis of CdSe and CdS nanoparticles. J. Solid State Chem. 172, 102–110 (2003) 36. W.Z. Wang, Y. Geng, P. Yan, F.Y. Liu, Y. Xie, Y.T. Qian, A novel mild route to nanocrystallineselenides at room temperature. J. Am. Chem. Soc. 121, 4062–4063 (1999) 37. W.Z. Wang, P. Yan, F.Y. Liu, Y. Xie, Y. Geng, Y.T. Qian, Preparation and characterization of nanocrystalline Cu2–xSe by a novel solvothermal pathway. J. Mater. Chem. 8, 2321–2322 (1998) 38. J.-J. Zhu, S. Xu, H. Wang, J.-M. Zhu, H.-Y. Chen, Sonochemical synthesis of CdSe hollow spherical assemblies via an in-situ template route. Adv. Mater. 15, 156–159 (2003) 39. H. Wang, S. Xu, X.-N. Zhao, J.-J. Zhu, X.-Q. Xin, Sonochemical synthesis of size-controlled mercury selenide nanoparticles. Mater. Sci. Eng. B 96, 60–64 (2002) 40. B. Li, Y. Xie, J. Huang, Y. Qian, Sonochemical synthesis of silver, copper and lead selenides. Ultrason. Sonochem. 6, 217–220 (1999) 41. J. Zhu, Y. Koltypin, A. Gedanken, General sonochemicalmethod for the preparation of nanophasicselenides: synthesis of ZnSenanoparticles. Chem. Mater. 12, 73–78 (2000) 42. K. Okitsu, Y. Nagata, Y. Mizukoshi, Y. Maeda, H. Bandow, T.A. Yamamoto, Synthesis of palladium nanoparticles with interstitial carbon by sonochemical reduction of tetrachloropalladate(II) in aqueous solution. J. Phys. Chem. B 101, 5470–5472 (1997) 43. K.S. Suslick, T. Hyeon, M. Fang, J.T. Ries, A.A. Cichowlas, Sonochemical synthesis of nanophase metals, alloys, and carbides. Mater. Sci. Forum 225–227, 903–912 (1996) 44. Y. Mizukoshi, K. Okitsu, Y. Maeda, T.A. Yamamoto, R. Oshima, Y. Nagata, Sonochemical preparation of bimetallic nanoparticles of gold/palladium in aqueous solution. J. Phys. Chem. B 101, 7033–7037 (1997) 45. T. Egami, Magnetic amorphous alloys: physics and technological applications. Rep. Prog. Phys. 47, 1601–1725 (1984) 46. K. Shafi, A. Gedanken, R. Prozorov, Sonochemical preparation and characterization of nanosized amorphous Co–Ni alloy powders. J. Mater. Chem. 8, 769–773 (1998)

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47. Q. Li, H. Li, V.G. Pol, I. Bruckental, Y. Koltypin, J. Calderon-Moreno, I. Nowik, A. Gedanken, Sonochemical synthesis, structural and magnetic properties of air-stable Fe/Co alloy nanoparticles. New J. Chem. 27, 1194–1199 (2003) 48. K. Vinodgopal, Y. He, M. Ashokkumar, F. Grieser, Sonochemically prepared platinum ruthenium bimetallic nanoparticles. J. Phys. Chem. B 110, 3849–3852 (2006) 49. A.-L. Morel, S.I. Nikitenko, K. Gionnet, A. Wattiaux, J. Lai-Kee-Him, C. Labrugere, B. Chevalier, G. Deleris, C. Petibois, A. Brisson, M. Simonoff, Sonochemical approach to the synthesis of Fe3O4@SiO2 core shell nanoparticles with tunable properties. ACS Nano 2, 847–856 (2008) 50. D.N. Srivastava, S. Chappel, O. Palchik, A. Zaban, A. Gedanken, Sonochemical synthesis of mesoporous tin oxide. Langmuir 18, 4160–4164 (2002) 51. D.N. Srivastava, N. Perkas, A. Gedanken, I. Felner, Sonochemicalsynthesis of mesoporousiron oxide and accounts of its magnetic and catalytic properties. J. Phys. Chem. B 106, 1878–1883 (2002) 52. J.C. Yu, L. Zhang, J. Yu, Direct sonochemical preparation and characterization of highly active mesoporous TiO2 with a bicrystalline framework. Chem. Mater. 14, 4647–4653 (2002) 53. Y. Wang, L. Yin, A. Gedanken, Sonochemical synthesis of mesoporous transition metal and rare earth oxides. Ultrason. Sonochem. 9, 285–290 (2002) 54. S. Zhu, H. Zhou, M. Hibino, I. Honma, M. Ichihara, Synthesis of MnO2 nanoparticles confined in ordered mesoporous carbon using a sonochemical method. Adv. Funct. Mater. 15, 381–386 (2005) 55. K. Bhatte, S. Fujita, M. Arai, A. Pandit, B. Bhanage, Ultrasound assisted additive free synthesis of nanocrystalline zinc oxide. Ultrason. Sonochem. 18, 54–58 (2011) 56. S.-H. Jung, E. Oh, K.-H. Lee, Y. Yang, C.G. Park, W. Park, S.-H. Jeong, Sonochemical preparation of shape-selective ZnO nanostructures. Cryst. Growth Des. 8, 265–269 (2008) 57. R. Vijaya Kumar, Y. Diamant, A. Gedanken, Sonochemical synthesis and characterization of nanometer-size transition metal oxides from metal acetates. Chem. Mater. 12, 2301–2305 (2000) 58. T.T. Kodas, M. Hampden-Smith, Aerosol Processing of Materials (Wiley-VCH, New York, 1999) 59. K. Okuyama, W. Lenggoro, Preparation of nanoparticles via spray route. Chem. Eng. Sci. 58, 537–547 (2003) 60. G.L. Messing, S.-C. Zhang, G.V. Jayanthi, Ceramic powder synthesis by spray pyrolysis. J. Am. Ceram. Soc. 76, 2707 (1993) 61. R.W. Wood, A.L. Loomis, The physical and biological effects of high-frequency sound-waves of great intensity. Phil. Mag. 7, 417–436 (1927) 62. R.J. Lang, Ultrasonic atomization of liquids. J. Acoust. Soc. Am. 34, 6–8 (1962) 63. W.H. Suh, K.S. Suslick, Magnetic and porous nanospheres from ultrasonic spray pyrolysis. J. Am. Chem. Soc. 127, 12007–12010 (2005) 64. W.H. Suh, A.R. Jang, Y.-H. Suh, K.S. Suslick, Porous, hollow, and ball-in-ball metal oxide microspheres: preparation, endocytosis, and cytotoxicity. Adv. Mater. 18, 1832–1837 (2006) 65. S.E. Skrabalak, K.S. Suslick, Porous carbon powders prepared by ultrasonic spray pyrolysis. J. Am. Chem. Soc. 128, 12642–12643 (2006)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Supported Nanoparticle Synthesis by Electrochemical Deposition Jon Ustarroz*, Annick Hubin and Herman Terryn Research Group Electrochemical and Surface Engineering (SURF), Vrije Univeristeit Brussel, Brussel, Belgium

Abstract In this chapter, first, a survey on the early stages of electrochemical nucleation and growth is provided with special emphasis on recent discoveries which provide new insights on electrochemical nanoparticle formation. Then, a comprehensive review of nanoparticle electrodeposition from aqueous solutions is provided, analyzing the different electrochemical processes employed to obtain nanoparticle distributions with desired morphology and low size dispersion. Finally, the functional properties obtained with the resulting nanostructured materials are described.

Keywords Aggregative growth; Electrodeposition; Nucleation and growth; Supported nanoparticles

Introduction Metallic nanoparticles are of great interest due to their unique properties, which differ from their bulk counterpart and can be tuned by adjusting their size and shape. When supported over different substrates, they represent the cornerstone for numerous applications in different fields such as electrocatalysis (fuel cells) or electroanalysis (sensors). When synthesized as colloids, their properties may be affected by organic ligands or aggregation during deposition. In contrast, electrochemical deposition allows the growth of the nanoparticles directly on the final support improving the electron pathway within the substrate, nanostructure and electrolyte. Consequently, the technique has been proven effective to obtain nanostructured materials with potential for fuel cell or sensing applications.

Supported Nanoparticles Properties and Applications Nanoscale materials are responsible for many technological advances over the last decade. Due to their reduced dimensions (1–100 nm), they behave halfway between a macroscopic solid and an atomic or molecular system, hence exhibiting unique properties which differ from their bulk counterpart, and can be tuned by adjusting their size and shape [1, 2]. Since their surface to volume ratio becomes increasingly high for decreasing dimensions, thermodynamic properties such as chemical potential or surface energy among others, are size dependent. In addition, quantum confinement effects within small nanoparticles (NPs) (d
1–10 nm) lead to optoelectronic [3, 4], plasmonic [5–7], and electrochemical [8] properties which vary with particle diameter and shape. *Email: [email protected] *Email: [email protected] Page 1 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Table 1 Selected references that provide an overview of the most common applications of supported nanoparticles Ref. 1 [2] 2 [9] 3 [10] 4 [16] 5 [17] 6 [18] 7 [19] 8 [11] 9 [12] 10 [13] 11 [20] 12 [21] 13 [22] 14 [23] 15 [24] 16 [6] 17 [25] 18 [26] 19 [14] 20 [15] 21 [27]

Year 2010 2009 2012 2009 2005 2012 2011 2006 2010 2011 2006 2008 2009 2009 1983 2006 2012 2003 2000 2013 2008

Application Electrocatalysis and electroanalysis Catalysis Electrocatalysis – fuel cells Fuel cells Electrocatalysis – fuel cells Catalysis Electrocatalysis and electroanalysis Electroanalysis Electroanalysis Electroanalysis (environmental monitoring) Electroanalysis (arsenic detection) Electroanalysis (nitrite detection) Electroanalysis (H2O2 detection Electroanalysis (Glucose detection) Electroanalysis – (Bio)sensors LSPR based sensors LSPR based sensors LSPR based sensors Electronic, optical and sensor applications Electrochemical detection of explosives Solar cells

Material Platinum Various Pt-based alloys Various Various Various Noble metals Various Various Various Gold Cobalt oxide Gold Gold Various Noble metals Various Silver Various Various Quantum dots

Support Various Various Various Various Various Various Various Various Various Various ITO Glassy carbon ITO ITO Various Various Various Cover slip Various Various Various

Type of publication Review paper Review paper Review paper Book Catalyst benchmarking Review paper Review paper Review paper Review paper Review paper Journal paper Journal paper Journal paper Journal paper Review paper Review paper Review paper Journal paper Review paper Review paper Review paper

When supported over different substrates, metallic NPs represent the cornerstone for numerous applications in different fields such as electrocatalysis (fuel cells) [9, 10, 2] or electroanalysis (sensors) [11–13] among others [14, 15]. In both cases, supported metal NPs are the active materials whose development can boost both technologies to levels almost unimaginable a few years ago. An overview of the most common applications of supported nanoparticles is provided in Table 1. On the one hand, fuel cell technology is among the most active fields of research and it is widely known that platinum is the most effective catalyst to facilitate both anodic and cathodic reactions in a protonexchange membrane fuel cell [16]. Therefore, current fuel cell cathode catalyst standards consist of platinum NPs supported on carbon materials of high surface area (Pt/C) [17], and a lot of effort is being devoted to obtain different types of nanostructures with different combinations of materials, which can provide enhanced catalytic activity and thus improve the efficiency of chemical to electrical energy conversion [16, 18, 19]. On the other hand, monitoring water for hazardous pollutants is important to protect the environment and public health. Also, performing blood analyses to detect low concentrations of pathogens is essential for disease prevention. In both cases, electroanalytical sensors are among the most commonly used devices for such purposes. In most of the cases, different types of NPs supported over different substrates constitute the sensing electrodes which measure the electrical signal produced by the interaction of the target analyte with the electrode itself [11–13]. The use of supported NPs in this context enhances mass transport and electrochemical reactivity at the same time it provides large effective surface area and high signal to noise ratios, essential parameters to improve sensitivity and detection limit of electroanalytical sensors. Hence, electrodes made of supported Au, Pt, Pd, Ag, Ru, Cu, Ni, and other NPs have been proven effective to sense arsenic [20, 21], H2O2 [22], glucose [23], and many other analytes in different

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Fig. 1 Schematic illustration of the process of electrochemical deposition to prepare supported nanoparticles

electrolytes with high selectivities, high sensitivities, and ultra-small detection limits. Several reviews on the use of NPs on electrochemical (bio)sensors can be found elsewhere [11–13, 24] In addition, supported noble metal NPs are also used in sensors based on surface plasmon resonance (SPR) [6, 25]. SPR consists in the collective oscillation of the conduction electrons in a solid when stimulated by photons, and it is the basis of many spectroscopic techniques such as surface-enhanced Raman scattering (SERS) and color-based biosensors. These techniques can be used in sensing applications because molecules adsorbing on the surface of the illuminated material cause changes in the resonance conditions of the surface plasmon waves. The enhancement of local electromagnetic fields near the surface of a nanoparticle is orders of magnitude higher than near a bulk material, giving rise to localized surface plasmon resonance (LSPR) phenomena. Such signal enhancement allows supported nanoparticle LSPR based sensors being sensitive down to the zeptomole [26]. Supported semiconductor NPs or quantum dots (QDs) are also used for solar cells [27]. This represents a field of its own, hence, this chapter will only cover supported metallic NPs.

Synthesis Methods Metal NPs can be synthesized by multiple methods either in solution or in the gas phase, as reviewed many times [1, 2, 28], colloidal synthesis and other solution based methods being the most common approach [29–32]. Nonetheless, when generated particles are required to be attached to a surface, previously mentioned methods do not always provide the best solution. Physical vapor deposition methods such as sputtering or electron beam deposition require expensive high-vacuum facilities, whereas colloids may lose some of their properties due to the organic ligands used during the synthesis procedure, or because of unwanted aggregation during deposition on a given support [33–35]. Alternatively, electrochemical deposition allows the growth of the nanostructures in one step, directly onto the final support, without needing further sample preparation, thus improving the electron pathway within the substrate, nanostructure and environment (see Fig. 1). Consequently, the technique has been proven effective to obtain highly electroactive nanostructures with potential for fuel cell [36–39] or (bio) sensing [11, 12] applications. Moreover, the technique is surfactant free, highly selective, cost effective and allows the nature of the nanoclusters to be easily tuned by changing electrolyte composition and deposition parameters [40, 41]. In order to benefit from the properties of supported NPs and use them as electrocatalysts or in sensing devices, distributions of small NPs with low size dispersions need to be obtained in a reproducible way. In addition, good control over their morphological and structural parameters needs to be achieved. However, compared to other synthesis methods, the reliability of the electrochemical synthesis procedures,

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

tunability of nanoparticle size and shape, or size dispersion control are far from being at the same level of development. Over the last decades, to catch up with colloid scientists and UHV engineers, electrochemists have dedicated resources to improve nanoscale electrodeposition. Extensive research has been carried out in different directions. Firstly, to understand the causes of size, shape, and structure dispersion in nanoparticle electrodeposition processes, emphasis has been made to better understand the early stages of electrochemical nucleation and growth. Recent works have showed that traditional mechanistic models do not account for all the phenomena underlaying nanoscale electrode position. Secondly, research has been carried out to establish the optimal electrochemical procedures and experimental parameters to obtain the desired nanoparticle distributions. In this chapter, first, a short review of the current knowledge about the early stages of electrochemical nucleation and growth on low-energy substrates is provided. Then, the theoretical background needed to understand the different electrochemical strategies to obtain reproducible and monodisperse nanoparticle distributions is reviewed. Finally, a comprehensive review of the research carried out to obtain supported NPs and to evaluate their properties is presented.

Early Stages of Electrochemical Nucleation and Growth on Low-Energy Substrates To understand what needs to be taken into account to obtain reproducible distributions of NPs with desired size and shape, the way the particles are created and the way they grow need to be understood. Next section aims to delve into the fundamental aspects of the early stages of electrochemical nucleation and growth, which may in turn help to optimize the processes to successfully generate supported NPs by electrochemical deposition.

Theoretical Background and Classical Approach Nucleation and Growth Nucleation and growth phenomena have been thoroughly studied since more than a century for colloidal syntheses [42], thin film growth [43], and electrochemical deposition processes [44] among others, resulting in a classic nucleation and growth theory which predicts that nanocrystals grow irreversibly by atomic addition until the reaction is halted. When the nucleation of a new phase occurs within an uniform medium without preferential nucleation sites, it is referred to as homogeneous nucleation. This is the case in colloidal synthesis, inert-gas condensation, or crystallization of liquids at temperatures below their melting point (metal casting). If nucleation takes place on specific sites on surfaces contacting the liquid or vapor, it is referred to as heterogeneous nucleation. This is the case in physical vapor deposition methods (sputter deposition, electron beam deposition) or electrochemical deposition. In both cases, an excess of free energy is needed to compensate for the creation of new interfaces at the boundaries of the new nuclei. Such free energy is the driving force for nucleation and arises from a higher thermodynamic stability of the new phase compared to the old one. The term supersaturation is commonly accepted to account for such a driving force and has different meanings depending on the system studied. Therefore, in metal casting, it is related to the supercooling below the melting point; in solution-based synthesis, it is related to the concentration and chemical potential of different species; in condensation, it is related to the partial pressure; and in electrodeposition, it is related to the electrochemical potential.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

A given nucleus will only grow if the addition of another atom to its lattice results in a negative change of Gibbs free energy and it will otherwise disappear. Therefore, only nuclei larger than a critical size will prosper. The critical radius for electrochemical nucleation, rCrit is inversely proportional to the overpotential,
. Based on that, the nucleation rate J according to the classical approach is a probability process connected with the energy of formation of critical clusters. This leads to a first order kinetic model in which, the evolution of the number of nuclei on a surface N, after the application of a single overpotential
(single pulse potentiostatic approach), follows the following equation. N ðt Þ ¼ N 0 ½1  expðAt Þ

(1)

N0 is the saturation number density (maximum number of nuclei within the surface); A is the nucleation rate constant; and AN0 = J is the nucleation rate. Further details about the continuum and atomistic approach and their implication in determining accurately the critical radii for nucleation can be found elsewhere [40, 41, 44–46]. Depending on the interactions between metal and substrate, three different growth modes are generally accepted. When the deposited metal atoms are more tightly bound to each other than to the substrate, nuclei form hemispherical islands which grow radially by the so-called Volmer-Weber 3D island growth mechanism. This is the case of metals on alkali halides or carbonaceous materials such as glassy carbon (GC) or graphite. When the deposited atoms are more tightly bound to the substrate than between themselves, growth proceeds layer by layer by the Frank Van Der Merwe mode in which every deposited layer is slightly less tightly bound than the previous until reaching the bulk crystal value. This is the case of underpotential electrodeposition in several metal-metal systems. In intermediate cases, the layer-plus-island or StranskiKastanov growth mode applies, due most of the time to lattice misfits between substrate and deposit. The electrochemical deposition of NPs relies on the fact that for several metal-substrate combinations, metal atoms are more tightly bound to each other than to the substrate. Hence nuclei grow three-dimensionally through the Volmer-Weber mode and result into random distributions of supported nanoparticles. Independently from the growth mode, two processes are considered. First, a metal ion can be discharged into an adatom on an arbitrary site of the electrode surface. Such adatom migrates randomly by surface diffusion and may end up being incorporated into a nucleus. The concentration of adatoms on the electrode surface is a function of the overpotential but gets depleted around growing nuclei, and the growth rate becomes a function of the gradient of the adatom concentration. The second possibility is that direct reduction of a metallic ion takes place over the nucleus. In this case, the number of atoms incorporated to the growing nucleus is proportional to its surface area. Experimental observations have shown that the amount of material deposited by the first process is several orders of magnitude lower than that of the second (see [47] and references therein). Thus, the contribution of atomic surface diffusion is neglected and direct reduction of metallic ions onto growing nuclei is considered as the only mechanism involved in electrochemical growth. Such a mechanism is henceforth referred to as direct attachment. Contrarily to other nanoparticle synthesis or thin film deposition methods, electrochemical deposition processes can be followed in situ by recording the current (or potential) transients after applying different potential (or current) pulses. In the case of potentiostatic single pulse (SP) electrodeposition, the evaluation of the current-time transients, or chronoamperograms, provides invaluable time-resolved information about nucleation and growth processes and it is hence performed and reviewed in countless occasions [45, 48–51]. If a homogeneous surface such as amorphous carbon is considered, when a given overpotential,
, is applied, nuclei are supposed to form at random locations over the surface according to Eq. 1. In principle, all formed nuclei have r  rCrit, so they will grow irreversibly until the potential pulse is stopped or the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

concentration of active species in their surroundings decreases below a certain level. By considering that the only growth mechanism is that of direct reduction of ions onto the surface of three-dimensional hemispherical nuclei (direct attachment), plenty of theoretical work has been carried out to relate the chronoamperometric response I(t) to the nucleation rate and N(t) (Eq. 1) [48, 52–54, 50]. The important feature to emphasize here is that, independently of the slight modifications of the mathematical description of the processes, all the models describing electrochemical nucleation and growth are based on several assumptions that have no direct proof. One of them is the fact that all nuclei are pinned to a specific site on the surface and another is that they only grow by direct attachment. This concept has been discussed in some recent publications summarized in section “Inconsistencies of the Classical Models and New Insights into the Early Stages of Electrochemical Nucleation and Growth.”

Inconsistencies of the Classical Models and New Insights into the Early Stages of Electrochemical Nucleation and Growth Although qualitative agreement of the current transients with the referred models has been reported in countless occasions, several inconsistencies have also been revealed by performing a quantitative evaluation. In some cases, nucleation rates obtained from the model fits are in good agreement with those obtained through imaging techniques [55–58]. However, in most of the cases, experimental and modeled data may differ up to 4–5 orders of magnitude [59–62]. Several hypothesis have been suggested to account from such inconsistencies and can be found elsewhere [58–61, 63–66]. Unfortunately, none of the suggested hypothesis can be easily proven due to missing information arising from the uncertainties and lack of resolution of the techniques employed. Recently, by using carbon coated TEM grids (CCTGs) as electrodes, atomic-scale characterization has been directly linked with electrochemical data for the cases of Ag [67, 68] and Pt [69] electrodeposition. This way, contradictory findings have been the object of a deeper study to unravel the reasons of deviation from classical nucleation and growth theories. These studies have led to a revision of the classical Volmer-Weber 3D island growth mechanism, which assumes that electrochemical growth is only driven by direct attachment. Instead, an electrochemical aggregative growth mechanism has been proposed, as shown by Fig. 2 [70, 71]. This mechanism includes nanocluster self-limiting growth, surface diffusion, aggregation, coalescence, and recrystallization as important processes of the early stages of nanostructure growth [70]. In fact, these phenomena mimic the atomistic processes of the early stages of thin-film growth [72] by considering nanoclusters of a few nm as building blocks instead of single atoms. These findings do not only represent an important scientific breakthrough in the fundamental understanding of electrochemical deposition. From a practical point of view, a better control of electrochemical deposition processes may be achieved. Although its practical implications have not been studied yet, the possibility of electrochemical nanostructuring by having nanoclusters as building blocks may lead to different electrochemical deposition strategies that may lead to supported NPs with enhanced properties. In addition, some of the issues related with achieving small nanoparticle distributions with narrow size dispersions may be related to self-limiting growth or aggregation processes. A complete understanding of all the phenomena occurring through the early stages of electrochemical growth may therefore be the key for new advances in the field of nanoparticle electrodeposition.

Nanoparticle Electrodeposition To synthesize NPs by electrochemical deposition, a large number of variables need to be taken into account. In this sense, numerous studies have been performed to determine the influence of substrates, Page 6 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Fig. 2 Top: Schematic diagram showing the different stages of the generalized electrochemical aggregative growth mechanism and respective potentiostatic current transients and evolution of particle size, number density, and surface coverage. Dots represent the nongrowing nanoclusters and blue circles around the aggregates represent the projection of their corresponding nucleation exclusion zones [70] (Adapted with permission from Ref. [70]. Copyright (2013) American Chemical Society). Bottom: HAADF-STEM images of Ag NPs [68] and three-dimensional electron tomography reconstructions of Pt NPs [69], electrodeposited on CCTGs

electrolyte composition, electrochemical waveforms, additives, pH, etc. A thorough review of all these aspects cannot be written in a single book chapter. Hence, the current section is focused on understanding the influence of the applied electrochemical waveforms. In this sense, several potentiostatic, galvanostatic, or potentiodynamic approaches have been extensively studied, aiming at controlling the synthesis parameters to obtain distributions of NPs with low size and shape dispersion. On the one hand, the formation of alloy NPs [73–75] or core-shell structures [76–78] by electrodeposition has been studied by some groups. On the other hand, several studies have aimed at manipulating the shape of electrodeposited NPs, as it is well documented that their properties are shape dependent. Hence, different nanoparticle morphologies can be obtained varying parameters such as overpotential [78–81]. In turn, several shapes such as tetrahexahedral platinum nanocrystals [37, 82], cubic and octahedral Cu-Cu2O core-shell NPs [78], or platinum flowerlike nanostructures [80, 81, 83–85] are just an example of the shape-tuning possibilities that are offered by electrochemical deposition. These topics could deserve a fully dedicated chapter. Alternatively, this section is focused on the strategies aimed at obtaining hemispherical (or spherical) NPs, whose chemical composition is known, with controllable size and reduced size dispersion.

Understanding the Different Electrodeposition Strategies To electrodeposit NPs on a given substrate, cathodic overpotentials should be applied so that metallic ions in solution are electrochemically reduced leading to the formation of metallic nuclei on the substrate (

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Fig. 3 (a) Schematic representation of a potentiostatic SP waveform. (b) Current transients derived from potentiostatic SP experiments of Pt electrodeposition onto carbon substrates (Reprinted with permission from Ref. [70]. Copyright (2013) American Chemical Society). Typical FESEM images of Ag (c) and Pt (d) NPs electrodeposited on carbon substrates by means of a SP approach [86, 87]

M zþ þ ze ! M 0). To achieve that, plenty of different electrochemical waveforms are possible and can be classified as potentiostatic, potentiodynamic, galvanostatic, or others. Potentiostatic Methods Potentiostatic pulse techniques are the most common way to generate supported NPs. These methods consist in the application of a number of electrochemical pulses of constant potential, aimed at controlling the particle number density and size distribution by changing potential and duration of the pulses. In principle, increasing the complexity of the applied waveforms may lead to a better control of nanoparticle growth and thus to smaller size dispersions. However, complex waveforms have more parameters to be tuned. Hence, more effort is needed to understand their effect on nanoparticle properties and to infer optimal synthesis conditions. Different potentiostatic approaches with increasing degree of complexity are reviewed in the next sections. Potentiostatic Single Pulse Electrodeposition This is the simplest method one can think of. It consists of applying a given potential for a given time, as shown in Fig. 3a. Only two parameters are available: the nucleation potential, EN, and the nucleation time, tN. Normally, an anodic potential is kept prior to begin the elctrodeposition process, to avoid unwanted electroless deposition at open circuit potential (ocp). Due to its simplicity, this method has been highly reported for nanoparticle electrodeposition on different substrates. However, NPs electrodeposited by the application of a single pulse (SP) show normally very broad size dispersion, s, larger than 40–50 % (see Fig. 3c and d). Therefore, this method is mostly used to gain fundamental understanding of the electrodeposition process by studying the current response to the application of different potentials, as shown by Fig. 3b. The analysis of these transients is Page 8 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

an important method to determine the nucleation mechanism and the nucleation rate (see section “Theoretical Background and Classical Approach)”. The main reasons for the broadening of the size dispersion are the following. First, particle nucleation and growth will occur simultaneously [88]. Second, for almost every envisaged application, a large particle number density is required and hence large overpotentials are needed. Hence, the particles will grow under diffusion control and develop diffusion zones with lower concentration of active species. Therefore, some diffusion zones will coalesce and neighboring particles that “share” their diffusion zones will grow slower due to a reduced flux of active species. Contrarily, particles that do not “share” their diffusion zone will grow faster. Consequently, nanoparticle electrodeposition by potentiostatic SP is mostly carried out for fundamental purposes [38, 56, 57, 89–93]. In some cases, despite a relatively broad size dispersion, supported NPs synthesized by means of this approach have been used to study their optical [94–96] and magnetic properties [97], their electrocatalytic activity [91, 98–103], or to build up electrochemical [20, 104–106] and LSPR based sensors [107, 108]. Although in some cases, relatively lower size dispersions (s
15–30 %) have been found for Ag [98, 108] and Pt [103, 109] NPs, the most common way to reduce particle size dispersion is by physically decoupling nucleation and growth and by making particles grow under kinetic control. This is achieved by the potentiostatic double pulse (DP) technique described in section “Potentiostatic Double Pulse Electrodeposition.” Potentiostatic Double Pulse Electrodeposition Potentiostatic DP technique was developed by Penner’s [110–112] and Plieth’s [89, 113] research groups in the late 1990s to generate metallic NPs on highly oriented pyrolytic graphite (HOPG) and indium doped tin oxide (ITO), respectively. So far, it is the most widely explored and referred approach. It consists in the application of a very short nucleation pulse with large overpotential followed by a much longer growth pulse of smaller overpotential, as shown in Fig. 4a. This approach aims first at decoupling particle nucleation and growth and second at lowering down particle growth rates. This way, nanoparticle nucleation will proceed only over a very short time with high density, and particle growth will occur under kinetic control avoiding diffusional coupling. Therefore, narrower size distributions can be obtained. In this case, apart from EN and tN, two more parameters are available: the growth potential, EG, and the growth time tG. In a nutshell, the nucleation parameters establish the particle number density and the growth parameters determine the final nanoparticle size. Application wise, a large number of particles and large surface coverage are needed. Hence, large nucleation overpotentials are chosen, being other side reactions (e.g. hydrogen evolution, supporting electrolyte decomposition) the limiting factors to take into account. In the hypothetical case of instantaneous nucleation, all nuclei would be formed at tN = 0. In practice, nucleation spans over a range of time. To avoid a broad size dispersion at the end of the nucleation pulse, tN is chosen as small as possible, provided that a large number of particles are formed. Normally, tN  tPeak, being tPeak the time at which a current peak is observed when applying a SP. An appropriate growth potential should guarantee that no more nucleation on the bare substrate happens and that particle growth occurs under kinetic control. To evaluate these aspects, common practice is to carry out cyclic voltammetry (CV) using a fresh substrate as working electrode. This way, the plot of the current density j versus potential E allows the range of potentials in which the electrochemical reactions of interest are happening to be determined. The typical procedure consists of performing several scans starting from a more anodic potential than the standard potential of the electrochemical reaction of interest. The difference in the cathodic sweeps of the first scan compared to the following allows an estimation of the nucleation and growth onsets. When a metal is deposited over a low-energy substrate such as carbon, the first scan shows a reduction onset being more negative than the standard redox Page 9 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

a A n o d i c

Anodic Pre-Pulse

0.00 –0.05 –0.10 –0.15

ocp

C Eg a tg t Growth Pulse h o d E i n c tn Nucleation Pulse

j, mA/cm2

P o t e n t i a i

b

–0.20

No nucleation on fresh substrate

–0.25 –0.30 –0.35 ITO - Scan 1 ITO - Scan 2 GCNewScan1 GCNewScan2

–0.40 –0.45 –0.50 0.15

Time

0.20

0.25

0.30

0.35

0.40

E, V Vs Ag/AgCl

c

d

Fig. 4 (a) Schematic representation of a potentiostatic DP waveform. (b) Detail of the two first scans of cyclic voltammograms of Ag electrodeposition on GC and ITO substrates. Typical FESEM images of Ag NPs electrodeposited on GC (c) and ITO (d) substrates by means of a DP approach [86, 87]

potential due to the need of extra energy (overpotential) to compensate for the creation of new metalsubstrate and metal-electrolyte interfaces. Subsequent scans show a shift in the reduction onset to more anodic potentials as not all the metal is stripped off in the anodic sweep and hence the metallic ions reduce over the metal itself without the need of a large overpotential [114]. The potential range between the reduction onset in the first and posterior scans is the range in which prenucleated particles grow but further nucleation on the substrate is arrested (see Fig. 4b). Once this is known, potentials as close as possible to the onset of particle growth should be chosen in order to guarantee that particles will slowly grow under kinetic limitations. The transition from kinetic to diffusion control depends on the relation between the kinetics of the electrochemical reactions and the diffusive conditions of the active species. This approach has been proven very effective to generate narrow size distributions (s  10 %) in the mesoscale (0.1 mm  d  1 mm) (see Fig. 4c) [110–112]. However, when particles with d  100 nm have been obtained, their size dispersion has normally been larger, of s = 20–40 % (see Fig. 4d). Only in a few cases, the size dispersion has dropped below 25 % [66, 106, 109, 115, 116]. Accordingly, this approach has been used to synthesize electrocatalysts [117, 118], to build up electrochemical sensors [106, 119], to prepare substrates with enhanced magnetic properties [97], to study electrochemical nucleation and growth phenomena [44, 120], and for fundamental studies on nanoparticle electrodeposition [66, 109–111, 113, 115, 121, 122]. Although the DP technique has been traditionally the most common method to deposit NPs with a decent size dispersion, the generation of narrowly dispersed distributions of small NPs (d
10–100 nm) remains still a challenge. In some cases, this may be due to the impossibility of avoiding diffusional coupling when the kinetics of the reaction is too fast. In these cases, the transition between kinetic and diffusion control may span over few mV. Hence, guaranteeing pure kinetic limitations becomes complicated and broader or even bimodal size distributions are obtained, as shown by Fig. 4d. Another reason may be the impossibility to limit the size dispersion after the nucleation pulse. This may be related to

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

ts

Potential

tG x N times With tG 20 17–100 10–20 – –

– 5–50 1–25 100 10–100 50–500 – 10 2–25 20 0.015–0.15 – – 5–50 – – –

24 [101]

Au

FESEM

50–900

–

–

Ecat (ORR)

25 [91] 26 [122]

Pt Ag

SP DP

AFM SEM

1.5–3(h) 240–370

35–56 25

40–220 1–4.5

Fundamental Fundamental

27 [98] 28 [108] 29 [133]

Ag Ag Pt

200–300 20–40 5–200

22–27 15–25 –

2.5–3 12–13 –

ECat LSPR Ecat (ORR)

Pd Au Pt

AFM,FESEM SEM SEM,TEM

10–80(h) 30–70 10–40

40–50 25–40 15–30

2–25 25–60 –

Fundamental Fundamental Ecat

33 [66] 34 [136]

Au Cu,Co, Ni Pt Ni AG

GC Nafion

SP SP Galv. MP SP DP SP,DP, MP DP Other

FESEM AFM,UV–vis TEM

30 [38] 31 [115] 32 [102]

GC, HOPG HOPG FTOTiO2 GC ITO NafionGC SWNTs FTO Carbons

CV SP,DP DP SP SP SP SP SP SP MP DP DP SP,MP SP DP,MP Other Galv. SP SP

Application ECat ECat ECat EC biosensor EC biosensor EC biosensor LSPR sensor Fundamental Fundamental Fundamental Fundamental Optical Optical Optical Fundamental Optical Fundamental Fundamental EC Sensor Fundamental Fundamental CNT growth Ecat (ORR)

FESEM TEM

50 5

20 4

2–5 –

Fundamental Ecat

Polymer ITO CILE

SP SP,DP DP

AFM,FESEM AFM SEM

70–500 130–250 100

10–25 30–40 –

– 0.3–2 –

Ecat Magnetism EC sensor

35 [103] 36 [97] 37 [119]

(continued)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

Table 2 (continued) References 38 [107] 39 [99] 40 [104]

Material Au Au Ag

41 [109] 42 [121] 43 [92] 44 [105] 45 [130] 46 [116] 47 [106]

Pt Pb Au Pt Au Ag Au

48 [131] 49 [134]

Au Pt

50 [142]

Cu

Substrate ITO GC CollagenGC HOPG Au SWNTs GC ITO ITO GC GC NafionGC Graphene

Method SP SP SP

Characterization AFM FESEM AFM

d(nm) 25–70(h) 5–500 14–60(h)

s (%) 35–50 – –

N(108p/cm2) 10–400 30–100 –

Application LSPR Ecat (ORR) EC sensor

SP,DP DP SP SP CV DP SP,DP, CV CV Galv. MP SP

AFM AFM AFM SEM SEM FESEM FESEM

1.4–42(h) 3.5–18(h) 15–70(h) 40–200 35–80 20–50 15–70

10–30 22–50 20–60 – 10–15 5–20 20–60

15–420 – 2–40 – – – 32–330

Fundamental Fundamental Fundamental Ecat LSPR LSPR EC sensor

FESEM TEM

30–120 2–5

20–35 30

– –

EC sensor Ecat

SEM

60–260

40

1–9

Fundamental

d average diameter, s standard deviation, N particle density, (h) particle height measured by AFM, BDD boron doped diamond, D diamond, FTO fluorine-doped tin oxide, PPY polypyrrole, SWNTs single-walled nanotubes, Galv galvanostatic, SP single pulse, DP double pulse, MP multiple pulse, CV cyclic voltammetry, ECat electrocatalysis, ORR oxygen reduction reaction, EC Sensor electrochemical sensor, CNTs carbon nanotubes

be forgotten that one of the advantages of electrodeposition compared to colloidal synthesis is the absence of surfactants. Hence, achieving low size dispersions in surfactant-free conditions would be an asset. In this context, some alternatives to the potentiostatic DP method have been successfully tested, indicating that further research could lead to an important improvement in monodispersity. The electrodeposition of Cu on HOPG by means of a potentiostatic MP approach has led to NPs of d
50–70 nm and size dispersions down to s
10–20 % [125]. Alternatively, Au NPs electrodeposited on ITO by CV has led to particles of d
35–80 and s
10–15 % [130]. A galvanostatic MP method on a Nafion/GC electrode has resulted in Pt NPs of d
2–5 nm with s  30 % [134]. So far, the best monodispersity has been obtained by a pseudoelectrodeposition method in which impregnation of a nafion substrate with metallic ions is followed by electrochemical reduction in a supporting electrolyte.

Functional Properties of Electrodeposited Nanoparticles Despite the problems with size polydispersity, electrochemical deposition has been proven useful to obtain supported NPs with interesting properties, hence with applicability in different fields. The evaluation of their functional properties has been mostly directed toward the fields of electrocatalysis, electrochemical (bio)sensing, and LSPR based sensing. Less frequently, research has also been devoted to evaluate their optical and magnetic properties.

Electrodeposited Nanoparticles for Electrocatalysis Current fuel cell cathode catalyst standards consist of platinum NPs supported on carbon materials of high surface area (Pt/C) and have a mass-specific surface area (MSA) around 30–90 m2/gPt, a specific activity

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

around 100  200 mA=cm2Pt, and a mass-specific activity of 0.1 0.2 A/mgPt at 0.9 V [17]. Recently, a lot of effort is continuously being devoted to improve these standards by different approaches. Catalytic performance may be increased by changing the chemical composition and forming multimetallic nanostructures [10, 143] or by tuning the shape and surface atomic arrangement to obtain nanostructures enclosed by high-index crystallographic planes [37]. However, structural complexities of these systems make large scale synthesis difficult so carbon-supported platinum nanomaterials are still the most commonly used electrocatalysts. One of the key issues to improve their performance and cost effectiveness is to increase their MSA and their ratio between real and geometric area (RRG). Therefore, tuning their morphology at the nanoscale is the ideal solution. In this context, nanoparticle agglomerates [36], dendritic nanostructures [143], or mesostructured platinum thin films [39] provide enhanced electrocatalytic activity because they conserve their size-specific properties, while they form threedimensional nanostructures with a high surface area and a high concentration of surface defects [36]. Due to their three-dimensional nature, these approaches provide a much higher RRG and thus eliminate the need for high surface area carbon supports that can degrade quickly under operating conditions [39]. In addition, these structures do not suffer from active area loss due to agglomeration under operating conditions, as it is the case for supported NPs [126]. Although supported platinum nanostructures may be prepared by multiple methods [2, 32, 143, 144], electrochemical deposition offers the advantage that the NPs grow directly on the final support. This may help increasing their catalytic activity due to the absence of surfactants that would affect the electron transfer between substrate, nanostructure, and medium. Consequently, the technique has been proven effective to obtain highly active nanostructures, such as nanoparticle aggregates [36], meso-structured platinum thin films [39], NPs enclosed by high-index crystallographic planes [37], and platinum clusters supported on CNTs [38, 145]. On many occasions, nanoparticle distributions have also been electrodeposited to assess their electrocatalytic properties toward different reactions such as hydrogen evolution reaction (HER) [100, 117, 118], oxygen reduction reaction (ORR) [99, 101, 118, 132–134], or methanol oxidation [102, 103, 105]. In this context, Pt NPs have been supported on different carbon substrates such as boron doped diamond (BDD) [117, 118], diamond [117], HOPG [100, 102, 118], macro-porous carbon [102], GC [102, 105], Nafion/GC substrates [133, 134], or conducting polymers [102, 103]. Au NPs electrodeposited on ITO [132], GC/PPY [101], and GC [99] substrates have also been proven to be interesting alternatives because of their electrochemical activity toward the ORR reaction. In addition, small and size-monodispersed Cu, Co, and Ni NPs electrodeposited on nafion films have also proven to exhibit enhanced electrocatalytic activity toward the reduction of H2O2 [136] and Ag NPs supported on GC have shown useful to catalyze the reduction of benzyl chloride [98].

Electrodeposited Nanoparticles for Electrochemical Biosensing Electroanalytical sensors are normally formed by electrodes consisting of different types of NPs supported over different types of substrates [11–13]. These electrodes provide enhanced mass transport, electrochemical reactivity, large surface areas, and high signal-to-noise ratios. Hence, electrodes made of supported Au, Pt, Pd, Ag, Ru, Cu, Ni, and other NPs have been proven effective to sense arsenic [20, 21], H2O2 [22], glucose [23], and many other analytes in different electrolytes with high selectivities, high sensitivities, and ultra-small detection limits. Several reviews on the use of NPs on electrochemical (bio) sensors can be found elsewhere [11–13, 24]. Similarly to the case of supported NPs for electrocatalysis, electrochemical deposition may be a beneficial alternative compared to other synthetic methods because of the growth of the nanoparticles directly on the electrode surface. An enhanced electron pathway within the substrate, nanostructure, and analyte may help to increase the sensitivity and to bring down the detection limit. Therefore, Page 17 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

electrodeposited NPs have been reported to be used for electrochemical sensors on many occasions. This way, the detection of Arsenic (III) [20, 146], H2O2 [104, 119], nitrite [21], or trace analysis of Hg(II) [106, 131] have been successfully tested. Besides, supported NPs have also implemented in biosensors to electrochemically detect H2O2 [22], glucose [23], cholesterol [73], or others [128]. Gold is the selected material in most of the cases [20, 22, 23, 106, 128, 131] due to its electrochemical activity toward the referred analytes, but also due to its ability to immobilize different enzymes required for the detection of biological compounds. Another noble metal such as silver is also used, mostly for the electrochemical detection of H2O2 [104, 119]. Nanoparticles of cheaper materials, such as cobalt oxide, have been proved useful for the detection of arsenic (III) [146] or nitrite [21]. Regarding the substrates where the electrochemically active NPs are supported, ITO [20, 22, 23, 128] and GC [104, 106, 131] are the preferred ones due to their inertness, conductivity and reasonably low price. Other alternatives under development consist of carbon ionic liquid electrode (CILE) [119], ionic liquid-chitosan composite films [73], or type I collagen-modified GC electrodes [104].

Electrodeposited Nanoparticles for LSPR Based Sensing Surface enhanced Raman scattering (SERS) and local surface plasmon resonance (LSPR) based techniques can be very useful to detect very small amounts of a given analyte because of the signal enhancement of the surface plasmon resonance phenomena. Such signal enhancement allows supported nanoparticle LSPR based sensors being sensitive down to the zeptomole [26]. Due to the same reasons put forward for electrocatalytic or electroanalytical applications, electrochemical deposition of NPs may boost the enhancement of the LSPR phenomena. Hence, several research groups have tested electrodeposition as the method to engineer substrates for LSPR or SERS based sensors. Normally, noble metals such as Au, Ag, or Cu show the best enhancement of the Raman scattering effect. Therefore, Au [22, 107, 130] and Ag [108, 116] NPs of d
20–80 nm have been electrodeposited for these purposes. In these cases, ITO is normally chosen as the substrate due its conductivity and transparence.

Optical and Magnetic Properties of Electrodeposited Nanoparticles Materials with enhanced optical or magnetic properties are normally synthesized by means of other methods such as colloidal synthesis or UHV techniques. However, extensive research carried out by Penner’s group in the 1990s showed that QDs could be synthesized, supported on Silicon or HOPG, by a hybrid electrochemical/chemical approach, reviewed elsewhere [147]. This way electrodeposited Cu, Cd, or Zn NPs could be converted on Cul [94], CdS [95, 123, 148], or ZnO semiconductor [96] QDs, exhibiting narrow photoluminescence emission lines. Furthermore, Nickel NPs showing magnetic properties have also been electrodeposited on ITO [97]. Electrochemical deposition to obtain magnetic materials has not been commonly used though.

Conclusions From the work summarized in this review, it is clear that the synthesis of supported nanoparticles by electrochemical deposition attracts considerable attention. Plenty of work is devoted to come up with optimized synthesis conditions which allow obtaining nanoparticle distributions of desired size and low size dispersion. The aim of this review has been to understand the influence of the applied electrochemical waveforms on the resulting nanostructured substrates and their applications. Although electrodeposition cannot compete yet with colloidal synthesis in terms of size monodispersity, plenty of room for improvement is available and research is being redirected toward new strategies. These approaches consist of further developing multiple pulse or potentiodynamic waveforms so that large size dispersions Page 18 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_5-1 # Springer International Publishing Switzerland 2015

for nanoparticles of d
10–100 nm can be avoided. Besides, recent research on the early stages of electrochemical nucleation and growth has shown that nanocluster surface diffusion, aggregation, and coalescence influence the electrochemical formation and growth of nanoparticles. These phenomena need probably to be considered in future nanoparticle electrodeposition approaches. In this sense, albeit not reviewed in this chapter, the use of complexing agents or non-aqueous electrolytes such as ILs or DESs may enhance size monodispersity. Nonetheless, in applications where size-monodispersity is not mandatory, nanostructured substrates obtained by electrodeposition are being successfully implemented. On the one hand, electrodeposited nanoparticles show very high electrocatalytic activity toward electrochemical reactions of interest for fuel cell industry. On the other hand, several electrochemical (bio)sensors have been built off substrates with electrodeposited nanoparticles which have shown enhanced electrochemical activity toward the detection of different analytes. Finally, substrates made of electrodeposited nanoparticles on transparent substrates are more and more commonly used in LSPR based sensing devices.

Acknowledgments The authors acknowledge the support from the Fonds Wetenschappelijk On-derzoek in Vlaanderen (FWO, contract no. FWOAL527) and the Société Française de Bienfaisance et d’Enseignement (S.F.B. E.) de San Sebastian-Donostia (Spain).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_6-1 # Springer International Publishing Switzerland 2015

Melting Temperature of Metallic Nanoparticles Fan Gao and Zhiyong Gu* Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA, USA

Abstract Melting temperature is one of the fundamental properties of materials. In principle, the melting temperature of a bulk material is not dependent on its size. However, as the size of a material decreases toward the nanometer size and approaches atomic scale, the melting temperature scales with the material dimensions. The melting temperature of a nanomaterial such as nanoparticles (isotropic) and nanorods/nanowires (anisotropic) is related to other fundamental physical properties for nanomaterial applications, including catalysts, thermal management materials, electronics materials, and energy materials. This book chapter focuses on both the theoretical and experimental studies of metallic nanoparticle melting temperature depression. Thermodynamic modeling and molecular dynamic (MD) simulations are discussed regarding the melting behavior of different nanostructures, such as spherical nanoparticles and nanowires. The currently available measurement techniques by using classical differential scanning calorimetry (DSC), recently developed nanocalorimeters, transmission electron microscope (TEM), and optical methods are introduced. In addition, the applications of metal nanoparticles with lower melting temperatures are discussed, such as nanosoldering and sintering for electronics assembly and packaging.

Keywords Metal nanoparticles; Melting points; Electronics assembly; Flexible electronics

Introduction to Nanoparticle Synthesis Metallic nanoparticles have extensive applications in catalysis, sensors, electronics, and environmental and biomedical fields. By far, most metallic nanoparticles and their alloys were prepared by either vaporphase or liquid-phase synthesis, and few started directly from a solid phase. The vapor-phase synthesis methods usually include inert gas condensation, laser ablation, and vapor-liquid-solid (VLS) [1, 2], while the liquid-phase synthesis methods mainly include chemical reduction, microemulsion, electrodeposition, and solvothermal processing [3, 4]. The solid-phase synthesis involves mechanical thermal cycles, such as milling/attrition and reaction between solids [5]. Table 1 summarizes the typical synthetic methods for metallic nanoparticles. Due to the different synthesis methods and growth mechanisms, the shapes of nanoparticles can be classified into the following types: (i) spherical [14]; (ii) polygonal, such as triangle, square, pentagon, hexagon, disk, etc. [15]; (iii) polyhedral, such as tetrahedron, cube, truncated cube, octahedron, etc. [16]; (iv) rodlike, such as nanorod, nanobelt, nanowire, and nanotube [17]; and (v) others, including branched structures (e.g., nanostar) [18] and hollow structures [19]. Figure 1 shows several typical shapes of nanoparticles and nanowires. The metallic nanowires and nanorods have drawn a lot of research interest from the viewpoint of device applications, due to their unique 1D structural property [23]. The main bottom-up synthesis methods of metallic 1D nanostructures include template-assisted *Email: [email protected] Page 1 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_6-1 # Springer International Publishing Switzerland 2015

Table 1 Typical synthetic methods for metallic nanoparticles Gas-phase synthesis

Liquid-phase synthesis

Solid-phase synthesis

Synthesis method Inert gas condensation Laser ablation Vapor-liquid-solid (VLS) Chemical reduction method Microemulsion Electrodeposition Solvothermal Milling/attrition

Reference [1, 2] [6] [7] [8, 9] [10] [11, 12] [13] [5]

Fig. 1 Different shapes of metal nanoparticles. (a) Spherical Sn/Ag alloy nanoparticle (Adapted from Ref. [20]); (b) gold coresilver shell triangular nanocrystal (Adapted from Ref. [15]); (c) palladium nanoparticle cube (Adapted from Ref. [16]); (d) Pt octahedron (Adapted from Ref. [21]); (e) gold nanostar (Adapted from Ref. [18]); (f) gold nanorod (Adapted from Ref. [22]); (g) three-segment (Sn-Au-Sn) nanowire (Adapted from Ref. [12]) (Reprinted with permission from American Chemical Society, Copyright (2007), (2009), (2014), (2005), (2012), (2008), (2009), respectively)

electrodeposition, capping agent confined chemical reduction method, nanoparticle self-assembly, vaporliquid-solid methods, and so on [8]. For macroscopic (bulk) materials (e.g., size scale larger than one micrometer), the percentage of atoms at the surface is minuscule relative to the total number of atoms of the material; hence, the bulk material should have constant melting point regardless of its size. However, a certain number of physical and chemical properties of nanomaterials, including nanoparticles and nanowires, differ significantly from those at the macroscopic scale due to the high surface area over volume ratio, significant edge effect, and

Page 2 of 25

Melting Temperature

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_6-1 # Springer International Publishing Switzerland 2015

Nanoparticle size

Fig. 2 Schematic of size-dependent melting temperature of nanoparticles

possible appearance of quantum effects at the nanoscale. In this chapter, the size effect on the melting temperature will be discussed.

Melting Temperature Depression Theory The melting temperature (also referred as melting point or liquidus temperature for alloys) of a solid is the temperature at which it changes state from solid to liquid at atmospheric pressure. At the melting temperature, the solid and liquid phases exist in equilibrium. Studies of melting process and thermodynamic properties of nanoparticles have attracted both the theoretical and experimental interests because of the dramatically different melting behaviors from the bulk materials. In order to better understand the nanoparticle melting behavior, first, let us consider the example of melting for a piece of ice (bulk material) at 1 atmosphere of pressure. When heating up the ice by a constant energy input, the ice will change in three stages, from solid to solid-liquid equilibrium to liquid phases. Before reaching the melting temperature (0
C), the temperature of the entire piece of ice is kept increasing in the solid state. At 0
C, the melting temperature, the ice turns to water with absorbing energy, but the temperature of the ice/water mixture does not change till all the ice is changed to the liquid phase. This certain amount of energy required to change from solid state to liquid state (ice to water) at a constant temperature is called a latent heat of fusion. The enthalpy change associated with melting is often called as the enthalpy of fusion. After that, the temperature of water will keep increasing again under heating. If we “cut” this piece of ice into nanoscale size, the surface-to-volume ratio is much higher than the bulk ice, which dramatically alters its thermodynamic properties. Hence, the melting temperature of nanoscaled ice will melt below 0
C, and the phenomenon is called melting temperature depression. There is similar phenomenon for the metals and metallic nanomaterials. As the dimensions of a material decrease toward the atomic scale, the melting temperature scales with the material dimension, as shown in Fig. 2. Except few low-melting-temperature ( Y203 - Yttrium Oxide

20

30

40

50

60

70

80

Two-Theta (deg)

b

[Y3-204.raw] NDY(23) 715C(3h) - Standart condition

Intensity(CPS)

7500

5000

2500

0 41-1105> Y203 - Yttria

20

30

40

50

60

70

80

Two-Theta (deg)

Fig. 10 The results of X-ray analysis of compacts after annealing at the temperature 530  C (a) and 715  C (b) in air within 3 h

After annealing of compacts in the air in the temperature range of long-term exothermal process, the nanoparticles remain in the monoclinic phase (Fig. 10а). However, while annealing temperature is becoming higher, stable increase of volume of elementary cell from V = (411.7  0.2)  1030 to (412.6  0.2)  1030 m3 is found in the non-annealed and annealed compacts at Т = 530  С. In the compacts, complete transition to cubic phase (Fig. 10b) occurs after annealing within 3 h at minimal temperature TQ = 715  С corresponding to completion of long-term exothermal process (Fig. 9). In the non-compacted nanopowders, temperature and time of phase transition increase, and time of transition decreases with the growth of annealing temperature. Partial transition is found at Т = 800  С in them, and complete transition to cubic phase, after annealing within 10 h at 900  С or 5 h at 950  С.

Page 13 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Based on the fact that the phase transition starts at a temperature which corresponds to final stage of long-term exothermal process (Fig. 9), it should be concluded that a required condition for transition g-Y2O3 ! a-Y2О3 is a saturation of nanoparticles by oxygen (full oxidation of yttrium oxide) to content which is close to stoichiometric composition. It does not contradict [34], where it is shown that “value 0.3 % is a critical concentration of anion vacancies, and cubic structure does not withstand it and begins rearranging itself into monoclinic modification.” This conclusion also gives a reason of availability of local areas of monoclinic phase in the ceramics being sintered in a vacuum at T 1,950  С from compacts which are not sufficiently saturated by oxygen [35]. The second required condition for any crystallization process is a formation of seeds for a new phase. There is no reason to believe that oxidizing of the non-compacted nanopowders is less intensive than that of the compacted nanopowders. That is why dependence of dynamics of phase transition on density of powder should be correlated exactly with process of seed formation. Results of X-ray phase analysis demonstrate that minimal size of grains of cubic phase in the compacts is about 25 nm and in the nanopowder of free filling is 50–60 nm. It means that the grains represent several merged nanoparticles. It indicates that probability of formation of seed for cubic phase in one free nanoparticle of size 15 nm is much less than in the mechanically contacting nanoparticles. In the compacts of density rcom = 2.44 g/cm3, such contacts are ensured automatically. In the non-compacted nanopowder of density rpow = 0.1 g/cm3, availability of layer of the adsorbed molecules of air, in which desorption energy ed = 0.1–0.8 eV is more than the average energy of the nanoparticle heat motion кТ < 0.1 eVat temperature of phase transition, interferes with formation of direct contacts. That is why formation of direct contacts in the case of “collision” of nanoparticles is possible when they collide by surfaces which are free of adsorbed molecules. Share of such surface is equal to [36] y ¼ ð1 þ b
na Þ1 800  С and this process is slower than in the case of compacts.

Page 15 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Required conditions for transition are a saturation of nanoparticles by oxygen to content which is close to stoichiometric composition and formation of seeds of cubic phase. There is a high degree of probability that these seeds are formed in case of merging of several nanoparticles into grains of dimension 25–50 nm. Critical dimension of these grains decreases with increase of density of package of nanopowder at that.

Synthesis of Complex Nanopowders in Preset Stoichiometry The ability of synthesis of such nanopowders has been demonstrated with an example of 1 % neodymiumdoped YAG (Nd3+:Y3Al5O12) [16]. The main difficulty in solving this task is related to the need for evaporating a target so as to ensure the desired stoichiometry of the deposit. This problem is known for a long time, since it was encountered in the 1980s in the development of the technology of depositing high-temperature semiconductor (HTSC) films with complex compositions. Then, it was established that the goal could be achieved by using short laser radiation pulses with durations on the order of 108 s [37]. Unfortunately, lasers that generate such pulses provide a rather low average radiation power and, hence, cannot ensure high product yield. Yet, this disadvantage was not critical for depositing HTSC films for research purposes. For these reasons, CO2 lasers generate much longer albeit high-power pulses were either not employed or used for the additional heating of the target and/or substrate (see, e.g., [38]). However, the efficiency of low-power short-pulse lasers is not acceptable for production of nanopowders for the synthesis of novel materials such as optical ceramics [27]. At the beginning the problem was solved theoretically for choosing of optimal conditions. Theoretical analysis employed a three-dimensional (3D) model of the interaction of laser radiation with substances. The model was based on a 3D equation of heat conduction cðT Þ

@T ¼ ∇ðlðT Þ∇T Þ þ Qin @t

supplemented by the equations of motion of the liquid melt [39]:   ! div v ¼ 0 !

@v þ @t



! !

v
∇



!

v¼ 

1 ! ! ∇ P þ nD v r

(9)

(10)

(11)

where c is the bulk heat capacity, l is the thermal conductivity, Qin is the internal heat source, P is the pressure, r is the density, and n is the kinematic viscosity of the melt. A laser beam that propagates along the z-axis is incident onto the target surface that coincides with the xy plane, which creates a volume source of heat with the power density Qin ¼ aI ðx, y, z, tÞ

(12)

where a is the radiation absorption coefficient and I(x, y, z, t) is the radiation intensity distribution in the target medium. This distribution can be described as follows: I ðx, y, z, t Þ ¼ ð1  RÞI 0 ðx, yÞexpðazÞf ðtÞ

(13)

Page 16 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Fig. 11 Waveform of our CO2 laser radiation pulse. Insets show the (upper) adopted laser radiation intensity distribution in the focal spot and (lower) experimental laser trace on a target film

where I0(x, y) is the intensity distribution in the focal spot, R is the reflection coefficient, and f(t) is the form factor that takes into account temporal variation of the laser radiation intensity. The initial condition was set as the target temperature of 300 K. The same value was used as a boundary condition in the target bulk (for x, y, z ! 1). Figure 11 (upper inset) shows the adopted laser radiation intensity distribution I0(x, y) in the focal spot, which well approximates the experimental data (lower inset). The size of the focal spot measured in experiments was 0.5  0.7 mm. The coefficient of radiation reflection from the target surface was selected with allowance for the depth and shape of a crater produced in the target and the amount of material evaporated from it by a single pulse of focused laser radiation. The laser pulse waveform and peak power used in calculations were also analogous to the characteristics observed in experiments (Fig. 11) at laser pulse energy of 1 J. The dependence of a vapor pressure on the temperature was described by the Clapeyron–Clausius equation [40]. The necessary thermal parameters for calculations were taken from data published in handbooks [20, 41, 42]. The results of numerical calculations allowed us to trace the dynamics of evaporation of the target material and displacement of the liquid melt under the action of excess vapor pressure, which leads to the formation of a crater. The displacement of melt leads to the formation of the crater with a rib on the target surface (Fig. 12). The rib becomes visible at an exposure time of about 100 ms (Fig. 12a). The subsequent 100 ms period involves the rapid growth of the rib and deepening of the crater due to both the evaporation and displacement of melt. As the laser pulse intensity decays, the melt continues to move by inertia so that the process (for a YAG target) ceases by about 400 ms (Fig. 12b). Since the displaced melt cannot flow back into crater because of crystallization, the rib is retained on the target surface. This pattern qualitatively agrees with the image of a crater formed on the target upon the action of a single laser pulse (Fig. 12c). This experimental microphotograph was obtained using a Zygo NewView 5000 optical interference microscope. The displacement of melt under the pressure of vapor in the laser flare is a factor that accounts for the violation of stoichiometry in evaporated oxide mixture, since the components possess different boiling temperatures. The low-boiling component evaporates faster and its concentration drops unless the

Page 17 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Fig. 12 Shapes of rib and crater formed on a YAG target surface under the action of pulsed laser radiation: (a, b) results of numerical simulation for various moments of time; (c) digital image obtained in an optical interference microscope

evaporation rates of the two components would become equal. However, the displacement of melt exposes new areas of the target with the initial composition to laser radiation. As a result, the laser plume and, hence, the deposited nanopowder are characterized by an excess content of the low-boiling component, whereas the solidified melt retained on the target surface is depleted of this component. Figure 13 shows plots of the volumes of evaporated material and displaced melt, as well as the degree d of nonstoichiometry of the nanopowder versus laser pulse energy. The value of d was defined as follows: d ¼ ð½Y =½Al Þm =ð½Y =½Al Þnp

(14)

where subscripts “m” and “np” refer to the initial target material and nanopowder, respectively. The laser radiation pulse waveform was maintained constant and the energy was varied only by changing the peak intensity. As can be seen from these data, the degree of nonstoichiometry of the nanopowder decreases Page 18 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Fig. 13 Plots of (1, 2) volumes V of evaporated material and melt displaced out of the evaporation zone, respectively, and (3) degree d of nonstoichiometry of the obtained nanopowder versus laser pulse energy W and peak power Pmax

with increasing pulse energy, which is explained by an increase in the ratio of the evaporated to displaced volume. As will be shown below, on the whole, the results of calculations well agree with the experimental data. The nanopowder was synthesized using the laser evaporation setup which has been described above. Examination of the obtained nanopowder in a transmission electron microscope showed that the particles are weakly agglomerated and possess spherical shapes with an average size on the order of 10 nm. The X-ray phase analysis performed on a D/Max 2,200 V/PC diffractometer showed that the nanopowder is amorphous. Elemental analyses indicated that the ratio of yttrium and aluminum concentrations ([Y]/[Al] = 3/5) corresponded to that for YAG. The nanopowder yield rate was 24 g/h. In order to form a crystalline structure, the nanopowder was pressed into disks with a diameter of 15 mm and thickness of 2.5 mm, which had a relative density of 0.5. The compaction was carried out on a static press under the conditions of ultrasonic action upon nanoparticles. The static pressure amounted to 200 MPa, and the ultrasound generator was operating at an output power of 1.5 kW. The pressed disks were annealed in air at T = 1,100  C for 3 h. The X-ray phase analysis of annealed compacts indicated that a cubic garnet phase accounted for 100 % of the annealed material. However, the accuracy of X-ray phase analysis is on the order of 3 %. The garnet content was determined more precisely upon the sintering of compacts at 1,700  C for 20 h in a vacuum furnace with tungsten heater. The ceramic samples obtained upon an additional annealing in air, grinding, and polishing were transparent (Fig. 14). The content of scattering centers in these ceramics was determined using an optical microscope (Olympus), which showed that the garnet phase accounts for more than 99.9 % of the material. Thus, we have theoretically and experimentally studied the process of laser evaporation of a composite target. By means of laser ablation of a target by radiation pulses with duration above 200 ms, nanopowders with a preset stoichiometry of YAG:Nd3+ were obtained for the first time with a high yield of 24 g/h. Using these nanopowders, YAG:Nd3+ ceramics with a cubic structure possessing an optical transmittance of about 77 % at a wavelength of 1.06 mm has been obtained.

Page 19 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

Fig. 14 Photograph of a YAG ceramic disk made from the sintered nanopowder

Conclusion A cycle of investigations on the production of nanopowders at laser ablation of oxide targets by emitting of repetitively pulsed CO2 laser has been carried out. The following has been concluded. In the case of occurrence of laser plume, output of nanopowder production is proportional to average emission power. Moreover, it depends on the properties of the target material. In the case of average emission power ~500 W, among all substances to be examined, the maximal output was for Ce0,8Gd0,2O2d (80 g/h) and minimal one, for FexOy (11 g/h). Thus, energy consumption of laser emission was within the range 6.25–45(W
h)/g. The nanoparticles are of low agglomeration, and they have a shape which is close to spherical one. Their average diameter varies depending on pressure and composition of buffer gas from  7 nm (dBET = 9.4 nm, air–He, p = 20 kPa) to dBET = 43 nm (Ar, p = 250 kPa). Thus, width of size distribution function of nanoparticles increases from 12 nm (air–He, p = 20 kPa) to 40 nm (air, p = 100 kPa). Basically, the formed nanoparticles have metastable phase. In particular for Y2O2, Lu2O3, and Nd2O3, it is a monoclinic phase for which oxygen deficiency is typical. In the case of annealing of nanopowder in the air, its saturation by oxygen to stoichiometric relationship is a required condition for its transition from monoclinic phase into cubic phase. This transition in the non-compacted nanopowder begins at higher temperatures, and it is slower than in the case of compacts. It was found that in the case of evaporation of targets consisting of mixture of several oxides, the maximal rate of evaporation is for those that have lower boiling point.

References 1. E. Muller, Ch. Oestreich, U. Popp, G. Michel, G. Staupendahl, K.-H. Henneberg, ed. by Galassi C. In Proceedings of the 4th Conference of the European Ceramic society, Vol. 1: Basic Science –Developments in Processing of Advanced Ceramics –Part1 (Gruppo editoriale faenza editrice, Faenza, Italy, 1995), p. 219 2. U. Popp, R. Herbig, G. Michel, E. Muller, C. Oestreich, J. Eur. Ceram. Soc. 18, 1153 (1998) 3. G. Michel, G. Staupendahl, G. Eberhardt, E. Muller, Ch. Oestreich Key Eng. Mater. 132–136, 161 (1997)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

4. K. Manabu, Jpn. J. Appl. Phys. 15(5), 757 (1976) 5. V.N. Antsiferov, A.M. Shmakov, V.G. Khalturin, A.F. Ainagos, Powder Metall. Met. Ceram. 34 (1–2), 1 (1995) 6. V.N. Snytnikov, V.N. Snytnikov, D.A. Dubov, V.I. Zaikovskii, A.S. Ivanova, V.O. Stoyanovskii, V.N. Parmon, J. Appl. Mech. Tech. Phys. 48(2), 292 (2007) 7. H.-D. Kurland, C. Stotzel, J. Grabow, I. Zink, E. Muller, G. Staupendahl, F.A. Muller, J. Am. Ceram. Soc. 93(5), 1282 (2010) 8. H.-D. Kurland, J. Grabow, G. Staupendahl, W. Andre, S. Dutz, M.E. Bellemann, J. Magn. Magn. Mater 311, 73 (2007) 9. M. Ivanov, Y. Kotov, O. Samatov, O. Timoshenkova, T. Demina, Adv. Sci. Technol. 62, 22 (2010) 10. A. Reinoldt, R. Detemple, A.L. Stepanov, T.E. Weirich, U. Kreibig, Appl. Phys. B 77, 681 (2003) 11. V.V. Osipov, Yu.A. Kotov, M.G. Ivanov, O.M. Samatov, S.Y. Sokovnin, P.B. Smirnov in Proceedings of the 12th International Conference on High-Power Particle Beam, Israel, Haifa, 7–12 June 1998, vol. 2 (1998), p. 1023 12. Y.A. Kotov, V.V. Osipov, M.G. Ivanov, O.M. Samatov, V.V. Platonov, E.I. Azarkevich, A.M. Murzakaev, A.I. Medvedev, Tech. Phys. 47(11), 1420 (2002) 13. Y.A. Kotov, V.V. Osipov, O.M. Samatov, M.G. Ivanov, V.V. Platonov, A.M. Murzakaev, E.I. Azarkevich, A.I. Medvedev, A.K. Shtolts, O.R. Timoshenkova, Tech. Phys. 49(3), 352 (2004) 14. V.V. Osipov, Y.A. Kotov, M.G. Ivanov, O.M. Samatov, V.V. Lisenkov, V.V. Platonov, A.M. Murzakayev, A.I. Medvedev, E.I. Azarkevich, Laser Phys. 16(1), 116 (2006) 15. M. Ivanov, V. Osipov, Y. Kotov, V. Lisenkov, V. Platonov, V. Solomonov, Adv. Sci. Technol. 45, 291 (2006) 16. V.V. Osipov, V.V. Lisenkov, V.V. Platonov, Appl. Phys. B 105(3), 583 (2011) 17. V.V. Osipov, V.V. Platonov, M.A. Uimin, A.V. Podkin, Tech. Phys. 57(4), 543 (2012) 18. V.V. Osipov, M.G. Ivanov, V.V. Lisenkov, Quantum Electron. 32(3), 253 (2002) 19. A.F. Ainagos, V.G. Khalturin, A.M. Shmakov, Fizika i Khimiya Obrabotki Materialov (Physics and Chemistry of Materials Treatment), 3, 108 (1995), (in Russian) 20. K.E. Kazenas, J.V. Tsvetkov, The evaporation of oxides (Nauka, Moscow, 1997) (in Russian), pp. 387–403 21. V.V. Osipov, V.V. Platonov, V.V. Lisenkov, Quantum Electron. 39(6), 541 (2009) 22. V.V. Osipov, V.I. Solomonov, V.V. Platonov, O.A. Snigireva, V.V. Lisenkov, M.G. Ivanov, Laser Phys. 16(1), 134 (2006) 23. V. Lupei, A. Lupei, A. Ikesue, J. Alloys Comp. 380(1–2), 61 (2004) 24. U. Aschaur, P. Bowen, S.C. Parker, J. Am. Ceram. Soc. 89(12), 3812 (2006) 25. M.O. Ramirez, J. Wisdom, H. Li, Y.L. Aung, J. Stiff, G.L. Messing, V. Dierolf, Z. Liu, A. Ikesue, R.L. Byer, V. Gopalan, Opt. Express 16(9), 5965 (2008) 26. A.R. Denton, N.W. Ashcroft, Phys. Rev. A 43(6), 3161 (1991) 27. S.N. Bagaev, V.V. Osipov, M.G. Ivanov, V.I. Solomonov, V.V. Platonov, A.N. Orlov, A.V. Rasuleva, S.M. Vatnik, Opt. Mater. 31(5), 740 (2009) 28. M.G. Ivanov, Y.A. Kotov, A.I. Medvedev, A.M. Murzakaev, V.V. Osipov, A.K. Shtolts, V.I. Solomonov, J. Alloys Compd. 483, 503 (2009) 29. B. Wu, M. Zinkevich, F. Aldinger, D. Wen, L. Chen, Solid State Chem. 180(11), 3280 (2007) 30. H.K. Hoekstra, K.A. Gingerich, Science 146, 1163 (1964) 31. G. Skandan, C.M. Foster, H. Frase, M.N. Ali, J.C. Parker, H. Hahn, Nanostruct. Mater. 1(4), 313 (1992) 32. T. Atou, K. Kusaba, K. Fukuoka, M. Kikuchi, Y. Syono, Solid State Chem. 89(2), 378 (1990) 33. W. Chang, F. Cosandey, H. Hahn, Nanostruct. Mater. 2(1), 29 (1993) Page 21 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_8-1 # Springer International Publishing Switzerland 2015

34. A.E. Solov’eva, Inorg. Mater. 21(5), 808 (1985) (in Russian) 35. V.V. Osipov, A.V. Rasuleva, V.I. Solomonov, Tech. Phys. 53(11), 1525 (2008) 36. B.S. Bokstein, C.V. Kopetskii, L.S. Shvindlerman, Thermodynamics and kinetics of grain boundaries in metals (Metallurgiya, Moscow, 1986), p. 272 (in Russian) 37. A. N. Zherikhin, in Modern problems in Laser Physics, Laser Atomic-Molecular Technology and Diagnostics of Elementary Processes, vol. 1 (VINITI, Moscow, 1990), pp. 197–222 (in Russian) 38. P.E. Duer, A. Issa, P.H. Key, P. Monk, Supercond. Sci. Technol. 3(9), 472 (1990) 39. L.D. Landau, E.M. Lifshitz, Mechanics of continuous media (Nauka, Moscow, 1953) (in Russian) 40. V.P. Skripov, M.Z. Faizullin, Crystal–liquid–Gas transitions and thermodynamic similarity (WileyVCH Verlag GmBH & Co. KGaA, Weinheim, 2006) 41. I. S. Grigoriev and E. Z. Meilikhov (ed), Handbook of physical quantities (Energoatomizdat, Moscow, 1991; CRC Press, Boca Raton, 1997) 42. V.L. Balkevich, Technical ceramics (Stroiizdat, Moscow, 1984) (in Russian)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Syntheses, Structures and Properties of Boron Nitride Nanoparticles Takeo Oku* Department of Materials Science, The University of Shiga Prefecture, Hikone, Shiga, Japan

Abstract Synthesis, structures, and properties of boron nitride (BN) nanoparticles and nanocapsules were reviewed. They were prepared by various synthetic methods, such as thermal annealing, chemical vapor deposition, and arc melting. The structural characterization was performed by X-ray diffraction, transmission electron microscopy, and theoretical calculations. The properties were also investigated and discussed. Multiply twinned nanoparticles were investigated for chemical vapor-deposited BN with hexagonal, rhombohedral, and cubic crystal systems. A process for mass production of magnetic nanoparticles encapsulated with BN nanolayers was developed. The nanocapsules exhibited soft magnetic properties and excellent oxidation resistances. These BN nanoparticle materials are expected as various applications for recording media, nanoelectronic devices, and sensors for biological devices with good protection against wear and oxidation.

Keywords Arc-melting; Boron nitride (BN); CVD; Structure; Thermal annealing

Introduction Boron nitride (BN) has very similar structures to carbon (C) materials such as graphite, diamond, fullerene, nanotube, and amorphous structures. The BN has more superior properties of high oxidation resistance [1], insulator, and direct band transition, compared with C materials [2]. Since the development of BN nanotubes [3], various kinds of BN nanomaterials have been produced and reported because of their potential for using the nanomaterials in an isolated nanospace. Much studies have been performed on BN nanomaterials and BN single crystals such as BN nanotubes, bundled-type tubes, nanohorns, nanocorns, nanoparticles, nanocapsules, BN clusters, metallofullerenes, and BN nanosheets. They are anticipated to be applied for field-effect transistors, electronic devices, insulator lubricants, magnetic nanoparticles, nanocables, gas-storage materials, heat-resistant semiconductors, and optoelectronic applications such as ultraviolet light-emitting diodes. In addition, theoretical calculations and predictions on the BN nanostructured materials such as BN nanotubes, cluster-encapsulated nanotubes, clusters, metallofullerenes, BN cluster solids, nanocorns, nanohorns, and hydrogen gas storage have been performed for the prediction and estimation of their properties. With control of the size, compositions, layer numbers, chirality, and contained clusters, these BN nanocaged structures with energy gap of 5 ~ 6 eV and nonmagnetism would bring the various optical, electronic, magnetic, and gas-storage properties. Structures of the BN are hexagonal (h-BN, ABAB. . . stacking), rhombohedral (r-BN, ABCABC, etc. stacking), cubic (c-BN, ABCABC, etc. stacking), wurtzite type (w-BN, ABAB, etc. stacking), amorphous (a-BN), and turbostratic type (t-BN) [3, 4], as shown in Fig. 1. *Email: [email protected] Page 1 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

N

B

B N h-BN

r-BN

B N

B

N c-BN w-BN

Fig. 1 Structure models of hexagonal BN, rhombohedral BN, wurzite BN, and cubic BN

The present chapter displays BN nanoparticle materials and nanocapsules, which were synthesized by thermal annealing, chemical vapor deposition, and arc melting. Structures of the BN nanomaterials were characterized by using X-ray diffraction, transmission electron microscopy (TEM), electron diffraction, and high-resolution electron microscopy (HREM) [5, 6], and the properties were also investigated and presented. To confirm and investigate their atomic structures, electronic states, stabilities, and hydrogen gas storage, energy calculations were performed by using molecular orbital and molecular mechanics calculations. The present studies serve as a guide for design and synthesis of BN nanoparticle and nanocapsule materials, and they are expected as future nanoscopic-scale devices.

Formation of BN Nanoparticles by Chemical Vapor Deposition Boron nitride synthesized by chemical vapor deposition (CVD-BN) has been used in various practical fields as crucibles for semiconductor materials, high-temperature jigs, and insulators, utilizing its high purity, high density, and chemical inertness. The effects of deposition temperature and total gas pressure on the crystal structure, density, and microstructure of CVD-BN had been studied [7, 8]. The purpose of the present work is to investigate the formation of BN nanoparticles in CVD-BN by TEM, electron diffraction, and molecular orbital calculations. TEM, HREM, and electron diffraction studies were carried out for structural analysis, since they are very important methods for atomic structure analysis [9]. The effects of deposition temperature, total gas pressure, and the synthesis gas on the structures of BN nanoparticles were also investigated. The present work will give us guidance for the synthesis of CVD-BN with nanostructures. BN nanoparticles were produced from BCl3–NH3–H2 and B3N3H6 systems at gas pressures of 0.2 ~ 30 Torr and temperatures of 1,400 ~ 2,100
C on the graphite substrates. Figure 2a, b are transmission electron microscope images of BN nanoparticles produced from BCl3NH3H2 system at 1,800
C and 2,000
C, respectively. In Fig. 2a, b, many particles with star-

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 2 Transmission electron micrographs of boron nitride nanoparticles produced from BCl3–NH3–H2 system at (a) 1,800 and (b) 2,000
C and a total gas pressure of 5 Torr. (c) and (d): enlarged images of nanoparticles

and pentagon-shaped structures are observed, respectively. The particles satisfying Bragg diffraction conditions can be seen in these images. A number of BN particles exist in the CVD-BN samples, which was approved by tilting the samples. Enlarged images of BN nanoparticles in Fig. 2a, b are shown in Fig. 2c, d, respectively. Five boundaries are seen in the BN nanoparticles in Fig. 2c, d. The dark contrast would result from strain due to defects in the BN particles [10]. A TEM image of CVD-BN produced from B3N3H6 gas system at 1 Torr and 2,000
C is shown in Fig. 3a. Many particles are observed in the image with the shape of a maple leaf. An enlarged image of the BN nanoparticle in Fig. 3a is shown in Fig. 3b. Each region of the particle grows outwards in spite of even the shortness of twin boundaries in the particle. Figure 3c, d are from CVD-BN produced from B3N3H6 gas system at 1,800
C and 1,600
C, respectively (1 Torr). Star- and triangle-shaped particles are observed in Fig. 3c, d. Electron diffraction patterns of CVD-BN produced from B3N3H6 gas system at 2,000
C and 1,600
C (1 Torr) are shown in Fig. 3e, f, respectively. The electron diffraction of Fig. 3e was taken in an area of ~1 mm and indicates a number of diffraction reflections due to nanocrystalline particles and Debye–Scherrer rings due to turbostratic BN (t-BN) matrix. The rings are indexed as 002, 100, 102, 110, and 112 of hexagonal BN (h-BN). In Fig. 3f, the 002, 102, and 112 reflections are very weak, which indicates that the c-axis of the h-BN is almost perpendicular to the CVD-BN plate. Size dependences of BN nanoparticles on the deposition temperatures of CVD-BN produced from BCl3NH3H2 and B3N3H6 systems are shown in Fig. 4a, b, respectively. The sizes of BN nanoparticles in these systems were increased by the increase of deposition temperatures. Figure 4c, d show size Page 3 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 3 Transmission electron micrographs of boron nitride nanoparticles produced from B3N3H6 at various deposition temperatures and a total gas pressure of 1 Torr. (a) and (b) 2,000, (c) 1,800, and (d) 1,600
C. Electron diffraction patterns of CVD-BN synthesized at deposition temperatures of (e) 2,000 and (f) 1,600
C and a total gas pressure of 1 Torr

dependences of BN nanoparticles on the gas pressures produced from BCl3NH3H2 and B3N3H6 systems, respectively. Sizes of nanoparticle were decreased by the increase of pressures. It is considered that low pressure and high temperature affect the formation of BN nanoparticles with fivefold symmetry, which might be due to the growth speed of the boron nitride on graphite substrates. Schematic illustrations of chemical vapor deposition reaction for the BCl3NH3H2 and B3N3H gas systems are shown in Fig. 5a, b, respectively. The B3N3H6 molecule has a h-BN ring structure, and it is

Page 4 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

350

Particle Size (nm)

b

0.2 torr B3N3H6

300

350

1000 nm

250

1 torr

200 150

5 torr

100

BCl3-NH3-H2

250 200

10 torr

150 100

30 torr

50

50 0 1500

1600

1700

1800

1900

2000

0 1300 1400 1500 1600 1700 1800 1900 2000 2100

2100

Temperature (ºC)

d

350

2000ºC 250 200 150

1800ºC

100

1600ºC

50 0

350

2000ºC

BCl3-NH3-H2

300

B3N3H6

300

Particle Size (nm)

Temperature (ºC)

Particle Size (nm)

c

5 torr

300

Particle Size (nm)

a

250 200

1800ºC

150 100 50

0

1

2

3

4

5

0

6

0

5

10

15

20

25

30

35

Total Pressure (torr)

Total Pressure (torr)

Fig. 4 (a, b) Size dependences of boron nitride nanoparticles produced from B3N3H6 and BCl3NH3H2, respectively, on the deposited temperatures. (c, d) Size dependences of boron nitride nanoparticles produced from B3N3H6 and BCl3NH3H2, respectively, on the gas pressures. ●: pentagonal-shaped particle, ★: fivefold star-shaped particle, ☆: a few star-shaped particle, ♦: hexagonal-shaped particle, ~: rhombohedral boron nitride, ■: hexagonal boron nitride

a

c

–50

N B H

B Cl

N

H

Cl N

H N

B

H

Gibbs energy (kJ mol–1)

–100

b

1/3B3N3H6(g)=BN+H2(g)

–150 –200 –250 –300 BCl3(g)+NH3(g)=BN+3HCl(g)

–350

B –400

0

500

1000 1500 2000 2500 Temperature (ºC)

Fig. 5 Schematic illustration of CVD reaction for (a) BCl3NH3H2 and (b) B3N3H6 gas system. (c) Calculated Gibbs energies for BN formation

suitable for the synthesis of h-BN nanoparticles. Thermodynamic calculations of Gibbs free energy for the BN synthesis are shown in Fig. 5c. Reactions of BN formation at 2,000
C are as follows: BCl3 ðgÞ þ NH3 ðgÞ ¼ BN þ HClðgÞ

(1)

1=3B3 N3 H6 ðgÞ ¼ BN þ H2 ðgÞ

(2)

Gibbs free energy (DG) for these reactions was calculated as 305 kJ mol1 and 217 kJ mol1 for the formulas Eqs. 1 and 2 at 2,000
C, respectively. From the results of TEM observation, growth sizes were Page 5 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Growth size (nm)

1000

100

10 0.4

0.45

0.5

0.55

1000/T (1/K)

Fig. 6 Growth size of fivefold BN nanoparticles at temperatures ranging from 1,600
C to 2,000
C

plotted as a function of deposition temperatures in the range of 1,600–2,000
C, as shown in Fig. 6. Activation energy of the nanoparticle growth was calculated to be 2.3 eV, which might be due to the lattice diffusion of boron and nitrogen atoms in BN [11].

Structures of Nanoparticles with Fivefold Symmetry Fivefold symmetry is allowed only in small particles and quasicrystals [12, 13]. Various kinds of multiply twinned particles with fivefold symmetry have been reported for face-centered cubic (fcc) structure in the early stages of particle growth [14–19]. However, the fivefold symmetry formed from an fcc structure should have distortion due to the geometrical arrangements along the fivefold axis. The maximum size of these particles without distortion has been reported to ~40 nm because the internal stresses of the crystals increase as they grow [20]. In the present section, structures of nanoparticles with fivefold symmetry were presented, which were studied by TEM and electron diffraction. In addition, semiempirical molecular orbital calculations and molecular mechanics calculations were performed for total-energy determination, in order to predict the structural stability of the clusters [21–23]. Figure 7a is a TEM image and electron diffraction patterns of BN nanoparticles with the size of ~300 nm. The electron diffraction patterns show the h-BN structure with {112} twin planes. A scanning electron micrograph (SEM) of the BN nanoparticles showed a structure of pentagonal pyramidal facets, as shown in Fig. 7b. Solid lines indicate twin boundaries, and the [002] directions of h-BN are designated by arrows. Figure 7c is an electron diffraction pattern of a nanoparticle, which was taken from the BN nanoparticles with a size of ~300 nm. All diffraction reflections in Fig. 7c can be indexed by the overlapping of twin-related five diffraction patterns, as indicated by five rectangles. A part of the five regions is indexed by h-BN structure with lattice parameters of a = 0.25044 and c = 0.66562 nm. Twin boundaries in the nanoparticles are {112} of h-BN, and its fivefold axis is 201 , which equals to the incident beam direction. An enlarged TEM image of BN nanoparticle with fivefold symmetry is shown in Fig. 8a. Figure 8b is an electron diffraction pattern of Fig. 8a, which indicates a twin structure. A high-resolution image of center

Page 6 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 7 (a) TEM image and selected-area electron diffraction patterns of BN nanoparticle ~300 nm in size. (b) SEM image of BN nanoparticles. (c) Electron diffraction pattern of fivefold BN nanoparticle

of the fivefold multiply twinned BN nanoparticle was obtained, and a Fourier transform of the highresolution image is shown in Fig. 8c, which was masked around the diffraction spots of 100 and 102. Figure 8d is the inverse Fourier transform of Fig. 8c, and a magnified image of the center of Fig. 8d is shown in Fig. 8e. Twin-related boundaries are indicated by arrows in Fig. 8d, e. In the HREM image, two-dimensional lattice fringes with lattice distances of 0.22 and 0.18 nm can be seen, which match with lattice distances of BN {100} and {102}, respectively. The image obviously shows that the five regions have twin relatives at the boundaries. Center of the nanoparticle corresponds to the fivefold axis, which indicates distortion in atomic arrangements. A projected structure model of the fivefold multiply twinned hexagonal BN nanoparticle is shown in Fig. 8f. Open circles correspond to atomic rows  of an alternate sequence of nitrogen and boron atoms arranging parallel to the fivefold symmetry axis 201 . The {112} twin planes are indicated by dotted lines, and the cell of h-BN is indicated by solid lines. The fivefold axis is perpendicular to the image at the fivefold star mark, which is inclined 37
from the c-axis of h-BN. Figure 9a is a TEM image of a BN particle tilted 37
away from the fivefold axis. The twin boundary is indicated by arrows. A selected-area electron diffraction pattern of Fig. 9a is shown in Fig. 9b. Diffraction spots are indicated by indices of h-BN structure, and the twin boundary is indicated by the 112 reflection, which agrees with the result of Fig. 7a. A HREM image of a part of Fig. 9a is shown in Fig. 9c. {002} planes of h-BN are observed, and the angle between them, across the twin boundary, is ~140
. Lattice distortion is observed at the twin boundary, and stacking faults are also observed as discontinuities in {002} planes of h-BN. From the results of Figs. 7, 8, and 9, a three-dimensional structure model is proposed, as shown in Fig. 10. Figure 10a, b are schematic illustrations of BN {002}-layer stacking viewed along the fivefold axis [201] and the [110] direction, respectively. The angle between the two neighboring {002} of h-BN is 136
, which almost agrees with experimental image of Fig. 9c. The present model agrees well with a surface structure consisting of pentagonal pyramidal facets observed by SEM image of Fig. 7b. Stacked structure models consisting of B164N156 and B656N624 clusters are shown in Fig. 10c, d. The layer angle at the top is 112
, which agrees with the angle of 136
that is 37
inclined from the fivefold axis [11, 24].

Page 7 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 8 (a) TEM image and (b) electron diffraction pattern of boron nitride nanoparticle. (c) Filtered Fourier transform of the center of BN nanoparticle. (d) Inverse Fourier transformation of (c). (e) Magnified HREM image of (d). (f) Atomic structure model

Atomic structure models of B731N713 observed along and perpendicular to fivefold axis are shown in Fig. 11a, b. A stacked structure model of B1462N1426 is shown in Fig. 11c. Lattice distances between BN layers in the BN nanoparticles in HREM image of Fig. 9c were measured to be 0.35 nm, and the structure models were built from the results. Since the hexagonal BN structure has atomic stacking of BN–BN along c-axis, stacking structures of two and four layers were also calculated. After the molecular mechanics calculation, optimized layer distances were ~0.37 nm. Total energies per atomic mol of the

Page 8 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 9 (a) Transmission electron micrograph of boron nitride nanoparticle tilted 37
away from the fivefold axis. (b) HREM image of a part of (a). Electron diffraction pattern of (a)

BN clusters were decreased by piling the BN layers as calculated in Figs. 10d and 11c, and it is considered that the p-electrons above and below hexagonal BN rings have a role of van der Waals bonding between the stacking layers, and the stacking structure of h-BN nanoparticles with the fivefold symmetry is stabilized by multiplying BN hexagonal rings. The electronic structure of the B23N22 clusters was investigated as shown in Fig. 11d, e. Optimization of the atomic structure was performed by molecular orbital calculation. Energy gap between lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) of the B23N22 cluster was calculated to be 1.308 eV. Although the HOMOLUMO gap of the B24N24 cluster has been calculated to be 4.94 eV [34], the present B23N22 cluster shows an energy gap of 1.308 eV, which indicates decrease of the HOMO–LUMO energy gap by introducing BB bonding and the fivefold structure [24]. For comparison, HREM images of Au nanoparticles with fivefold symmetry are shown in Fig. 12a, b. In these images, Au atoms are imaged as dark dots, and atomic arrangements of Au are observed directly [25]. For both Au nanoparticles, Au atoms exist at the center of nanoparticles, which indicates the fivefold axis of [111]. In Fig. 12b, a disordered twin boundary is observed, as indicated by a star mark. In Fig. 12a, there is no atomic disordering in the Au nanoparticle, with a smaller size of 3.8 nm compared to that in Fig. 12b (5.0 nm). A SEM image of a diamond particle with fivefold symmetry is shown in Fig. 12c. The particle with a size of 5 mm has a decahedral shape, and five twin boundaries are designated by arrows. An electron diffraction pattern of diamond particles is shown in Fig. 12d. The electron diffraction pattern shows many

Page 9 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

c

{002}

b {002}

d

{002}

Fig. 10 (a) Schematic illustration of BN {002}-layer stacking observed along (a) the fivefold axis and (b) the directions of hexagonal BN. Atomic arrangement of BN nanoparticle (c) along and (d) perpendicular to the fivefold axis

diffraction spots, and all diffraction reflections are understood by overlapping five twin-related diffraction reflections. One region of the five regions can be interpreted by indexing with a diamond structure with a lattice constant a = 0.35670 nm. Twin boundaries of the particle are {111}, and the fivefold axis is [110]. The fivefold symmetry is not perfect, and there is distortion, as indicated by splitted diffraction spots (arrows). Multiply twinned particles with a fivefold symmetry are sometimes observed in metal nanoparticles, such as Ag, Ni, and Co [14–16, 20]. The maximum size of these nanoparticles is ca. 40 nm, because the inner stress of a crystal increases as it grows. This stress would be induced by elastic deformation to accommodate the misfit angle of 7
200 between the twin units. The stress is released at one specific twin boundary and a small gap is produced, as observed in Fig. 12b. Au18, C25 diamond, and B12N13 clusters were optimized by molecular orbital and mechanics calculations, and the total energy was calculated to be 836, 8.5 and 1.1 kJ/atom  mol, respectively. The total energy per atom  mol of C25 structure is smaller compared with that of Au clusters. This small total energy would facilitate the growth of diamond particles. The stress is released at five regions between the twin boundaries by inducing many stacking faults and dislocations, which results in an increase in the diamond particle size of more than 1 mm. In addition, the B23N22 cluster showed the lowest total energy, which also results in the increase of the particle size. Considering the lattice parameters of hexagonal boron nitride [111], the misfit angle of the fivefold multiply twinned h-BN nanoparticle is calculated to be 1.6
. This value is considerably smaller compared

Page 10 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

b

e

d 10

10

5

Energy (eV)

Energy (eV)

5

0

–5

c

BB NN Total

0

–5

B-2s2p N-2s2p

NN

BB

–15 N

–15 B

–10

Total

–10

Density of States

Fig. 11 Atomic structure models of (a, b) B731N713 and (c) B1462N1426 observed along (a) and perpendicular (b, c) to fivefold axis. (d) Energy level diagram and (e) density states of B23N22 cluster

with 7
200 of fivefold multiply twinned fcc nanoparticles. This small misfit angle consents the relatively large growth with small inner distortion in the particle. An atomic cluster existing at the center of the BN nanoparticle consists of B23N22, and optimization of the structure was performed by molecular orbital calculation, to provide a total energy of 1.1 kJ/atom  mol [24]. BN clusters such as B36N36 and B24N24 had been studied to provide nanocage structures [26]. On the other hand, the present BN nanoparticles have stacked layered structure with fivefold symmetry. The formation energy of B24N24 cluster had been calculated to be 1.5 kJ/atom  mol. This value is a little larger compared with the energy of the B23N22 cluster with fivefold symmetry. The results would indicate that growth kinetics causes structural changes of the BN clusters from the octahedral shape into decagonal shape during BN cluster growth.

BN Nanoparticles with Rhombohedral and Cubic Structure r-BN is expected as a starting material for c-BN with high hardness and thermal conductivity next to diamond, because of the same periodicity in the stacking ABCABC. . . in crystallographic layers, and the r-BN was directly converted into c-BN by shock compression and high static pressure [27–31]. The purpose of the present work is to investigate formation and atomic structures of CVD-BN with a rhombohedral structure. In addition, nanostructures of cubic BN converted from r-BN were investigated. Page 11 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 12 HREM images of gold nanoparticles (a) without and (b) with distortion. Twin planes are indicated by arrows. (c) SEM image of diamond particle. (d) Electron diffraction pattern of the diamond nanoparticle

TEM, HREM, and electron diffraction study were carried out for structural analysis. The atomic structure models of the nanostructures in r-BN and c-BN will be proposed. Figure 13a is a TEM image of chemical vapor-deposited boron nitride produced from BCl3NH3H2 system at a deposition temperature of 1,600
C and a total gas pressure of 3 Torr [32]. A number of nanoparticles are observed in the specimen. Note that only nanoparticles satisfying Bragg diffraction conditions can be seen in the image, which was confirmed by inclining the crystal. A selected-area electron diffraction pattern of Fig. 13a, taken from the wide area (1 mm), is shown in Fig. 13b. Figure 13b shows many diffraction reflections corresponding to the nanoparticles in addition to the DebyeScherrer diffraction rings from t-BN matrix. The DebyeScherrer rings are indexed as 003, 101, 102, 110, and 113 of r-BN. A magnified image and an electron diffraction pattern of a r-BN nanoparticle is shown in Fig. 13c, d, respectively. The reflections of Fig. 13d are indexed as r-BN along the [211] direction. ATEM image and an electron diffraction pattern of r-BN nanoparticle, taken along [010], are shown in Fig. 13e, f, respectively. Streaks along c*-axis are observed, which are due to the microtwin and stacking faults of {001}. A high-resolution image of r-BN in Fig. 13e is shown in Fig. 14a. Figure 14b is a magnified highresolution image of r-BN after Fourier filtering. White dots correspond to BN atomic pair, as illustrated in Fig. 14b. HREM image of microtwin is shown in Fig. 14c, which agrees with the streaks along c*-axis in electron diffraction pattern of Fig. 13f. Figure 14d is a selected-area electron diffraction pattern of r-BN twinned nanoparticle taken along [010], which indicates a {101} twin structure of r-BN. A transmission electron micrograph of r-BN nanoparticle is shown in Fig. 14e, and a twin boundary is indicated by

Page 12 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

b

a

70 nm

600 nm

d

c

113

110

102

101 003 000

200 nm

e

113

f

c*

102 011

003 101

202

000 000

a*

Fig. 13 (a) Transmission electron micrograph of boron nitride nanoparticles produced from BCl3–NH3–H2 at 1,600
C and 3 Torr. (b) Transmission electron micrograph of r-BN nanoparticle. (c) Transmission electron micrograph of r-BN nanoparticle perpendicular to c-axis. (d–f) Electron diffraction patterns of (a–c), respectively. The diffraction patterns were taken in large area (a), along (b) [211] and (c) [010] of r-BN nanoparticles

  arrows. An electron diffraction pattern of Fig. 14e, taken along the 110 direction, is shown in Fig. 14f, which indicates a {113} twin structure of r-BN. ATEM image of r-BN nanoparticle with twin structures is shown in Fig. 15a, and three twin boundaries of r-BN are indicated with arrows. A high-resolution image of twin boundary at region A in Fig. 15a is shown in Fig. 15b, which indicates the mirror relation at the boundary. Figure 15c–f shows electron diffraction pattern of twin boundary at regions A–D in Fig. 15a, respectively. All diffraction patterns are Page 13 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

b N B

NB

N B c

c

a

0.5 nm

c

0.5 nm

a

d

c*

c*

003 101

000

c

a

2 nm

e

f

c*

c*

110 {003}

{003}

000

113

003

30 nm

Fig. 14 (a) High-resolution image of r-BN. (b) Magnified high-resolution image of r-BN after Fourier filtering. (c) HREM image of microtwin. (d) Electron diffraction pattern of r-BN twinned nanoparticle taken along [010]. (e) TEM image of twinned r-BN nanoparticle. (f) Electron diffraction pattern of (e), taken along [110]

taken along [211]. A {101} twin structure is observed in Fig. 15d, f, and a {113} twin structure is observed in Fig. 15e. These twin structures are often observed in the r-BN nanoparticles. A TEM image and a selected-area electron diffraction pattern of c-BN nanoparticles synthesized from r-BN are shown in Fig. 16a, b, respectively. DebyeScherrer rings indexed as 111, 220, and 311 of c-BN are observed in Fig. 16b. A TEM image and electron diffraction of c-BN nanoparticle

Page 14 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a 100 nm

b

C

B D {101} A 1 nm

c

113

d 012

101 101

012

000

113

e

000

111

f 012

012

101

000

000

111

Fig. 15 (a) Transmission electron micrograph of rhombohedral boron nitride nanoparticles with twin structures. (b) Highresolution image of twin boundary at region A in (a) after Fourier filtering. (c–f) Electron diffraction pattern of twin boundary at regions A–D in (a), respectively, taken along [121]

taken along [011] are shown in Fig. 16c, d, respectively. The electron diffraction pattern shows {111} twin structure of c-BN. From the above observation, structure models of four kinds of twin structure are proposed, as shown in Fig. 17. The proposed atomic structures have mirror relation at the twin boundaries. The {101} twin structures of Fig. 17a, d are completely the same model from different directions, and the {113} twin structures of Fig. 17b, e are also the same.

Page 15 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

b 311 220 111

000

100 nm

c

d 200

111 000

100 nm

Fig. 16 (a) TEM image and (b) electron diffraction pattern of cubic boron nitride nanoparticles synthesized from r-BN. (c) TEM image and (d) electron diffraction of cubic boron nitride nanoparticle taken along [011]

Calculated electron diffraction patterns of twin structures of Fig. 17a–f are shown in Fig. 18a–f, respectively. Figure 18a–d, f agree well with observed diffraction patterns of Figs. 14d, f, 15f, e, and 16d, respectively, which confirm the proposed atomic models of twin structures. The {001} twin structure of Fig. 18e does not agree well with Fig. 13f, which is due to microtwins and stacking faults of h-BN and r-BN, as observed in Fig. 14c and streaks along c*-axis in Fig. 13f. Although one kind of {112} twin plane was found in h-BN [97, 98], three kinds of {101}, {113}, and {001} twin planes were found in r-BN in the present work. The {113} plane is consistent with {112} planes of h-BN, and the {001} twins of r-BN is due to the crystallographic characteristics such as ABCABC stackings. The {101} twins were often observed in r-BN, which would be due to low interfacial energy in r-BN.

BN Nanocapsules Synthesized by Arc-Melting Method Nanoclusters encapsulated in carbon hollow-cage structures are intriguing for both scientific research and future device applications such as cluster protection, nanostructure devices, and catalysis. Various types of carbon nanocapsules have been reported [2], and these materials are expected to be useful as solid-state lubricants, nano-ball bearings, and magnetic devices. However, the graphite sheets are conductive, and insulating sheets such as boron nitride (BN) are needed for the control of electrons in future nanoscale devices [33]. Page 16 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Fig. 17 Interfacial structure models of (a) {101}; (b) {113}; (c) {001}; (d) {101}; (e) {113} twin structures of r-BN along [010], [110], [010], [211], and [211], respectively. (f) Atomic structure model of {111} twin structure of c-BN along [011]. Circles indicate BN atomic columns along the projection model. Unit cells and twin interfaces are designated by solid and dotted lines, respectively

The purpose of the present work is to prepare BN nanocapsules with nanoparticles, which have magnetic and electronic properties. Iron oxide and cobalt nanoparticles were selected in the present work. Cobalt nanoparticles with BN sheets were expected to behave as quantum electronic devices. Ferrimagnetic Fe3O4 compounds are also expected to act as magnetic devices [34]. These iron oxide nanoparticles should be dispersed in a nonmagnetic matrix, and BN nanocapsules are very attractive for the formation of dispersed magnetic nanomaterials. Page 17 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

c*

c*

b 012

003 101

000

c

101 000

c*

d

c*

012 110 113

000

000

003 101

e

f 101 200 003 000

111 000

Fig. 18 (a–f) Calculated electron diffraction patterns of twin structures of Fig. 15a–f of r-BN and c-BN, respectively

Boron particles (99 %, 40 mm, 1 g, Niraco) were mixed with iron particles (10 nm, ULVAC), the atomic ratio of B:Fe particles was 8:2. The mixture powder was pressed at 15 kgf mm2 into pellets 1 mm deep and 20 mm in diameter. It was considered that the surface of iron powder was partially oxidized. The term “Fe(O)” is used here to refer to the starting iron particles. TEM observation of the particles showed the secondary diameter to be 20–40 nm. LaB6, Co, and only boron powders were also used for starting materials. The green compacts were put on the Cu mold in an arc furnace, and it was evacuated to 1  103 Pa. A gas mixture of Ar (0.06 MPa) and N2 (0.06 MPa) was introduced, and then the samples

Page 18 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

b

a

1 nm Fe3O4

Fe3O4

BN 5 nm

d 6.0

80

Magnetization (emu/g)

Magnetization (emu/g)

c

40 0 −40 FeOx NP

−80 −10000

10000

0

4.0 2.0 0.0 −2.0 −4.0 −6.0 −10000

Magnetic field (Oe)

e

Magnetic field

Fe3O4@BNNC 0

10000

Magnetic field (Oe) Ferromagnetic nanoparticles

BNNC

Superparamagnetic nanoparticles

S-Para

Para

H

S=

Q >0 T

endothermic

H

Fig. 19 (a) HREM image of BN nanocapsule encaging Fe3O4 nanoparticle. (b) Enlarged HREM image at the Fe3O4/BN interface in (a). Magnetization curve of (d) starting FeOx nanoparticles and (e) BN nanocapsule with Fe3O4 nanoparticles. (f) Schematic illustration of magnetic refrigeration

were arc discharged at an arc current of 200 A and a voltage of 60 V for a few minutes. After arc melting, a white or gray powder was obtained around the pellets. A high-resolution image of a BN nanocapsule with iron oxide nanoparticle is shown in Fig. 19a. Lattice fringes with distances of 0.23 and 0.20 nm, which correspond to the distances of {222} and {400} planes of Fe3O4, are observed in the clusters [9, 123, 124]. The number of BN sheets is in the range of 15–20 layers, and many plane defects of BN are observed. Figure 19b is an enlarged HREM image at the Fe3O4/BN interface in Fig. 19a. The interface is atomically smooth, and no specific distortion is observed. Page 19 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

b

2 nm

B {104} LaB6{110}

1 nm c

d

h-BN ~5 eV

PL intensity (A. U.)

2 nm

Co {111}

O, H

327 nm (3.8 eV) 3.8 eV 3.8 eV BN Co 0

250

300

350

400

450

Wavelength (nm)

f

Tunnel current (nA)

e

1 nm

Source

10 E

0

Drain

Gate Metal

BN VG

V

–10 STM –20

Co

HOPG

BN layer –1.5 –1 0.5

0

0.5

1

1.5 2

Bias voltage (V)

Fig. 20 HREM images of BN nanocapsules encaging (a) LaB, (b) boron, and (c) Co nanoparticles. (d) PL spectrum of BN nanocapsules encaging Co nanoparticles. (e) Current–voltage curve of a single BN nanocapsule with Co nanoparticle. (f) Schematic illustration of single-electron transistor

The magnetization curve of starting materials (mixture powder of Fe(O) with boron) is shown in Fig. 19c. Coercive force is ~1,500 Oe and magnetization is ~60 emu/g. Coercive force of iron particles with a diameter of 20–40 nm is 1,000–2,000 Oe, which is in good accordance with the present data. Coercive force was decreased from 1,500 to 50–100 Oe, as shown in Fig. 19d, after arc melting was performed for starting materials. When the iron oxide nanoparticles were divided by BN nanocapsule sheets with thickness less than 5 nm, magnetic interaction between nanoparticles disappeared. The present result indicates that the BN nanocapsules behave as superparamagnetics. This kind of material is expected as magnetic refrigeration as illustrated in Fig. 19e. HREM images of BN nanocapsules encaging LaB6, B, and Co nanoparticles are shown in Fig. 20a–c, respectively. A photoluminescence (PL) spectrum of BN nanocapsules encapsulating Co nanoparticles is Page 20 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

shown in Fig. 20d. The background of PL spectrum was deducted from the whole spectrum. The PL peak is seen at 3.8 eV (327 nm), and it might be due to the impurity level (such as oxygen or hydrogen) in the energy gap (5 eV) of the BN layers [35]. The current–voltage (I–V) characteristic of a single BN nanocapsule with Co nanoparticle (the diameter of 35 nm) is shown in Fig. 20e. The data were obtained from four I–V measurements [33]. The first data were taken on the BN nanocapsule, and the other data were taken on the background of the highly oriented pyrolytic graphite. The IV curve was calculated by subtracting background data from whole data. A sequence of IV data exhibiting Coulomb staircase-like behavior is observed. A schematic illustration of the IV measurements is shown in Fig. 20e as an inset. BN layer produced the double-tunnel junction. One-tunnel junction is provided by the BN layers and the gap between the STM tip and BN nanocapsule. The other is provided only by BN layers. It is believed that the present Coulomb staircase-like behavior would be due to the BN layers around the Co nanoparticles. These BN layers control carrier transport, which would be expected as future nanoscale devices. Boron is a semiconductor, and LaB6 and Co show a metallic property. It is expected that metal and/or semiconductor encapsulated in BN nanocapsules enable control of a single electron through the insulator sheets, and they can be applied to single-electron transistors [36, 37], as illustrated in Fig. 20f. Formation of the BN layer around nanoparticles is also useful for cluster protection.

BN Nanocapsules with Ag Nanoparticles The arc-melting technique is an excellent procedure to synthesize BN cage materials; however, the amount of produced BN nanocapsules was small (ca. 10 mg), and synthesis of a larger amount of BN nanocapsules was required. Several methods have been reported [38, 39], and one of them is explained here [40]. The purpose of the present work was to develop a new synthetic process to provide large amounts (>1 g) of BN nanocapsules containing nanoparticles with electronic properties. Urea [CO (NH2)2] and boric acid (H3BO3) were selected in an attempt to prepare BN layers. A mixture of these two reagents is expected to form BN layers upon annealing in hydrogen [41]. In the present work, silver nitrate was selected as the source of silver nanoparticles, a quantum electronic material which behaves as single-electron transistors [36, 37]. Furthermore, since all the precursors are soluble in water, it is possible to mix them homogeneously. To understand the formation mechanism of the nanocapsules, HREM and energy-dispersive spectroscopy (EDS) were carried out for microstructure analysis. The BN content was adjusted to between 70 and 95 vol.%. Boric acid, urea, and silver nitrate were dissolved in deionized water which was then removed using a rotary evaporator. The dried mixtures were reduced at 300
C and 700
C in H2 for 7 h, and the samples were investigated by X-ray diffraction (XRD). A HREM image of Ag nanoparticles in a BN matrix prepared at 300
C is shown in Fig. 21a with a BN content of 95 vol.%. The particle size of the Ag nanoparticles in the BN matrix was ca. 2 nm, with a low size distribution (0.5 nm). Lattice fringes with a distance of 0.24 nm corresponding to the {111} separation of Ag were observed in the clusters while the BN matrix was amorphous. A HREM image of Ag nanoparticles in a BN matrix prepared at 700
C is shown in Fig. 21b with a BN content of 70 vol.%. No clear differences were seen for the 70 and 95 vol.% BN matrices. The amorphous BN is crystallized in a t-BN structure. The size distribution of the Ag nanoparticles was in the range 5–60 nm with most particles of size 10–20 nm. All Ag nanoparticles are encapsulated in BN {002} sheets, which indicates the formation of BN nanocapsules. An XRD pattern of the BN nanocapsules prepared at 700
C is shown in Fig. 21c. Strong 111, 200, 220, and 311 Ag reflections are observed. A weak 002 peak of BN is also observed, indicating formation of t-BN. An undetermined weak peak is observed at 0.318 nm (2y ~ 28.02
), which cannot be indexed to AgO or B2O3 but probably arise from oxides of some type. Page 21 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

c Ag 111

Intensity (A. U.)

a

Ag Ag Ag

Ag 200

Ag 311

Ag 220 BN 002

10

20 40 60 Diffraction Angle 2θ(deg)

80

2 nm

d

b

3.7eV

10 nm

3.4eV

Intensity (A. U.)

Ag@BN Ag

Ag

BN powder

Ag

300

320

340 360 380 Wavelength (nm)

400

Fig. 21 HREM image of Ag nanoparticles in a BN matrix prepared at (a) 300 and (b) 700
C. (c) XRD pattern of (b). (d) PL spectrum of BN nanocapsules with Ag nanoparticles

The grain size of the Ag nanoparticles as calculated from XRD is 34.7 nm which can be compared with the size distribution of Ag nanoparticles, 5–60 nm, as determined by HREM. However, clusters of small size would not show strong XRD peaks, and only the larger Ag nanoparticles would be detected by XRD. PL spectra of the present BN nanocapsules and commercial BN powder (Denka, 9 mm) are shown in Fig. 21d. The luminescence was observed at 336 and 360 nm, which corresponds to 3.7 and 3.4 eV, respectively. The mechanism of the photoluminescence is considered to originate in interband transition of BN by impurities of carbon and hydrogen [35]. The blue shift of the PL spectra of the BN nanocapsules is believed to be the spherical structure of hexagonal BN bonding formed by BN nanocapsules. Figure 22a shows an HREM image of a single BN nanocapsule containing an Ag nanoparticle prepared at 700
C. The BN nanocapsule size is ca. 10 nm and lattice fringes of Ag{111} are observed. {002} planes of BN are observed around the Ag nanoparticle, surrounded by four BN layers. Figure 22b shows a BN nanocapsule surrounded by four BN nanocapsules. The Ag nanoparticles are separated by BN {002} layers. An enlarged Fourier-filtered HREM image of a part of Fig. 22b is shown in Fig. 22c. Ag atoms are directly observed in the image. BN nanocapsules containing nanoparticles were sometimes observed  AgO  as shown in Fig. 22d. The incident beam is along the 111 direction of the AgO. Ag oxides were not detected by XRD, owing to their small size and amount. EDX spectra of Ag nanoparticles in BN matrices prepared at 300 and 700
C are shown in Fig. 23a, b, respectively. After annealing at 300
C, a large amount of oxygen is detected, and the intensity of the nitrogen signal is weak. A peak of Cu corresponds to the TEM grid. After annealing at 700
C, the oxygen peak is reduced and the nitrogen peak becomes as intense as the boron peak, which indicates the formation of boron nitride. Although oxygen atoms remain in the sample, no carbon is detected. As observed in the high-resolution lattice images, the BN structure is highly disordered and oxygen would be incorporated in the BN matrix.

Page 22 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

b

a

Ag{111}

Ag{111} Ag{111}

3 nm

c

2 nm

d AgO{011}

Ag Ag

AgO{101}

0.2 nm

2 nm

Fig. 22 HREM images of (a) a single BN nanocapsule containing an Ag nanoparticle, (b) a BN nanocapsule surrounded by four neighboring Ag nanoparticles, and (c) a BN nanocapsule containing an AgO nanoparticle. (d) Enlarged filtered image of (b)

The overall formation mechanism of BN nanocapsules synthesized in the present work is described by Eq. 3: 2H3 BO3 þ COðNH2 Þ2 þ AgNO3 þ H2 ! Ag þ 2BN þ 6H2 OðgÞ þ CO2 ðgÞ þ NO2 ðgÞ

(3)

After annealing at 300
C, silver clusters and amorphous BN with low nitrogen content were formed, and oxygen would be included in the BN matrix. After annealing at 700
C, t-BN layers were formed around the silver nanoparticles as a consequence of the reduction by H2 and crystallization of the BN matrix. Gibb’s energies on formula Eq. 3 were calculated as 282 and 611 kJ at 300 and 700
C, respectively, which support the proposed formulas. As well as obtaining a large amount of BN nanocapsules, we have also succeeded in preparing these at a low temperature of 700
C. Previous BN nanocapsules produced by arc-discharge or arc-melting methods required ca. 3,000
C, and it was difficult to control the formation of BN nanocapsules. Use of a lower temperature allows better control of BN nanocapsule formation. Formation of the BN layer around the nanoparticles is also useful for cluster protection. In the present work, AgO nanoparticles were also observed to be encapsulated in BN nanocapsules after annealing at 700
C despite the fact that AgO ordinarily decomposes at ca. 100
C. In conclusion, HREM observation and EDS analysis indicate the formation of silver nanoparticles encapsulated in BN nanocapsules, which were produced by a new chemical process using H3BO3, CO

Page 23 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

Intensity (A. U.)

a

B

N O Ag Ag

Cu Ag

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Energy (keV)

Intensity (A. U.)

b

O

B N Cu 0

Ag Ag

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Energy (keV)

Fig. 23 EDX spectra of Ag nanoparticles in a BN matrix prepared at (a) 300 and (b) 700
C

(NH2)2, and AgNO3. This type of chemical process is useful for large-scale production of BN nanocapsules containing nanoclusters.

BN Nanocapsules with Magnetic Nanoparticles Synthesized by Annealing Nanoparticles have been widely studied for both for the fundamental properties and for application such as magnetic and electronic transport properties, which have potential for future nanoscale devices. Metal nanoparticles such as Co- and Fe-based alloys provide high magnetization properties. However, wear and oxidation resistances of the nanoparticle surface are demerit of these magnetic nanoparticles. A number of magnetic nanomaterials bring exothermic heat, which is due to the eddy current loss for high frequency. To solve this problem, insulating layers had been used. Boron nitride provides good protection against wear and oxidation, and the energy gap is ~5 eV, indicating the insulating property. Then, magnetic nanoparticles encapsulated with the insulating BN layers have important advantages for magnetic applications. Co and Fe nanoparticles encapsulated with boron nitride layers have been produced by thermal annealing and arc-discharge methods [33, 40]. However, the arc-discharge method is not appropriate for mass synthesis because of its limited plasma area. In addition, control of the particle size and number of BN layers is difficult. Fe nanoparticles encapsulated by BN layers have been produced by annealing a-Fe2O3 and boron powders [42]. Because the starting powder included oxygen in the materials, a high temperature was needed for annealing to eliminate the oxygen. BN nanocrystals with whisker

Page 24 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015 100 6Co + N2(g) = 2Co3N 6Ni + N2(g) = 2Ni3N 50

ΔG °(kcal/mol)

4Fe + N2(g) = 2Fe2N

0 8Fe + N2(g) = 2Fe4N

–50 2B + N2(g) = 2BN

–100

0

500

1000 1500 Temperature (˚C)

2000

2500

Fig. 24 Ellingham reaction diagram of metal nitrides

morphology were produced by a reaction of NH4Cl and KBH4 at 650
C and 22 MPa [43], whose production method does not include oxides in these starting materials. The purpose of this work is to produce magnetic nanoparticles encapsulated with boron nitride layers and to examine magnetic properties and nanostructures. The Ellingham diagram of metal nitrides for nitrogen gas was calculated, as shown in Fig. 24. Since boron atoms react with nitrogen more easily than Fe, Fe4N nanoparticles could be reduced to Fe entirely by annealing with B atoms. Likewise, several metal nitrides could be reduced into pure metal forms by reacting with boron. Here, Co and Fe were chosen as magnetic nanoparticles, and mixed powders of Co(NH3)6Cl3/KBH4 and Fe4N/B were reacted for the production, respectively [44]. Fe4N (99 %, Kojundo Chemical Laboratory) and boron powders (99 %, Kojundo Chemical Laboratory) were provided as raw, starting materials [44] for BN nanocapsules encaging Fe nanoparticles. The particle diameters were c.a. 50 and 45 mm, respectively. When Fe4N and boron with weight ratio (WR) of 1:1 were blended and mixed well, the specimens were put on the Al2O3 boat and heated in a furnace. The furnace was heated from room temperature to 1,000
C and kept for 60 min and then cooled down to the room temperature. Nitrogen gas pressure was ambient pressure of 0.10 MPa, and the gas flow was 100 standard cubic centimeter per minute. BN nanocapsules encaging cobalt nanoparticles were synthesized by annealing ammine complex. After the KBH4 and Co(NH3)6Cl3 (atomic ratio = 3:1) powders were well mixed, the specimens were put on the Al2O3 boat. Since the KBH4 powder was easily deliquesced in air, all manipulations were carried out in an inert gas. The samples were annealed in flowing nitrogen gas (100 or 200 sccm) at temperatures in the range of 500–1,000
C for 2 h and cooled down to room temperature in the furnace. Annealed samples were washed and filtrated several times with distilled water and ethanol. Figure 25a is X-ray diffraction patterns of annealed Fe4N/B specimens with two kinds of weight ratios annealed at 1,000
C. Peaks of a-Fe and h-BN were detected for all the specimens, and no peak due to boron and Fe4N was observed. Average diameters of a-Fe nanoparticles are listed in Table 1, which were obtained from full widths at half maximum (FWHM) of a-Fe 110 by using the Scherrer equation. Sizes of a-Fe nanoparticles were calculated to be below ~30 nm.

Page 25 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

α-Fe 110

Fe4N : B = 9 : 1 (1000 ºC, 1 h)

Intensity (A. U.)

h-BN 002

α-Fe 200

α-Fe 110

h-BN 002

α-Fe 211

Fe4N : B = 5 : 5 (5 h) α-Fe 200

h-BN 002

211

Fe4N : B = 5 : 5 (1 h)

α-Fe 110

α-Fe 200 20

30

40

b

50 60 2θ (degrees)

70

211 80

90

cubic-Co 111 1000 ºC, N2 200 sccm cubic-Co 200 cubic-Co 220

Intensity (A. U.)

h-BN 002

cubic-Co 111

h-BN 002

cubic-Co 200

1000 ºC, N2 100 sccm 220

α-Co * CoBx

20

30

**

40

*

700 ºC, N2 100 sccm

*

50

60

70

80

90

2θ (degrees)

Fig. 25 X-ray diffraction diagrams of (a) Fe4N/B specimens heated at 1,000
C and (b) Co(NH3)6Cl3/KBH4 specimens heated at ~1,000
C

Table 1 Diameters of a-Fe nanoparticles and measured magnetic properties of a-Fe nanoparticles encapsulated with boron nitride layers. Ms* and Hc* of a-Fe nanoparticles encapsulated with boron nitride layers were investigated after pressure cooker tests. Degauss coefficient was obtained by using a following equation: (Ms*  Ms)  100/Ms % Composition of Fe4N: B 5: 5 5: 5 7: 3 9: 1

Annealing time at 1,000
C 1h 5h 1h 1h

Particle diameter (nm) 24 28 – 30

Ms (emu/g) 95.0 92.6 134.2 174.9

Hc (Oe) 24.4 22.5 20.9 19.0

M s* (emu/g) 78.3 78.9 117.4 149.9

H c* (Oe) 42.5 39.8 33.8 37.5

Degauss coefficient (%) 17.6 14.8 12.5 14.3

Page 26 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

b

Fe Fe Fe BN 30 nm

5 nm

c

d BN BN

Co

Co

BN Co Co Co Co 50 nm

30 nm

Fig. 26 Transmission electron micrographs of (a) a-Fe nanoparticles encapsulated in boron nitride layers, (b) bamboo-shaped boron nitride nanotubes with a-Fe nanoparticles, (c) cobalt nanoparticles encapsulated in boron nitride layers, and (d) magnified image of the cobalt-encapsulated boron nitride nanoparticles

X-ray diffraction patterns of Co(NH3)6Cl3/KBH4 specimens heated at ~1,000
C for 2 h is shown in Fig. 25b. Although boron nitride nanocapsules were produced, boron powders did not react with nitrogen entirely for the specimen heated at 700
C. Diffraction reflections of hexagonal BN and fcc Co were detected for specimens heated at 1,000
C. Nanoparticle sizes were obtained from FWHM of 111 reflection of fcc cobalt by using the Scherrer equation as summarized in Table 1. The sizes of nanoparticles are dependent on the heating temperatures rather than the flowing rates of nitrogen gas. Figure 26a is a transmission electron micrograph of a-Fe nanoparticles encapsulated with boron nitride layers synthesized from mixture powders of Fe4N/B (1:1) at 1,000
C. Bamboo-shaped BN nanotubes with cell size of ~30 nm were formed by heating the mixed powders at 1,000
C, as shown in Fig. 26b. Width and length of bamboo-shaped BN nanotubes are ~40 nm and ~10 mm, respectively. Nanoparticles consisting of Fe were frequently observed at the top of bamboo-shaped BN nanotubes. Figure 26c is a transmission electron micrograph of fcc cobalt nanoparticles encapsulated with BN layers synthesized by heating the mixed powders of Co(NH3)6Cl3/KBH4 at 1,000
C in flowing nitrogen gas. A magnified image of BN nanocapsules encapsulating fcc cobalt nanoparticles is shown in Fig. 26d. Numbers of BN layers encapsulating fcc cobalt nanoparticles are 15 ~ 30 layers, which is larger compared to 5 ~ 10 layers in the specimen heated at 700
C. A hysteresis loop of Fe nanoparticles encapsulated in BN nanocapsules is shown in Fig. 27a, which was synthesized from Fe4N/B (9:1) starting materials heated at 1,000
C in nitrogen gas. The specimen provides a soft magnetism, and saturated magnetization (Ms) and coercivity values (Hc) were 174.9 emu/g Page 27 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

b

200

80

150

60

100

40 Ms (emu/g)

Ms (emu/g)

a

50 0 –50 –100

0 –20 –40

–150 –200 –10

20

–60

Fe@BN nanocapsules –5

0

5

10

Co@BN nanocapsules

–80 –10

H (kOe)

–5

0 H (kOe)

5

10

Fig. 27 Magnetization curves of (a) a-Fe and (b) cobalt nanoparticles encapsulated in boron nitride layers

Table 2 Diameters of cobalt nanoparticles and magnetic properties of cobalt nanoparticles encapsulated in boron nitride cages. Ms* and Hc* were investigated after pressure cooker tests. Degauss coefficient was obtained by using a following equation: (Ms*  Ms)  100/Ms % Temperature (
C) 700 1,000 1,000

Flow rate (sccm) 100 100 200

Particle diameter (nm) 27 40 37

Ms (emu/g) 48.6 74.5 72.3

Hc (Oe) 342.9 88.0 134.1

M s* (emu/g) 22.1 54.0 61.7

Hc* (Oe) 396.1 106.9 143.2

Degauss coefficient (%) 54.6 27.5 14.7

and 19.0 Oe, respectively. These Ms and Hc values are 80 % and 88 % of bulk Fe (217.6 emu/g and 21.5 Oe), respectively. Table 1 shows a result of vibrating sample magnetometer (VSM) measurements. Surface-oxidized Fe powders provide Ms of 130 emu/g, and Ms of magnetite (Fe3O4) is 92 emu/g. For the Fe nanoparticles encapsulated in BN layers, the Ms was reduced by weight loss of BN layers and shows high purity like Fe metal. A hysteresis loop of Co nanoparticles encapsulated in BN nanocapsules formed at 1,000
C in nitrogen gas is shown in Fig. 27b. Ms and Hc values of the specimen were 74.5 emu/g and 88 Oe, respectively, as listed in Table 2. Ms of specimens produced at 1,000
C are higher compared with that at 700
C. On the contrary, Hc decreased at raised temperatures, which might be due to the effect of particle size. Hc of metal nanoparticles with soft magnetism is dependent on the size of nanoparticles. Ms was inversely proportional to the Hc values. Hence, decrease of the present Hc of the specimens prepared at 1,000
C should be described by the particle size. To investigate wear and oxidation resistances, Ms* and Hc* values of the specimens were measured by VSM after pressure cooker test at 120
C for 12 h in 100 % humidity, and results are listed in Table 1 and 2. Values for the degauss coefficient were obtained by calculating the following equation: (Ms*  Ms)  100/Ms %. A specimen of Fe4N/B (7:3) provided better wear and oxidation resistances compared with other specimens of BN nanocapsules encapsulating Fe particles. Although Ms increased for the Fe4N-rich specimen, suitable amount of boron powder is necessary to preserve the high Ms against wear and oxidation by encapsulating Fe nanoparticles with boron nitride layers. Co nanoparticles in BN nanocapsules produced at 1,000
C provided better stability compared with the nanoparticles prepared at 700
C, which seems to be due to strong bonding of nitrogen and boron atoms in the specimens prepared at 1,000
C.

Page 28 of 32

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_9-1 # Springer International Publishing Switzerland 2015

a

Fe4N

+

B powder

BN covering >> exfoliation

BN covering 95 %) phenylboronic acid moieties exist in a tetrahedral anionic form. Since the affinity of D-/L-fructose with phenylboronic acid is very high in basis aqueous media (the binding constant between the phenylboronate anion and fructose is ~4,370 M
1) [60], sufficient binding between the surface MPB and fructose occurs. Figure 11a shows absorption spectra of the Ag nanocluster compound as a function of the D-/L-fructose concentration. Fructose did not provide significant absorption changes of the MPB-protected Ag nanoclusters, indicating that surface complexation hardly influences the electronic states of the Ag nanocluster compound, and consequently, the Ag core rearrangement or size growth is unlikely to take place upon complexation. The CD spectrum of uncomplexed nanocluster species exhibited no chiroptical responses reasonably. In stark contrast, the nanoclusters showed appreciable chiroptical responses when complexed with D-fructose (and L-fructose) (Fig. 11b). Interestingly, an almost perfect mirror-image relationship could be detected in the region of metal-based electronic transitions, implying that enantiomeric binding produces well-defined stereostructures in the Ag nanoclusters. Note that chiral fructose has no CD signatures in the wavelength longer than ~300 nm. Furthermore, the CD signal intensity was increased with an increase in the fructose concentration and nearly saturated at between 10
3 and 10
2 M. This saturation behavior is correlated with the binding yield of the phenylboronic acid moiety with chiral fructose and suggests that induced chiroptical response is controllable by the concentration of chiral fructose added. We have also tried chiral induction for MPB-protected Au nanocluster compound with the core diameter of 1.1 nm [55]. The MPB-protected Au nanocluster compound can be synthesized in a similar manner to the Ag nanocluster compound. Similarly, addition of D-/L-fructose into the basic solution of the Au nanocluster led to appreciable Cotton effects with an opposite sign (mirror-image relationship) in the metal-based electronic transition region (Fig. 12a, b). In the present Au nanocluster system, pH-switchable (or pH-responsive) optical activity can be demonstrated. The binding constant of the anionic boronate-diol is very much larger than that of the neutral boronic acid-diol [60], so that significant decomposition of the complexes is expected in acidic conditions. Figure 12c shows (induced) CD spectra of the Au nanocluster compound in the presence of D-/L-fructose (10
3 M) in oxalate buffer solution (pH = 1.68). In contrast to Fig. 12b, no CD signals were detected, suggesting no complexation of surface Page 16 of 22

Fig. 11 (a) Effect of D-/L-fructose addition on the absorption spectrum of 3-MPB-protected Ag nanocluster compound in aqueous solution (pH = 9.8). For clarity, absorbance is normalized at the peak position. (b) CD spectra of the 3-MPB-protected Ag nanocluster compound upon adding various concentrations of D-/L-fructose

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_12-1 # Springer International Publishing Switzerland 2015

Page 17 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_12-1 # Springer International Publishing Switzerland 2015

Fig. 12 (a) CD spectrum of pure MPB-protected Au nanocluster compound. No CD signals were detected. (b) Effects of
3 D-/L-fructose on the CD spectrum of the Au nanocluster in the basic solution ([fructose] = 10 M). Mirror-image relationship can be seen. (c) CD spectra of the Au nanocluster compound in the presence of D-/L-fructose in methanolic acid solution (pH = 1.68)

MPB moieties with chiral D-/L-fructose under the acidic condition. Note that no absorption spectral alternations were detected, so the electronic state coupling of the dissymmetrically decorated ligands and gold atoms in the nanocluster would be the most probable origin of the induced circular dichroism. In any case, optical activity of the Au nanoclusters can be here simply controlled by external parameters such as the pH value.

Conclusion Chiral metal (gold and silver) nanoclusters are particularly interesting since the bulk phase of these metals has a face-centered cubic (fcc) structure and hence symmetric. The nanoclusters are typically protected by a certain kind of ligands (frequently chiral thiols) on their surface, and a whole new range of optical and chiroptical properties is observed. In this chapter, a review on the synthesis, size separation, chiroptical responses, postsynthetic asymmetric transformation, as well as mechanisms to explain the observable optical activity of the chiral monolayer-protected metal (particularly gold) nanoclusters was made, which highlights their importance in both fundamental research and potential applications such as enantioselective catalysis, reaction, or sensing. Circular dichroism (CD) responses of well-defined, magic-numbered, atomically monodisperse gold nanocluster systems such as Au25(SR)18 and Au38(SR)24, where SR denotes thiolates, were also mentioned from a viewpoint of nanocluster structures including the core, ligand, and outermost staple motif. In addition, chiral phase transfer of optically inactive nanoclusters and the boronic acid-saccharide chemistry on the achiral nanocluster’s surface were demonstrated, giving chirality onto the metal nanoclusters. The author believes optically active or chiral nanomaterials will play an enormous role in future life and material sciences and this area should be much Page 18 of 22

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_12-1 # Springer International Publishing Switzerland 2015

more fruitful and exciting. The author thinks big progresses in study of chiral nanoclusters have been made in recent years, but further systematic research both in experiments and theories will improve fundamental understanding and potential applications of chiral nanoclusters.

References 1. M.C. Daniel, D. Astruc, Gold nanoparticles: assembly, supramolecular chemistry, quantum-sizerelated properties, and applications toward biology, catalysis, and nanotechnology. Chem. Rev. 104, 293–346 (2004) 2. C.M. Aikens, Electronic structure of ligand-passivated gold and silver nanoclusters. J. Phys. Chem. Lett. 2, 99–104 (2011) 3. P.D. Jadzinsky, G. Calero, C.J. Ackerson, D.A. Bushnell, R.D. Kornberg, Structure of a thiol monolayer-protected gold nanoparticle at 1.1 Å resolution. Science 318, 430–433 (2007) 4. M.W. Heaven, A. Dass, P.S. White, K.M. Holt, R.W. Murray, Crystal structure of the gold nanoparticle [N(C8H17)4][Au25(SCH2CH2Ph)18]. J. Am. Chem. Soc. 130, 3754–3755 (2008) 5. M. Zhu, C.M. Aikens, F.J. Hollander, G.C. Schatz, R. Jin, Correlating the crystal structure of a thiolprotected Au25 cluster and optical properties. J. Am. Chem. Soc. 130, 5883–5885 (2008) 6. M. Zhu, W.T. Eckenhoff, T. Pintauer, R. Jin, Conversion of anionic [Au25(SCH2CH2Ph)18]
cluster to charge neutral cluster via air oxidation. J. Phys. Chem. C 112, 14221–14224 (2008) 7. N.K. Chaki, Y. Negishi, H. Tsunoyama, Y. Shichibu, T. Tsukuda, Ubiquitous 8 and 29 kDa gold: alkanethiolate cluster compounds: mass-spectrometric determination of molecular formulas and structural implications. J. Am. Chem. Soc. 130, 8608–8610 (2008) 8. H.F. Qian, W.T. Eckenhoff, Y. Zhu, T. Pintauer, R. Jin, Total structure determination of thiolateprotected Au38 nanoparticles. J. Am. Chem. Soc. 132, 8280–8281 (2010) 9. K.J. Taylor, C.L. Pettiette-Hall, O. Cheshnovsky, R.E. Smalley, Ultraviolet photoelectron spectra of coinage metal clusters. J. Chem. Phys. 96, 3319–3329 (1992) 10. I. Katakuse, T. Ichihara, Y. Fujita, T. Matsuo, T. Sakurai, H. Matsuda, Mass distributions of copper, silver and gold clusters and electronic shell structure. Int. J. Mass Spectrom. Ion Process. 67, 229–236 (1985) 11. J. Li, X. Li, H.-J. Zhai, L.-S. Wang, Au20: a tetrahedral cluster. Science 299, 864–867 (2003) 12. H.-J. Zhai, L.-S. Wang, Chemisorption sites of CO on small gold clusters and transitions from chemisorption to physisorption. J. Chem. Phys. 122, 051101 (2005) 13. M. Walter, J. Akola, O. Lopez-Acevedo, P.D. Jadzinsky, G. Calero, C.J. Ackerson, R.L. Whetten, H. Grönbeck, H. H€akkinen, A unified view of ligand-protected gold clusters as superatom complexes. Proc. Natl. Acad. Sci. U. S. A. 105, 9157–9162 (2008) 14. R.C. Price, R.L. Whetten, All-aromatic, nanometer-scale, gold-cluster thiolate complexes. J. Am. Chem. Soc. 127, 13750–13751 (2005) 15. H. Qian, M. Zhu, Z. Wu, R. Jin, Quantum sized gold nanoclusters with atomic precision. Acc. Chem. Res. 45, 1470–1479 (2012) 16. F.J. Parker, C.A. Fields-Zinna, R.W. Murray, The story of a monodisperse gold nanoparticle: Au25L18. Acc. Chem. Res. 43, 1289–1296 (2010) 17. L. Barron, Molecular Light Scattering and Optical Activity, 2nd edn. (Cambridge University Press, Cambridge, 2004)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_12-1 # Springer International Publishing Switzerland 2015

18. J. Zhang, M.T. Albelda, Y. Liu, J.W. Canary, Chiral nanotechnology. Chirality 17, 404–420 (2005) 19. P. Barbaro, V. Dal Santo, F. Liguori, Emerging strategies in sustainable fine-chemical synthesis: asymmetric catalysis by metal nanoparticles. Dalton Trans. 39, 8391–8402 (2010) 20. T.G. Schaaff, R.L. Whetten, Giant gold-glutathione cluster compounds: Intense optical activity in metal-based transitions. J. Phys. Chem. B 104, 2630–2641 (2000) 21. M. Brust, M. Walker, D. Bethell, D.J. Schiffrin, R. Whyman, Synthesis of thiol-derivatised gold nanoparticles in a two-phase liquid-liquid system. J. Chem. Soc. Chem. Commun. 801–802 (1994). 22. T.G. Schaaff, G. Knight, M.N. Shafigullin, R.F. Borkman, R.L. Whetten, Isolation and selected properties of a 10.4 kDa gold: glutathione cluster compound. J. Phys. Chem. B 102, 10643–10646 (1998) 23. Y. Negishi, Y. Takasugi, S. Sato, H. Yao, K. Kimura, T. Tsukuda, Magic numbered Aun clusters protected by glutathione monolayers (n = 18, 21, 25, 28, 32, 39): isolation and spectroscopic characterization. J. Am. Chem. Soc. 126, 6518–6519 (2004) 24. Y. Negishi, K. Nobusada, T. Tsukuda, Glutathione-protected gold clusters revisited: bridging the gap between gold(I)–thiolate complexes and thiolate-protected gold nanocrystals. J. Am. Chem. Soc. 127, 5261–5270 (2005) 25. K. Kimura, N. Sugimoto, S. Sato, H. Yao, Y. Negishi, T. Tsukuda, Size determination of gold clusters by polyacrylamide gel electrophoresis in a large cluster region. J. Phys. Chem. C 113, 14076–14082 (2009) 26. C. Gautier, T. B€ urgi, Chiral N-isobutyryl-cysteine protected gold nanoparticles: preparation, size selection, and optical activity in the UV–vis and infrared. J. Am. Chem. Soc. 128, 11079–11087 (2006) 27. H. Tsunoyama, P. Nickut, Y. Negishi, K. Al-Shamery, Y. Matsumoto, T. Tsukuda, Formation of alkanethiolate-protected gold clusters with unprecedented core sizes in the thiolation of polymerstabilized gold clusters. J. Phys. Chem. C 111, 4153–4158 (2007) 28. R. Tsunoyama, H. Tsunoyama, P. Pannopard, L. Limtrakul, T. Tsukuda, MALDI mass analysis of 11 kDa gold clusters protected by octadecanethiolate ligands. J. Phys. Chem. C 114, 16004–16009 (2010) 29. D.B. Amabilino, Chiral nanoscale systems: preparation, structure, properties and function. Chem. Soc. Rev. 38, 669–670 (2009) 30. H. Yao, K. Miki, N. Nishida, A. Sasaki, K. Kimura, Large optical activity of gold nanocluster enantiomers induced by a pair of optically active penicillamines. J. Am. Chem. Soc. 127, 15536–15543 (2005) 31. H. Yao, Optically active gold nanoclusters. Curr. Nanosci. 4, 92–97 (2008) 32. H. Yao, T. Fukui, K. Kimura, Chiroptical responses of D-/L-penicillamine-capped gold clusters under perturbations of temperature change and phase transfer. J. Phys. Chem. C 111, 14968–14976 (2007) 33. E. Gutierrez, R.D. Powell, F.R. Furuya, J.F. Hainfeld, T.G. Schaaff, M.N. Shafigullin, P.W. Stephens, R.L. Whetten, Greengold, a giant cluster compound of unusual electronic structure. Eur. Phys. J. D. 9, 647–651 (1999) 34. I.O. Sosa, C. Noguez, R.G. Barrera, Optical properties of metal nanoparticles with arbitrary shapes. J. Phys. Chem. B 107, 6269–6275 (2003) 35. C. Noguez, Optical properties of isolated and supported metal nanoparticles. Opt. Mater. 27, 1204–1211 (2005)

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36. M.-R. Goldsmith, C.B. George, G. Zuber, R. Naaman, D.H. Waldeck, P. Wipf, D.N. Beratan, The chiroptical signature of achiral metal clusters induced by dissymmetric adsorbates. Phys. Chem. Chem. Phys. 8, 63–67 (2006) 37. R. Jin, H. Qian, Z. Wu, Y. Zhu, M. Zhu, A. Mohanty, N. Garg, Size focusing: a methodology for synthesizing atomically precise gold nanoclusters. J. Phys. Chem. Lett. 1, 2903–2910 (2010) 38. H. Qian, R. Jin, Controlling nanoparticles with atomic precision: the case of Au144(SCH2CH2Ph)60. Nano Lett. 9, 4083–4087 (2009) 39. M. Zhu, E. Lanni, N. Garg, M.E. Bier, R. Jin, Kinetically controlled, high-yield synthesis of Au25 clusters. J. Am. Chem. Soc. 130, 1138–1139 (2008) 40. Z. Wu, C. Gayathri, R.R. Gil, R. Jin, Probing the structure and charge state of glutathione-capped Au25(SG)18 clusters by NMR and mass spectrometry. J. Am. Chem. Soc. 131, 6535–6542 (2009) 41. M. Zhu, H. Qian, X. Meng, S. Jin, Z. Wu, R. Jin, Chiral Au25 nanospheres and nanorods: synthesis and insight into the origin of chirality. Nano Lett. 11, 3963–3969 (2011) 42. A. Sánchez-Castillo, C. Noguez, I.L. Garzón, On the origin of the optical activity displayed by chiralligand-protected metallic nanoclusters. J. Am. Chem. Soc. 132, 1504–1505 (2010) 43. J. Akola, M. Walter, R.L. Whetten, H. H€akkinen, H. Grönbeck, On the structure of thiolate-protected Au25. J. Am. Chem. Soc. 130, 3756–3757 (2008) 44. D. Jiang, M.L. Tiago, W. Luo, S. Dai, The “Staple” Motif: a key to stability of thiolate-protected gold nanoclusters. J. Am. Chem. Soc. 130, 2777–2779 (2008) 45. Y. Pei, Y. Gao, X.C. Zeng, Structural prediction of thiolate-protected Au38: a face-fused bi-icosahedral Au core. J. Am. Chem. Soc. 130, 7830–7832 (2008) 46. D. Jiang, W. Luo, M.L. Tiago, S. Dai, In search of a structural model for a thiolate-protected Au38 cluster. J. Phys. Chem. C 112, 13905–13910 (2008) 47. P. Maksymovych, J.T. Yates Jr., Au adatoms in self-assembly of benzenethiol on the Au(111) surface. J. Am. Chem. Soc. 130, 7518–7519 (2008) 48. O. Voznyy, J.J. Dubowski, J.T. Yates Jr., P. Maksymovych, The role of gold adatoms and stereochemistry in self-assembly of methylthiolate on Au(111). J. Am. Chem. Soc. 131, 12989–12993 (2009) 49. I. Dolamic, S. Knoppe, A. Dass, T. B€ urgi, First enantioseparation and circular dichroism spectra of Au38 clusters protected by achiral ligands. Nat. Commun. 3, 798 (2012) 50. O. Lopez-Acevedo, H. Tsunoyama, T. Tsukuda, H. Hakkinen, C.M. Aikens, Chirality and electronic structure of the thiolate-protected Au38 nanocluster. J. Am. Chem. Soc. 132, 8210–8218 (2010) 51. R. Gausepohl, P. Buskens, J. Kleinen, A. Bruckmann, C.W. Lehmann, J. Klankermayer, W. Leitner, Highly enantioselective aza-Baylis–Hillman reaction in a chiral reaction medium. Angew. Chem. Int. Ed. 45, 3689–3692 (2006) 52. H. Yao, T. Fukui, K. Kimura, Asymmetric transformation of monolayer-protected gold nanoclusters via chiral phase transfer. J. Phys. Chem. C 112, 16281–16285 (2008) 53. M. Sastry, Phase transfer protocols in nanoparticle synthesis. Curr. Sci. 85, 1735–1745 (2003) 54. H. Yao, M. Saeki, K. Kimura, Induced optical activity in boronic-acid-protected silver nanoclusters by complexation with chiral fructose. J. Phys. Chem. C 114, 15909–15915 (2010) 55. H. Yao, M. Saeki, A. Sasaki, Boronic acid-protected gold clusters capable of asymmetric induction: spectral deconvolution analysis of their electronic absorption and magnetic circular dichroism. Langmuir 28, 3995–4002 (2012) 56. N. Lygo, B.I. Andrews, Asymmetric phase-transfer catalysis utilizing chiral quaternary ammonium salts: asymmetric alkylation of glycine imines. Acc. Chem. Res. 37, 518–525 (2004) 57. K. Maruoka, Chiral designer phase-transfer catalysts for practical asymmetric synthesis. Pure Appl. Chem. 77, 1285–1296 (2005) Page 21 of 22

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58. T.D. James, K.R.A.S. Sandanayake, S. Shinkai, Chiral discrimination of monosaccharides using a fluorescent molecular sensor. Nature 374, 345–347 (1995) 59. E. Bassil, H. Hu, P.H. Brown, Use of phenylboronic acids to investigate boron function in plants. Possible role of boron in transvacuolar cytoplasmic strands and cell-to-wall adhesion. Plant Physiol. 136, 3383–3395 (2004) 60. J.P. Lorand, J.O. Edwards, Polyol complexes and structure of the benzeneboronate ion. J. Org. Chem. 24, 769–774 (1959)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Characterization of Metallic Nanoparticles Based on the Abundant Usages of X-ray Techniques Anh Thi Ngoc Dao, Derrick M. Mott and Shinya Maenosono* School of Materials Science, Japan Advanced Institute of Science and Technology, Nomi, Ishikawa, Japan

Abstract Metallic nanoparticles have fascinated scientists for over a century because of their huge potential in nanotechnology. Today, these materials can be synthesized and modified with various structures which allow them to be applied widely in numerous branches of science. Nanomaterials could be single or multiple metals and have copious kinds of size, shape, and structure and, thus, lead to profusely beneficial properties. Understanding nanoparticle characteristics helps in validating the synthesis, deciphering the morphology evolution, improving the synthesis protocols, and comprehending the potential applications of nanoparticles. Among characterization technologies, X-ray techniques provide assessment of composition, crystal structure, surface state, bonding environment, and physical properties. For example, X-ray diffraction (XRD) is used for the determinations of crystal phase and crystallinity of nanoparticles; X-ray absorption spectroscopy (XAS) has been used to characterize unoccupied electronic states, the chemical composition, and bonding environment in nanoparticles; and many other X-ray techniques such as X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDS), and small-angle X-ray scattering (SAXS) have revealed information on nanoparticle characteristics. This chapter will give an overview of the utilizations of X-ray techniques for metallic nanoparticle characterization as well as discuss the classification of X-ray techniques based on their general usages and principles. The assessments of nanoparticle characteristics using X-ray techniques will be concretely described.

Keywords Nanoparticles; Metal; X-ray; Characterization

List of Abbreviations AES CHA CMA CNTs EDS ESCA EXAFS FWHM SAXS PACVD

Auger electron spectroscopy Concentric hemispherical analyzer Cylindrical mirror analyzer Carbon nanotubes Energy-dispersive X-ray spectroscopy Electron spectroscopy for chemical analysis Extended X-ray absorption fine structure Full width at half maximum Small-angle X-ray scattering Plasma-assisted chemical vapor deposition

*Email: [email protected] Page 1 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

PVP UHV WAXS XANES XAS XPS XRD XRF

Polyvinylpyrrolidone Ultrahigh vacuum Wide-angle X-ray scattering X-ray absorption near-edge structure X-ray absorption spectroscopy X-ray photoelectron spectroscopy X-ray diffraction X-ray fluorescence spectrometry

Introduction X-rays were first observed and documented in 1895 by Wilhelm Conrad Röntgen, and he referred to the radiation as “X” to indicate that it was an unknown type of radiation [1]. Röntgen also discovered its medical use when he made a picture of his wife’s hand on a photographic plate formed due to X-rays. The photograph of his wife’s hand was the first ever photograph of a human body part using X-rays. When she saw the picture, she said “I have seen my death” [2], marking a start to the surprising and powerful information that can be provided by X-ray-based analysis techniques. Since this time, the use of X-ray-based instrumentation to collect critical information not only in the medical field but also as a highly qualitative and quantitative analysis tool for materials science has become commonplace. X-ray-based technology has differentiated itself into an all-encompassing suite of analytical characterization techniques that provide complementary information on a wide range of materials systems. A wealth of knowledge on the characteristics of materials can be revealed including the atomic structure of crystalline materials, the composition and chemical state of elements in a complex mixture, the surface characteristics of materials, as well as a host of other information. The key information X-ray-based techniques provide on materials systems has been invaluable to the field of materials science in terms of understanding their basic properties. In addition, as nanotechnology has become prevalent in the formation of new nanoparticle-based materials with enhanced and accentuated properties, X-ray-based techniques have provided accentuated information on the nanoparticle characteristics. For example, the crystallite size of nanoparticles is reflected in the width of the peaks in X-ray diffraction patterns, while X-ray photoelectron spectroscopy provides information on electronic structure of nanoparticles and charge transfer between constituent elements in alloy and/or heterostructured nanoparticles. Indeed, X-ray-based techniques have proven integral in the analysis of the current generation of nanoparticlebased materials and represent many of the staple instrumental techniques in the analytical toolbox for materials scientists today. This chapter will focus on the wide range of X-ray-based techniques for the characterization of metallic-based nanoparticles. A brief overview of the basics of the most common Table 1 Overview of the primary X-ray-based techniques for materials characterization Year of discovery 1895 1912 1954 1980

Technique X-ray radiation X-ray diffraction (XRD) X-ray photoelectron spectroscopy (XPS) X-ray absorption spectroscopy (XAS)

Materials characteristics revealed X-rays are first discovered and used to create an image of the internal structure of the human body [1] Used to determine the atomic and molecular structure of crystals [3] Provides qualitative and quantitative elemental information [4] Reveals local geometric and/or electronic structure of a material [5]

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 1 The scheme of electron shells in an atom. The electronic transitions correspond to the X-ray emission lines in the quantum theory of Bohr

techniques will be presented followed by some of the best examples of the use of each technique in the characterization of metallic nanoparticles. The materials are intended to provide new scientists in the field of materials science with the basic information and knowledge required to become familiar with the use of X-ray-based techniques for the characterization of metallic nanoparticle-based materials. Table 1 provides an overview of the primary X-ray-based techniques for materials characterization, date of discovery, and most common use.

Classification of X-ray Techniques X-rays are relatively short-wavelength (around 0.1 ~ 100 Å) and high-energy (from 100 eV to 100 keV) electromagnetic radiation. All electromagnetic radiation is characterized by either its energy E, wavelength l, or frequency n (Eqs. 1–2): l¼

c v

E ¼ hv

(1) (2)

where c is the speed of light and h is Planck’s constant. When a material is irradiated by X-ray photons carrying excess energy, a photon could interact with the target matter causing effects like scattering, absorption, emission, refraction and reflection, and/or interference. Based on each effect or multiple effects and on characteristic photon or electron emission, scientists have built X-ray spectroscopy or microscopy, and each technique gives its own benefit for assessment of science in general and for metallic nanomaterials which are discussed in this chapter.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 2 X-ray spectrum for a typical anode material

Table 2 Characteristic X-ray emission lines for some common anode materials [6] Anode material Mg Al Cu Mo W

Atomic number 12 13 29 42 74

Photon energy [keV] Ka1 Kb1 1.25 1.30 1.49 1.56 8.05 8.91 17.48 19.61 59.32 67.24

Wavelength [Å] Ka1 9.890 8.339 1.541 0.709 0.209

Kb1 9.521 7.960 1.392 0.632 0.184

Generation of X-rays Basically, when a high voltage is applied to a cathode, electrons are accelerated and released at a high velocity. The high-velocity electrons collide with a metal target, the anode, and create the X-rays based on two different atomic processes: • The incident electron is deflected in the collision process with the target atom which is caused by the strong electric field near the high-Z (number of protons) nuclei. The radiation given off by these electrons has a continuous spectrum which is called bremsstrahlung. • If the electron has enough energy to kick out one of the most-inner bound electrons (K shell) in the target atom, a hole (or vacancy) is formed. According to the Bohr theory, an electron of the L or M shell can fall into the K shell, and a quantum of radiation is emitted. In this case, the lines Ka, Kb,. . . will appear in the emission spectrum (Fig. 1). If the electrons are knocked out of the L shell of the target atom, they will have the lines La, Lb,. . . in the emission spectrum. In a real system, the two processes above can happen simultaneously (Fig. 2 and Table 2).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

There are several types of source for excitation of characteristic X-radiation, including those based on electron, X-ray, g-rays, protons, and synchrotron radiation. The X-radiation is produced commonly by X-ray tube or synchrotron facility: • In a synchrotron facility, a charged particle passes through a magnetic field and is forced perpendicularly to the direction of the motion, in the direction of the field. This causes the particle to accelerate around a closed loop – a curve path. Accelerating (and decelerating) charged particles will give off electromagnetic radiation. When the particles are accelerated into the GeV range, intense and coherent X-radiation will be produced. • In the laboratory, X-rays are produced by using an evacuated tube which contains a cathode filament heated by an AC voltage. The anode is a water-cooled target made from a wide range of pure elements, such as Mg, Al, Cr, Fe, Cu, Mo, Ag, W, etc. (Table 1). When the accelerated electrons reach the target, they kick out the bound electrons in the target atom followed by generation of characteristic X-rays.

X-ray Elastic Scattering Techniques Scattering will occur when an X-ray photon collides with one of the electrons of the target atoms. When this collision is elastic, which means no energy is lost in the collision process, the scattering is called coherent (or Rayleigh) scattering [7]. Since no energy change is involved, the coherently scattered radiation will retain exactly the same wavelength as the incident X-ray beam. It can also happen that the scattered photon loses a part of its energy in collision, then the scattering is called incoherent (or Compton) scattering, and the wavelength of the incoherently scattered photon will be longer than the incident wavelength [8]. X-ray elastic scattering techniques are based on observing the scattered intensity of an X-ray beam hitting a sample as a function of incident and scattered (or reflected) angle, polarization, and wavelength. It could include several types such as SAXS which probes structure in the nanometer to micrometer range by measuring scattering intensity at scattering angles 2y close to 0 ; X-ray reflectivity which is an analytical technique for determining thickness, roughness, and density of single-layer and multilayer thin films; and wide-angle X-ray scattering (WAXS) which is a technique in which scattering angles 2y larger than 5 are studied. In the scattering process, the scattered waves could interfere with each other either constructively or destructively (overlapping waves either add together to produce stronger peaks or subtract from each other to some degree) and produce a diffraction pattern. The diffraction from a three-dimensional periodic structure such as atoms in a crystal is called Bragg diffraction. Bragg diffraction is also known as the basic principle for XRD technique which is often used for characterization of crystalline materials. About 95 % of all solids can be regarded as crystalline materials, and the X-ray diffraction pattern of a pure crystalline substance is like a fingerprint of the substance and thus ideally suited for characterization and identification of crystalline phases. In the later part, the principle and characterization method of XRD will be described in detail.

Fig. 3 Illustration of photon–electron emission process (Adapted with permission from [9], Copyright (2011) John Wiley & Son) Page 5 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

X-ray Emission Techniques Photon–electron interaction could go through several processes which are illustrated in Fig. 3. When they use X-radiation as the incident beam irradiated to materials, the photon’s energy might be strong enough to expel an electron in the inner shell of the target atom (e.g., see Fig. 3a). The expelled electron (photoelectron) having a certain kinetic energy is detected by a spectrometer, and then the information about the binding energy of the electron will be revealed which refers to the principle of XPS, also known as electron spectroscopy for chemical analysis (ESCA). The vacancy of emitted electron will be subsequently filled by an electron from the outer shell, with the simultaneous emission of a photon. This emitted radiation is the so-called fluorescence (Fig. 3b). The fluorescence wavelength depends on the difference of energy levels between before and after the electron relaxation and, thus, reflects atomic characteristics. The technique used to isolate and measure individual characteristic wavelengths following excitation by primary X-radiation is called X-ray fluorescence spectrometry (XRF). When this technique is equipped in electron microscopes which use an electron beam as the excitation source, it is generally called EDS. In another case, the energy released by an electron relaxation from the outer shell to the hole in the K shell can be used to expel another electron from one of the outer shells (Fig. 3c). This secondary electron is the so-called Auger electron, named after the French physicist Pierre Victor Auger who first discovered the process [10]. By analyzing the Auger electrons, one can get information about composition near the surfaces of samples. This is the so-called Auger electron spectroscopy (AES) which is one of the most common surface analytical techniques. However, they will not delve deeply into the AES technique in this chapter.

X-ray Absorption Techniques When X-rays travel through matter, it loses energy due to the processes which are mentioned above. This lost energy could be, in other words, absorbed by matter. The loss in the transmitted X-ray intensity, I, obeys the Beer–Lambert law: I ¼ I 0 emx

(3)

or ln

I ¼ mx I0

(4)

where I0 is the intensity of incident X-ray beam, x (cm) is the thickness of material, and m (cm1) is the linear absorption coefficient which is a constant related to the absorbing material. Electrons play an important role in all absorption processes above and thus make electron density of materials directly related to absorption ability of X-rays. The absorption coefficient is sometimes expressed as a mass absorption coefficient, obtained by dividing the linear absorption coefficient by the density of the material:

 number X of elements m m ¼ Xj r m r j j¼1

(5)

where (m/r)m and (m/r)j are the mass absorption coefficients of the mixture and the j-th constituent elements, respectively, and Xj is the weight fractions of the j-th elements present.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

C

A

H

D

q dhkl

B

E 2q G F

Fig. 4 Diffraction of X-rays by a crystal

The measurement of the X-ray absorption coefficient of a material as a function of energy is the so-called X-ray absorption spectroscopy (XAS). It includes both X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS). Both of them will be discussed in more detail in section “X-ray Absorption Spectroscopy”.

X-ray Methodologies for the Characterization of Metallic Nanoparticles X-ray Diffraction (XRD) Basic Principle and Instrumentation Diffraction occurs when waves scattered from an object constructively and destructively interfere with each other. For a fixed scatterer spacing, the angle will depend on the wavelength, with short wavelengths diffracting at higher angles than longer ones. A crystal structure is composed of a set of atoms arranged in a particular way and a lattice exhibiting long-range order and symmetry. Vectors and atomic planes in a crystal lattice can be described by a three-value Miller index notation hkl. The distance between two adjacent planes is given by the interplanar spacing dhkl with the indices specifying the Miller indices of the appropriate lattice planes. Bragg diffraction is a consequence of interference between waves reflecting from different crystal planes. The condition of constructive interference is demonstrated in Fig. 4 and given by Bragg’s equation: nl ¼ 2d hkl sin y

(6)

where l is the wavelength of incident X-ray, y is the angle of the diffracted X-ray, and n is an integer known as the order of diffraction. X-ray diffraction experiments are generally made at a fixed wavelength; thus, a measure of the diffraction angles will allow the associated d-spacings to be calculated. X-radiation has wavelength of 0.1–100 Å which is close to the interplanar distance in a crystal and thus allows the crystal structure to diffract X-rays. The basic components of an X-ray diffractometer are the X-ray source, specimen, and X-ray detector (Fig. 5), and they are all included in the circumference of a circle, which is called the focusing circle. The angle between the plane of the specimen and the X-ray source is y, the Bragg angle. The angle between the projection of the X-ray source and the detector is 2y. Therefore, the XRD patterns produced with this geometry are often known as y–2y scans. The X-ray excitation source could be generated using Mo, Cu, Cr, etc., as a metal target anode. Cu is the most frequently used target. To obtain high-quality XRD data, one of the most important parameters is the method by which the analytical wavelength is treated. The difficulty in data treatment is the polychromatic nature of the diffracted beam and the variability in the angular dispersion of the diffractometer. Therefore,

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

detector

scattering plane wavelength filter

slit

graphite monochromator

θ 2θ bulk or powder wafer sample Cu tube

Fig. 5 Schematic of a Bragg–Brentano parafocusing X-ray diffractometer (Reprinted from Acta. Mater., Vol.54, Gilles R, Mukherji D, Hoelzel M, et al. Neutron and X-ray diffraction measurements on micro- and nanosized precipitates embedded in a Ni-based superalloy and after their extraction from the alloy, pp. 1307–1316, Copyright (2006), with permission from Elsevier)

e d Intensity (a. u.)

c b (111)

(200) (220)

a 30

40

50

60

70

80

2q(degree)

Fig. 6 XRD patterns of the Cu nanoparticles prepared with various PVP to copper nitrate mass ratios: (a) 0, (b) 0.25, (c) 0.5, (d) 1, and (e) 1.5 (Reprinted from Mater. Res. Bull., Vol. 48, Seo JY, Kang HW, Jung DS, et al. One-step synthesis of copper nanoparticles embedded in carbon composites, pp. 1484–1489, Copyright (2013), with permission from Elsevier)

the monochromator is a very important component in a diffractometer. A monochromator is a single crystal which is commonly a quasi-single graphite crystal placed in the diffracted beam, in front of the detector. Placing the monochromator in the diffracted beam removes not only spectral impurities from the X-ray tube but also any fluoresced X-rays from the specimen.

Page 8 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 7 XRD patterns of small platinum nanoparticles (4.5 nm), large platinum nanoparticles (25.7 nm), and Pt@Ag core@shell nanoparticles with large platinum cores. The reference peak positions for fcc phase platinum and silver are also shown (Reprinted from [13])

XRD Analysis of Metallic Nanoparticles Here, they show same examples of the application of XRD in determining the crystal structure of metallic nanoparticles. Copper nanoparticles embedded in carbon composites to protect them from oxidation were prepared via spray pyrolysis method [11]. By tuning the mass ratio of polyvinylpyrrolidone (PVP) to copper nitrate, the size of the resulting copper nanoparticles was affected and characterized by XRD measurements. Figure 6 shows the XRD patterns of pure copper powders and Cu/carbon composites. All the patterns show peaks at 2y = 43.3 , 50.4 , and 74.1 which correspond to fcc copper phase. The mean crystalline sizes (Dxrd), calculated by using the Scherrer equation (Eq. 7), decreased when increasing PVP in the precursor solution: Dxrd ¼

Kl : b cos y

(7)

Here, K is the shape factor (Scherrer constant, dimensionless) which depends on the crystalline phase and shape of nanoparticles, l (nm) is the X-ray wavelength (here it is CuKa), b (rad) is the peak width at half the maximum intensity (FWHM), and y (rad) is the peak position [12]. Information on crystallinity of nanoparticles could also be extracted from XRD measurements. In characterization of Pt@Ag core@shell NPs, it has been found that the platinum core has a polycrystalline structure, whereas silver in the shell is single crystal [13]. In Fig. 7, XRD patterns of platinum and Pt@Ag core@shell nanoparticles are shown. Scherrer analysis (Eq. 7) of the primary peaks due to the (111) plane reflection for fcc platinum phase revealed a mean crystalline size of 7.3 nm for platinum cores, while the mean size estimated from transmission electron microscope (DTEM) images was 25.7 nm. This large discrepancy between Dxrd and DTEM indicates that the platinum nanoparticles are polycrystalline in

Page 9 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

a

Intensity (a.u.)

(111)

(200) (220)

(311)

(222) (100) (110)

20

30

(210) (211)

40

50

(300)

60

70

80

90

60

70

80

90

2q

Intensity (a.u.)

b

20

30

40

50 2q

Fig. 8 XRD patterns of (a) Pt3–Sn and (b) Pt–Sn intermetallic nanoparticles. The corresponding drop lines are the reference data (Adapted with permission from [14]. Copyright (2013) American Chemical Society)

nature. In the same manner, silver shells are found to be almost monocrystalline in nature. Besides, the clear separation of the (111) peaks of platinum and silver in core@shell nanoparticles indicated the phase segregation or non-alloy formation (Fig. 7). When metal nanoparticles have a more complicated crystal structure, XRD is also very useful in determination of crystal phases as well as differentiation in alloy structures. Pt–Sn bimetallic nanoparticles have important applications in a variety of heterogeneous catalytic processes because of their excellent catalytic activities and selectivities. The catalytic properties of a bimetallic system in general depend on not only the composition but also on the arrangement of both metals in the compound. Therefore, intermetallic nanoparticles composed of Pt–Sn can be more promising materials than random alloy nanoparticles. Wang and coworkers had been successful in synthesizing Pt–Sn intermetallic nanoparticles with controlling shape and structure [14]. Pt3–Sn and Pt–Sn intermetallic nanoparticles were synthesized in octadecene by a versatile hot injection method with 1,2-hexadecanediol as the reducing agent. The intermetallic structures of those nanoparticles were characterized by XRD measurements (Fig. 8). The XRD patterns are very well consistent with reference data of fcc Pt3–Sn and hexagonal Pt–Sn phases, respectively. Commonly, alloy nanoparticles are composed of a random composition distribution of the constituent elements. For nanocrystal alloys, the lattice constant and the concentration of the constituent elements

Page 10 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 9 (a) XRD patterns of Pt/Au nanoparticles with Pt feeding content: (a) 0, (b) 30, (c) 50, (d) 70, and (e) 100 at.%; (b) lattice parameter which is estimated from XRD patterns was plotted as function of [Pt]feeding (Adapted with permission from [16]. Copyright (2012) American Chemical Society)

should have a linear relationship which follows Vegard’s law [15]. In other words, one can use Vegard’s law to confirm the alloy formation or to estimate the composition of nanoparticles. Pt/Au nanoparticles were typically synthesized by laser ablation, and the concentration of platinum in the alloys could be easily tuned by varying the Pt/Au feeding ratio [16]. They can observe the peak shifts in all 5 main peaks of the Au fcc structure after introducing platinum, and there is no peak separation (Fig. 9a). This strongly indicates the formation of an alloy structure. To more fully support the conclusion of alloy formation, the fcc lattice parameter was plotted versus the platinum feeding ratio ([Pt]feeding) and shows a nearly linear relationship which follows Vegard’s law for binary metallic alloys [17]. It also suggests that the platinum content in alloy nanoparticles is indeed close to the platinum feeding content which shows the tuning ability of the Pt/Au alloy composition using this method.

X-ray Photoelectron Spectroscopy (XPS) Basic Principle and Instrumentation The fundamental principle of XPS is based on the photoelectron effect which was discovered by Heinrich Hertz in 1887 and then was explained theoretically by Albert Einstein in 1905. The first high-energy resolution XPS spectrum of cleaved sodium chloride (NaCl) was recorded in 1956 by Kai Siegbahn [4]. In Page 11 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Table 3 XPS peak notation and peak area ratio based on spin–orbit coupling Subshell s p d f

l 0 1 2 3

j 1/2 1/2, 3/2 3/2, 5/2 5/2, 7/2

Peak area ratio — 1:2 2:3 3:4

1981, Kai Siegbahn received the Nobel Prize to acknowledge his extensive efforts to develop XPS into a useful analytical tool [18]. When an X-ray beam is directed to the sample surface, core electrons are liberated from the atoms of the sample as a result of a photoemission process. Each atom in the surface has core electrons with the characteristic binding energy of their particular element that is conceptually, but not strictly, equal to the ionization energy of that electron. The emitted electron has the kinetic energy of Ek, and the binding energy Eb is given by the Einstein formula: E b ¼ hv  E k  f

(8)

where hv is the X-ray photon energy (see Table 1); Ek is the kinetic energy of the photoelectron, which can be measured by the energy analyzer; and f (ca. 4 ~ 5 eV) is the spectrometer work function. Since f can be compensated artificially, it is eliminated, giving Eb. The XPS technique contains mainly the following parts: a primary X-ray source and electron energy analyzer, combined with a detection system and a sample stage, all contained within a vacuum chamber. The X-ray source, which provides photons, must have sufficiently high energy to excite intense photoelectron peaks from all elements of the periodic table. The most commonly applied configuration consists of a twin anode, providing monochromatic AlKa and MgKa lines. The electron spectrometer and sample room must be operating under ultrahigh vacuum (UHV), usually ranging from 108 to 1010 torr. UHV is required for detection of electrons and avoiding surface reactions or contamination. Because XPS is a surface-sensitive technique, contaminates will produce an XPS signal and lead to incorrect analysis of the surface composition. There are two common types of electron energy analyzer which measures the energy distribution of photoelectrons, namely, the cylindrical mirror analyzer (CMA) and the concentric hemispherical analyzer (CHA). CMA is particularly suited to AES and older multitechnique instruments. CHA is now universally employed in high-performance XPS instruments. Tips for Analysis of XPS Spectra: Spin–Orbit Coupling In atomic physics, spin–orbit coupling describes a weak magnetic interaction, or coupling, of the particle spin and the orbital motion of the particle. One example is the electromagnetic interaction between the electron’s spin and the electron’s orbital magnetic moment. One of its effects is to separate the energy of the internal states of the atom. Based on the L-S coupling (Russell–Saunders coupling) approximation, they have j = l + s, where j is the total angular momentum quantum number, l is the orbit angular momentum quantum number, and s is the spin quantum number (s = 1/2). To understand how spin–orbit coupling appears in XPS, for instance, here they analyze the inner core electronic configuration of the initial state of a silver atom: Electron configuration of Ag : ð1sÞ2 ð2sÞ2 ð2pÞ6 ð3sÞ2 ð3pÞ6 ð3d Þ10 ð4pÞ6 ð5sÞ1 ð4d Þ10 The removal of an electron from the 3d subshell by photo-ionization leads to a (3d)9 configuration for the final state. Because the d-orbitals (l = 2) have nonzero orbital angular momentum, there will be coupling Page 12 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 10 XPS background subtracted methods: (a) linear, (b) Shirley, and (c) Tougaard backgrounds

between the unpaired spin and the orbital angular momenta. Therefore, when l = 0, there is a singlet XPS peak, and when l > 0, doublet XPS peaks (spin–orbit pairs) will be observed (Table 3). Chemical Shift Core electron binding energies are determined by electrostatic interaction between the electron and the nucleus. The electrostatic shielding of the nuclear charge from all other electrons in the atom (including valence electrons) will be altered by the removal or addition of electronic charge as a result of changes in binding energy. Therefore, Eb depends on the chemical environment of atoms emitting the photoelectrons. For a simple example, Eb will be increased in the case of withdrawal of valence electron charge and decreased with addition of valence electron charge. Atoms of higher positive oxidation state exhibit a higher Eb due to the extra Coulombic interaction between photoelectron and the cation core. The ability to discriminate between different oxidation states and chemical environment is one of the major strengths of the XPS technique. Surface Charge Effect Sample surface electrons that are lost due to a photoemission process will increase in positive charge. This charging effect could cause a shift in peak position, or sometimes the peak is lost entirely. Therefore, metal or other conducting samples are usually grounded to the spectrometer for charge compensation. On the other hand, if the sample is a relatively poor conductor or an acceptable conductor but is electronically isolated from any conductive source, e.g., the spectrometer probe, by an effective sea of nonconductor material, the charge can be purposely compensated. For these cases, an axial electron gun in the CMA component of the XPS instrument works effectively to compensate charge for the sample. Even then, the charging effect still occurs due to the photoelectron spectroscopy sampling depth or the depth of field of the neutralization device. If the sample has a nonuniform morphology (e.g., high roughness) including layered systems or clusters, the surface charging effect is also nonuniform and could cause a broadened peak. To avoid the peak shift caused by charging effect, carbon tape is commonly used as a substrate for the deposition of samples. Carbon tape is a good conductor and is thus less affected by the charging effect. During data analysis, the C 1 s peak may be oftentimes used as a reference to calibrate the position of other element peaks in a sample. Background Subtraction The XPS spectrum generally has a staircase-like shape because the background results from all electrons with initial energy greater than the measurement energy for which scattering events cause energy losses prior to emission from the sample. Moreover, during the photoemission process, excited electrons before escaping from the sample surface would collide with electrons of other atoms losing their kinetic energy. The photoelectrons that experienced collision will have lower kinetic energy than photoelectrons that did not experience collision, which contributes to the noise signal of the spectrum. The deeper the relative

Page 13 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

position of a photoelectron from the surface is, the more difficult it is to escape from the sample due to the increasing chance of collision. Therefore, though the X-ray can penetrate into the sample surface on the order of mm, the XPS spectrum only contains information of the top 3–10 nm from the surface of the sample. To subtract such a background from an XPS spectrum, they can use one of these methods: linear background subtraction method, Shirley method, or Tougaard method. For the case of linear background subtraction method (Fig. 10a), a straight line is drawn from a point close to the peak on the low-kinetic energy side of the peak to a point on the high-kinetic energy side and subtracted from the peak. Note that the binding energy becomes higher toward the left side of the horizontal axis. A problem with this method is that it is not highly accurate since the peak area changes depending on the position of the chosen end points. For the case of the Shirley method (Fig. 10b), the background intensity at any given binding energy is proportional to the integrated peak intensity in the binding energy peak range. The accuracy of this method is better than 5 %, and it is easy to use. The most accurate method is Tougaard background correction (Fig. 10c). This is for integrating the intensity of the background at a given binding energy from the spectral intensities to higher binding energies, and it is particularly used in complicated numerous peak overlaps. Quantification The XPS peak intensity could be calculated by the equation below [10], for a given polar emission direction m ¼ cos y (y is scattering angle), primary flux F, analyzer transmission T, detector efficiency D, analyzed area A, and signal electron production cross section sex: 1 ð

 I ðmÞ ¼ FTDADOsex f0 ðz0 , mÞc0 ðz0 dz0

(9)

0

The atomic fraction of pure element A within the surface region, XA, is related to intensity IA and given by IA I1 X A ¼ XA Ii I1 i i

(10)

where Ii is the measured intensity and I 1 i is the sensitivity factor of the i-th element [10]. XPS Analysis of Metallic Nanoparticles Chemical Analysis: Qualitative and Quantitative Binding energy is considered like a “fingerprint” of elemental information. Therefore, XPS has been mainly used for composition and chemical state of elemental analysis and thus useful for analysis of metallic nanoparticles. From the simple nanoparticles which contain 2–3 elements to more complicated nanoparticles, XPS spectra could directly give detailed information on composition and chemical state of each element existing in the nanoparticles. Each element in the sample could be in several oxidation states, and there is usually an overlap of these peaks due to the small binding energy shift. In such of case, peak fitting and deconvolution are necessary which use several functions such as Gaussian, Lorentzian, Gaussian–Lorentzian mixed functions, etc.

Page 14 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Table 4 Composition (at.%) of Ag–TiO2 nanosized composite thin films obtained at different AgNO3 concentrations determined by XPS analysis (Reproduced from Appl. Catal. B-Environ., Vol. 60, Yu J, Xiong J, Cheng B, Liu S, Fabrication and characterization of Ag–TiO2 multiphase nanocomposite thin films with enhanced photocatalytic activity, pp. 211–221, Copyright (2015), with permission from Elsevier) AgNO3 concentration (M) 0 0.01 0.02 0.03 0.04 0.05 0.06

O 64.7 61.8 56.3 55.9 55.1 53.1 50.7

Ti 31.2 29.2 26.6 23.1 21.7 19.1 18.3

Ag 0 5.6 14.5 18.9 21.3 25.7 29.3

Si 1.8 1.6 1.2 1.0 0.9 1.0 0.7

N 2.3 1.8 1.4 1.1 1.0 1.1 1.0

Ag–TiO2 nanocomposite thin films were prepared on quartz substrates by the liquid-phase deposition method, and the surface composition was analyzed with XPS [19]. The XPS results showed that the TiO2 thin films deposited on quartz included Ti, O, C, N, and Si elements. The appearance of C and N was due to residues from the precursor solution, and Si could be from SiO2 substrates. Ag element obviously appeared in Ag–TiO2 composite thin film with increasing amount when increasing concentration of AgNO3 precursor (Table 4). For the element which has several oxidation states, the XPS spectrum analysis must be done more carefully in terms of background subtraction and peak deconvolution. Figure 11 shows the peak fitting and deconvolution of multi-oxidation states of Fe and Au in XPS peaks. In Fig. 11a, the Fe 2p region has been found to include Fe0 and Fe3+ states. Two main distinct peaks with binding energy at 707.1 eV and 720.3 eV correspond to Fe 2p3/2 and Fe 2p1/2 spin–orbit pairs of metallic Fe0. The two peaks at 711.1 and 724.7 eV are the Fe 2p3/2 and Fe 2p1/2 spin–orbit pairs of Fe3+ ions. The two shoulders on the higherenergy side at 714.5 eV and 728.5 eV represent the satellite peaks associated with Fe 2p [20]. For the case of Au, three oxidation states are possible: 0, +1, and +3 (Fig. 11b). In untreated Au/Ce–Al nanostructure, the Au 4f region was characterized by two Au 4f7/2 and Au 4f5/2 spin–orbit pairs, which correspond to Au+ and Au3+ species. No metallic gold species (Au0) were found in the untreated samples. In the cases of treated samples (calcined in oxygen at 350  C and reduced in hydrogen at 350  C), on the other hand, only one 4f7/2 and 4f5/2 spin–orbit pair was found in the Au 4f region (Fig. 11b). It clearly indicates that the reduction of Au cations to form metallic Au0 took place during calcination treatment. Note that Au 4f7/2 peaks at binding energies of 83.8, 84.5, and 86.6 eV correspond to Au0, Au1+, and Au3+ species, respectively [21, 22]. Electronic Structure Analysis Binding energy of an element could be shifted due to not only chemical bonding but also charge transfer effect as described below. It has been found in XPS analysis of Au@Ag core@shell nanoparticles that the Ag 3d peaks of the shell shift toward lower binding energies by enclosing gold cores, whereas the Au 4f peaks shift toward higher binding energies [23]. Figure 12 shows the binding energy shifts of Ag 3d and Au 4f components in Au@Ag core@shell nanoparticles caused by electron transfer from the gold core to the silver shell because of charge compensation mechanism [25, 26]. The binding energy shifts were calculated from deconvoluted XPS data Gaussian–Lorentzian mixed function [24]. Moreover, the binding energy of the Ag 3d component of the silver shell in Au@Ag core@shell nanoparticles shifted toward the value of Ag 3d in pure silver nanoparticles (Fig. 12a) with increase in the silver shell thicknesses. This indicates that the electron transfer mostly occurred near the interface between gold and silver in Au@Ag core@shell nanoparticles.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 11 (a) XPS deconvoluted data for Fe 2p region in Ag50Fe50 nanophase alloy (Adapted from J. Alloy. Compd., Vol. 557, Santhi K, Thirumal E, Karthick SN, et al. Structural and magnetic investigations on metastable Ag–Fe nanophase alloy, pp. 172–178, Copyright (2013), with permission from Elsevier), (b) XPS fitting and deconvoluted data for Au 4f region of Au/Ce–Al nanostructure for untreated samples (1), samples calcined in oxygen at 350  C (2), and samples reduced in hydrogen at 350  C (3) (Reprinted from Appl. Catal. B-Environ., Vol. 115–116, Smolentseva E, Simakov A, Beloshapkin S, et al. Gold catalysts supported on nanostructured Ce–Al–O mixed oxides prepared by organic sol–gel, pp. 117–128, Copyright (2012), with permission from Elsevier)

Surface Analysis As mentioned above, XPS is a highly surface-sensitive technique because it only gives information from mainly the 3–10 nm of the sample surface. By taking advantage of the feature, one can precisely analyze the composition and/or chemical state at the surface. For example, thin films of TiO2 and N-doped TiO2 were prepared by plasma-assisted chemical vapor deposition (PACVD) and had a volume-averaged particle size range from 10 to 20 nm [27]. To evaluate the effects of the plasma treatment and annealing process, XPS analyses were carried out (Fig. 13). For the films prepared in Ar/O2 before annealing, the O 1s area is comprised of a main peak at 529.2  0.4 eV which corresponds to Ti–O bonding in TiO2 and a shoulder peak at 531.2  0.4 eV which is due to C–O, C–O–O, and O–H bonding [28]. Oxygen appeared in excess amount of what should be expected for stoichiometric TiO2 because of the presence of partially oxidized carbon which was contained in metal-organic precursor and addition of chemisorbed Page 16 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

a

0

ΔBE (meV)

–20 –40 –60

Ag 3d5/2 Ag 3d3/2

–80 –100 0

1

2

4

3

Ag Shell Thickness (nm)

b

60

ΔBE (meV)

50 40 30 Au 4f7/2 Au 4f5/2

20 10 0 0

1 2 3 Ag Shell Thickness (nm)

4

Fig. 12 XPS binding energy shifts of deconvoluted Ag 3d (a) and Au 4f (b) peaks in Au@Ag core@shell nanoparticles plotted as function of Ag shell thicknesses (Adapted with permission from [24], Copyright (2012) John Wiley & Son)

Before annealing Air-annealed (400 °C, 4 hrs)

3500

1s

Intensity

3000

2500

2000

1500

1000

526

528

530

532

534

536

538

Binding energy (eV)

Fig. 13 XPS spectra of O 1 s for a film prepared in Ar/O2 measured before and after annealing in air at 400  C for 4 h (Adapted with permission from [27]. Copyright (2007) American Chemical Society)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 14 (a) XPS spectra of Ni 2p region of Ni loaded inside (I-Ni/CNTs) and outside (O-Ni/CNTs) carbon nanotubes; (b) and (c) are the TEM images of O-Ni/CNTs and I-Ni/CNTs, respectively (Adapted from Fuel, Vol. 108, Ma Q, Wang D, Wu M, et al. Effect of catalytic site position: Nickel nanocatalyst selectively loaded inside or outside carbon nanotubes for methane dry reforming, pp. 430–438, Copyright (2013), with permission from Elsevier)

H2O. After annealing in air for 4 h, the shoulder peak decreased dramatically as the result of removal of the chemisorbed species. The annealing process has a major effect on the surface of thin films which could be understood and analyzed using the XPS measurement technique. On the other hand, surface sensitivity of XPS can be used as a “tip” in characterization of nanoparticles loaded inside or outside multiwall carbon nanotubes (MCNTs). Figure 14a shows XPS spectra of Ni loaded at the interior and exterior surfaces of CNTs in the Ni 2p area. It is noticeable that the intensity of the Ni 2p peaks from Ni loaded outside CNTs (O-Ni/CNTs) is much higher than that from Ni loaded inside CNTS (I-Ni/CNTs) although the nickel loading is similar [29]. Because the CNT wall thickness is about 6–7 nm, it could significantly decrease the signal of Ni 2p in the case of I-Ni/CNTs. The use of TEM images (Fig. 14b, c) clearly shows the structure of the I-Ni/CNTs with the Ni nanoparticles loaded inside carbon nanotubes.

X-ray Absorption Spectroscopy (XAS: XANES and EXAFS) Basic Principle and Instrumentation Absorption Edge XAS techniques are closely related to other atomic absorption techniques such as XPS or Auger spectroscopy. The primary difference however is that in XAS analysis, the final state of all electronic transitions is collected, providing a high degree of specificity and sensitivity to the technique. During absorption processes, the wavelength of the X-rays is gradually decreased due to the increasing energy of photons; the absorption coefficient also decreases until it reaches a limit and suddenly enters into another

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 15 The K edge X-ray absorption spectra of As and Se (Adapted from J. Organomet. Chem., Vol. 650, Gailer J, George GN, Pickering IJ, et al. Synthesis, X-ray absorption spectroscopy and purification of the seleno-bis (S-glutathionyl) arsinium anion from selenide, arsenite and glutathione, pp. 108–113, Copyright (2002), with permission from Elsevier)

absorption step. These discontinuities occur at the wavelengths where the energy of an absorbed photon corresponds to an electronic transition or ionization potential and appear in absorption spectra as a sharp edge which is the so-called absorption edge (Fig. 15). For example, the highest energy edge corresponding to the ionization potential of a K electron is called the K edge. Each element on the periodic table has a set of unique absorption edges corresponding to different binding energies of its electrons. This gives XAS high elemental specificity. XAS data are obtained by tuning the photon energy using a crystalline monochromator to a range where core electrons can be excited (0.1–100 keV photon energy). There are two main regions of data in a typical XAS-generated spectrum. The strong oscillations which extend beyond the edge for about 30–40 eV are the so-called X-ray absorption near-edge structure (XANES) area and involve the multiple scattering of excited photoelectrons. The absorption spectrum beyond the XANES region is referred to as extended X-ray absorption fine structure (EXAFS). XANES and EXAFS stem from the same phenomenon. The difference between them is due to the kinetic energy of the photoelectron in each case. At a low energy, the mean free path is high, which induces an important multiple scattering effect. On the other hand, in the EXAFS region, the mean free path of the photoelectrons is limited, so single scattering is the main process observed. XANES The near-edge structure in an X-ray absorption spectrum covers the range between the threshold and the point at which EXAFS begins. As mentioned above, the XANES regime is dominated by multiple scattering of the excited electrons which confers sensitivity to the details of the spatial arrangement of neighboring atoms, not only their radial distances but also the orientations relative to each other. XANES measurements may provide valuable information about the oxidation state, coordination environment, and bonding characteristics of specific elements in a sample. EXAFS EXAFS spectroscopy refers to the measurement of the X-ray absorption coefficient as a function of photon energy above the threshold of an absorption edge. EXAFS is the final state interference effect involving scattering of the outgoing photoelectron from the neighboring atoms. The regions of constructive and destructive interference are respectively seen as local maxima and minima giving rise to the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

a

Au-L3

b Normalized absorption (a.u.)

c

11840

d e f g h

11880

11920

11960

12000

E (eV)

Fig. 16 Normalized XANES spectra (Au L3 edge, *-white line) of samples reduced at T = 150  C, (a) Au–Al2O3, (b) Au–Al2O3–CeZrO2, and (c) Au–Al2O3–CeO2; samples reduced at T = 300  C, (d) Au–Al2O3, (e) Au–Al2O3–CeZrO2, and (f) Au–Al2O3–CeO2; and (g) Au foil and (h) Au2O3 (Adapted from Nucl. Instrum. Meth. A, Vol. 603, Kriventsov VV, Simakova IL, Simakov A, et al. XAFS study of a Au/Al2O3 catalytic nanosystem doped by Ce and Ce – Zr oxides, pp. 185–187, Copyright (2009), with permission from Elsevier)

oscillation in EXAFS. To represent the EXAFS region from the whole spectrum, a function w can be defined in terms of the absorption coefficient m as a function of energy: wðE Þ ¼

mðE Þ  m0 ðE 0 Þ m0 ð E Þ

(11)

where E is the incident photon energy and E0 is the threshold energy of a particular absorption edge. To relate w(E) to structural parameters, energy E is necessary to be converted into the photoelectron wavevector k, and   sin 2krj þ fij ðk Þ X 2 2 N j S i ðk ÞF j ðk Þe2sj k e2rj =lj ðk Þ (12) wðk Þ ¼ kr2j j where Fj(k) is the backscattering amplitude from each of the Nj neighboring atoms of the j-th type with a Debye–Waller factor of sj at distance rj away, fij(k) is the total phase shift experienced by the photoelectron, e2rj =lj corresponds to inelastic losses in the scattering process, and Sj(k) is the amplitude reduction factor due to many-body effects [30]. In order to complete the data extraction, a Fourier transform of this expression is used to convert into frequency space, which results in a radial distribution function where peaks correspond to the most likely distances of the nearest neighbor atoms. Instrumentation XAS instruments are unlike other commercial instruments. The equipment must be assembled from multiple components to suit the needs of the experiment and may involve a significant amount of custom

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 17 (a) Au L3-edge and (b) Au L2-edge XANES spectra of Au foil, Au NPs, Au@Ag NPs, and Au@Ag@Au NPs (Reprinted with permission from [32]. Copyright (2013) American Chemical Society)

engineering. The typical XAS experiment at a synchrotron radiation source may include two main parts: the set of components which produce and deliver a controllable high-intensity monochromatic X-ray beam and the set of instruments specific to the type of measurement, including sample handling, detectors, etc. The most unique point of the XAS instrument compared to other X-ray techniques is the synchrotron X-ray source. This makes the XAS an extremely sensitive measurement where the concentration of the absorbing element can be detected as low as a few ppm. XANES and EXAFS Analysis of Metallic Nanoparticles XANES The great power of XANES comes from its elemental specificity. Because XANES can quickly determine the chemical state of elements that are present in materials, it has found widespread use in environmental chemistry, materials science, catalysts and surface science, etc. An analysis of the XANES spectra has revealed the chemical state of Au in the Au/Al2O3 catalytic nanosystem [31]. Figure 16 shows the normalized Au L3-edge XANES spectra of all reduced samples at 150  C and 300  C. Samples reduced at 150  C have XANES spectra similar to each other and similar for that of Au2O3, so the main part of gold species in these samples is Au3+ cations. On the other hand, samples reduced at 300  C have XANES spectra that are similar to that of the Au foil reference which means the main part of gold is present as Au0. In addition, XANES has found use as a powerful tool to appraise the structure of unique nanoparticle systems, for example, the gold coated by silver core–shell system (i.e., Au@Ag NPs). In an analysis conducted by Nishimura et al., the Au L3- and Au L2-edge XANES spectra were taken for Au foil, pure Au NPs, Au@Ag NPs, and Au@Ag@Au NPs (a double-layer structure). The XANES analysis data is shown in Fig. 17 [32]. The XANES analysis revealed an increase in hole density of the 5d orbital of Au atoms for the Au@Ag NPs over Au foil or pure Au NPs. The phenomenon was even more enhanced for the Au@Ag@Au double-shell NPs and was a key piece of evidence elucidating a charge transfer mechanism from Au to Ag sites in these heterostructured particles. The identification of the charge transfer allowed the stability and optical properties of these plasmonic metal particles to be tuned for sensing and diagnostics applications.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

Fig. 18 Radical distribution functions for Ni standard, Ni/Cr2O3 and Ni/Al2O3 samples thermally treated at different temperatures (Reprinted from Superlattice Mircrost., Vol. 46, Pintea S, Rednic V, Mărginean P, et al. Crystalline and electronic structure of Ni nanoclusters supported on Al2O3 and Cr2O3 investigated by XRD, XAS and XPS methods, pp. 130–136, Copyright (2009), with permission from Elsevier)

EXAFS Ni nanoclusters supported on Al2O3 and Cr2O3 have been found to possess an active metal–oxide support interaction which creates a deformation in the local vicinity of the active metal [33]. The EXAFS measurement was the evidence for the decreasing of the coordination number in the first coordination shell of the nickel atoms (Fig. 18). The diminution of the FT magnitude in Fig. 18 is a result of the reduced average coordination number. The variation of the coordination number could be related with the catalytic activity, so this diminution was considered as proof of the strong interaction between nickel metal and the support oxide.

Conclusion X-ray-based analysis techniques have proven to be a key analytical tool in the study of not only a broad range of materials systems but also for metallic-based nanoparticles. The use of X-ray-based techniques to study metallic nanoparticle systems provides key information such as crystalline properties, particle composition, fine atomic structure and surface properties, as well as a wealth of additional information. Indeed, X-ray-based techniques have become indispensable to materials scientists for the basic and advanced characterization of metallic nanoparticle-based materials. X-ray-based techniques are expected to find even more widespread use as instrumentation becomes more compact, cost-effective, and more widely accessible (e.g., at synchrotron radiation sources). In addition, new analysis techniques are sure to be revealed in light of the versatile nature of X-ray technology. As a result, knowledge in the implementation and interpretation of X-ray-based analysis methods is critical for today’s materials scientists and is an important component in the studies of new researchers today.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

References 1. A. Stanton, On a new kind of rays. Nature 53, 274–276 (1896). doi:10.1038/053274b0 2. H. Markel (2012) “I have seen my death”: How the world discovered the X-ray. PBS NewsHour 3. M. Laue von (1914) Concerning the detection of X-ray interferences. Nobel Lecture-Physics 1901–1921 4. K. Siegbahn, K. Edvarson, b-Ray spectroscopy in the precision range of 1:105. Nucl. Phys. 1, 137–159 (1956) 5. C. Brouder, A history of the X-ray absorption fine structure. Ann. Phys. Fr. 14, 377–466 (1989). doi:10.1051/anphys:01989001404037700 6. J.A. Bearden, X-ray wavelengths. Rev. Mod. Phys. 39, 78–124 (1967) 7. C.F. Bohren, D.R. Huffman, Absorption and Scattering of Light by Small Particles (Wiley, New York, 1998) 8. M. Cooper, X-Ray Compton Scattering (OUP, Oxford, 2004) 9. J. Als-Nielsen, D. McMorrow, Elements of Modern X-Ray Physics (Wiley, Chichester, 2011) 10. D. Briggs, J.T. Grant, Surface Analysis by Auger and X-Ray Photoelectron Spectroscopy (IM Publications and SurfaceSpectra, Chichester, 2003) 11. J.Y. Seo, H.W. Kang, D.S. Jung et al., One-step synthesis of copper nanoparticles embedded in carbon composites. Mater. Res. Bull. 48, 1484–1489 (2013). doi:10.1016/j.materresbull.2012.12.070 12. S. Dutta, B.N. Ganguly, Characterization of ZnO nanoparticles grown in presence of folic acid template. J. Nanobiotechnol. 10, 29 (2012). doi:10.1186/1477-3155-10-29 13. A.T.N. Dao, D.M. Mott, K. Higashimine, S. Maenosono, Enhanced electronic properties of Pt@Ag heterostructured nanoparticles. Sensors 13, 7813–7826 (2013). doi:10.3390/s130607813 14. X. Wang, L. Altmann, J. Stöver et al., Pt/Sn intermetallic, core/shell and alloy nanoparticles: colloidal synthesis and structural control. Chem. Mater. 25, 1400–1407 (2013). doi:10.1021/cm302077w 15. A.R. Denton, N.W. Ashcroft, Vegard’s law. Phys. Rev. A 43, 3161–3164 (1991) 16. J. Zhang, D.N. Oko, S. Garbarino et al., Preparation of PtAu alloy colloids by laser ablation in solution and their characterization. J. Chem. Phys. C 116, 13413–13420 (2012). doi:10.1021/ jp302485g 17. E. Irissou, F. Laplante, S. Garbarino et al., Structural and electrochemical characterization of metastable PtAu bulk and surface alloys prepared by crossed-beam pulsed laser deposition. J. Chem. Phys. C 114, 2192–2199 (2010). doi:10.1021/jp908524u 18. K.M. Siegbahn (1981) Electron spectroscopy for atoms, molecules and condensed matter. Nobel Lecture-Physics 1981–1990 19. J. Yu, J. Xiong, B. Cheng, S. Liu, Fabrication and characterization of Ag–TiO2 multiphase nanocomposite thin films with enhanced photocatalytic activity. Appl. Catal. B-Environ. 60, 211–221 (2005). doi:10.1016/j.apcatb.2005.03.009 20. K. Santhi, E. Thirumal, S.N. Karthick et al., Structural and magnetic investigations on metastable Ag–Fe nanophase alloy. J. Alloy. Compd. 557, 172–178 (2013). doi:10.1016/j.jallcom.2012.12.161 21. A.M. Visco, F. Neri, G. Neri et al., X-ray photoelectron spectroscopy of Au/Fe2O3 catalysts. Phys. Chem. Chem. Phys. 1, 2869–2873 (1999) 22. F.-W. Chang, H.-Y. Yu, L.S. Roselin et al., Hydrogen production by partial oxidation of methanol over gold catalysts supported on TiO2-MOx (M = Fe, Co, Zn) composite oxides. Appl. Catal. A-Gen. 302, 157–167 (2006). doi:10.1016/j.apcata.2005.12.028 23. A.T.N. Dao, P. Singh, C. Shankar et al., Charge-transfer-induced suppression of galvanic replacement and synthesis of (Au@Ag)@Au double shell nanoparticles for highly uniform, robust and sensitive bioprobes. Appl. Phys. Lett. 99, 073107 (2011). doi:10.1063/1.3626031 Page 23 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_13-1 # Springer International Publishing Switzerland 2015

24. S. Maenosono, J. Lee, A.T.N. Dao, D. Mott, Peak shape analysis of Ag3d core-level X-ray photoelectron spectra of Au@Ag core-shell nanoparticles using an asymmetric Gaussian-Lorentzian mixed function. Surf. Interface Anal. 44, 1611–1614 (2012) 25. M. Kuhn, T.K. Sham, Charge redistribution and electronic behavior in a series of Au-Cu alloys. Phys. Rev. B 49, 1647–1661 (1994) 26. W. Drube, R. Treusch, Sublifetime-resolution Ag L3 -edge XANES studies of Ag-Au alloys. Phys. Rev. B 58, 6871–6876 (1998) 27. L.K. Randeniya, A. Bendavid, P.J. Martin, E.W. Preston, Photoelectrochemical and structural properties of TiO2 and N-doped TiO2 thin films synthesized using pulsed direct current plasmaactivated chemical vapor deposition. J. Phys. Chem. C 111, 18334–18340 (2007) 28. A.V. Naumkin, A. Kraut-Vass, S.W. Gaarenstroom, C.J. Powell, NIST X-ray photoelectron spectroscopy database (2000), http://srdata.nist.gov/xps/ 29. Q. Ma, D. Wang, M. Wu et al., Effect of catalytic site position: Nickel nanocatalyst selectively loaded inside or outside carbon nanotubes for methane dry reforming. Fuel 108, 430–438 (2013). doi:10.1016/j.fuel.2012.12.028 30. B.K. Teo, EXAFS: Basic Principles and Data Analysis (Springer, Berlin, 1986) 31. V.V. Kriventsov, I.L. Simakova, A. Simakov et al., XAFS study of a Au/Al2O3 catalytic nanosystem doped by Ce and Ce – Zr oxides. Nucl. Instrum. Meth. A 603, 185–187 (2009). doi:10.1016/j. nima.2009.03.004 32. S. Nishimura, A.T.N. Dao, D. Mott et al., X-ray absorption near-edge structure and X-ray photoelectron spectroscopy studies of interfacial charge transfer in gold  silver  gold double-shell nanoparticles. J. Chem. Phys. C 116, 4511–4516 (2012). doi:10.1021/jp212031h 33. S. Pintea, V. Rednic, P. Mărginean et al., Crystalline and electronic structure of Ni nanoclusters supported on Al2O3 and Cr2O3 investigated by XRD, XAS and XPS methods. Superlattice Mircrost 46, 130–136 (2009). doi:10.1016/j.spmi.2009.01.003

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Nucleation Kinetics, Size Effects, and Surface Treatment Toshio Takiyaa*, Karin Furukawaa, Naoaki Fukudab, Min Hanc and Minoru Yagad a Hitachi Zosen Corporation, Osaka, Japan b Office of Society-Academia Collaboration for Innovation, Kyoto University, Kyoto, Japan c Department of Materials Science and Engineering, Nanjing University, Nanjing, China d Faculty of Engineering, University of the Ryukyus, Okinawa, Japan

Abstract The rate equations that describe nanoparticle formation have been derived on the basis of kinetic theory and statistical thermodynamics. In the formation processes, the critical size of the nucleus of the nanoparticle can be determined to be the nucleus generated under near-equilibrium conditions. Nanoparticles larger than the critical size can continue to grow; nanoparticles smaller than the critical size may become smaller by evaporation. However, under strongly nonequilibrium conditions such as the supersonic expansion of a neutral gas, the concept of a critical nucleus becomes irrelevant because the calculated critical size becomes smaller than the atomic diameter. Consideration of very small clusters from a kinetic standpoint is very important for understanding the early stages of nanoparticle formation under nonequilibrium conditions. In the present chapter, the rate equations that describe condensation and evaporation during nanoparticle formation and growth are described using molecular partition functions based on statistical thermodynamics. The equations are used to determine nanoparticle size, which accounts for the characteristics of the materials. The effects of size and surface treatment of nanoparticles are also described, the objective being practical application of this information.

Keywords Nanoparticle formation; nanoparticle size; size distribution; nanocoating; nanocomposite; kinetic theory; statistical thermodynamics; nonequilibrium phenomena; heterogeneous nucleation

Introduction Nanometer-sized particles, or nanoparticles, are assemblies composed of up to several tens of thousands of atoms or molecules, most of which are located on or near the surface of the nanoparticles. The structure of nanoparticles is responsible for the fact that they have characteristics substantially different from bulk materials in the gas, liquid, or solid phases [1]. Furthermore, because of the small size of nanoparticles, thermal or quantum fluctuations, which have never been observed in macroscopic systems, become an important factor in determining the dynamics of the nanoparticles. The discrete nature of electronic energy levels leads to the emergence of anomalous specific heat, thermal, chemical, and magnetic properties even at room temperature [2]. The appearance of new absorption bands in the range of the near infrared and the far infrared is a phenomenon different from bulk materials. Due to peculiar quantum and surface effects, nanoparticles possess great potential to exhibit new, useful properties. Highly functional devices synthesized from nanoparticles have been studied for use in various fields, such as *Email: [email protected] Page 1 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

semiconductors [3], photocatalysis [4], gas sensors [5–7], secondary batteries [8–10], superconductors [11], and bonding substances [12, 13]. There are two broad categories of methods for creating nanoparticles: gas-phase and liquid-phase method. Cooling occurs during expansion of a vapor evaporated from a solid surface by mechanisms such as gas evaporation [14], arc discharge [15], magnetron sputtering [16, 17], plasma deposition processes [18], and pulsed laser ablation [19–21]. In contrast, coprecipitation processes [22], sol–gel processes [23], reduction processes [24], and hydrothermal synthesis processes [25] are possible ways of controlling the size of nanoparticles in the liquid phase. Use of nanoparticles in a semiconductor device or a chemical sensor is widely expected to facilitate the application of quantum effects. The size of the nanoparticles greatly influences the onset of the effects and is therefore a very important consideration in the synthesis of nanoparticles. Understanding the process of nanoparticle formation with an adequate physical model is necessary for size control. In the conventional droplet model, the number density and particle size are determined on the basis of growth equations after calculating the critical conditions for nucleation [26]. Although the droplet model method has produced many successful results [27, 28], some cases have also been incompatible with the model. In these cases the critical nuclei become very small under strongly nonequilibrium conditions [29]. In such cases, the nanoparticle size and number density must be calculated at an early stage, and kinetic theory must be used to take into consideration dimer formation [30]. In the present chapter, kinetic theory will be used to describe the mechanism of nanoparticle formation. The description will enable the reader to understand what controls the size of nanoparticles and to make use of the size effect. Whereas the rate equations for nanoparticle formation are expressed by statistical mechanics in the kinetic theory, a molecular partition function will assume a large role in the process described here. In section “Kinetics of Nanoparticle Formation” of the chapter, the kinetics and statistical thermodynamics needed to formulate the phenomenon and to compare the process with classical nucleation were reviewed. After providing analytical methods and models for making calculations, an example of nanoparticle formation, the options for controlling size, and an illustration of size effects were presented in section “Size Effect of Nanoparticles.” Surface coating and surface modification of relevance to industrial applications will be introduced in section “Surface Treatment of Nanoparticles.” Finally, conclusions are given in section “Conclusion.”

Kinetics of Nanoparticle Formation In this section, a physical model related to the generation and growth of nanoparticles will be explained in detail, and the assumptions of the model will be scrutinized. The work may prove to be useful for improvement and reconstruction of the physical model and, by extension, may eventually contribute to the design of a device for generating and classifying nanoparticles for industrial use.

Dynamics of Cluster Behavior Nanoparticle formation is based on an equilibrium phase transition that involves atomic or molecular condensation, but at an early stage of the formation process, nonequilibrium phenomena possibly occur. Here, a cluster is defined as an assembly of atoms or molecules before a stable nanoparticle forms. Because cluster generation or nucleation at an early stage of the process will determine the characteristics of the nanoparticles that are produced, it is very important to understand the dynamics of clusters. The following equations characterize reactions that allow for every possible pathway for the generation and growth of atomic clusters [31]:

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

A þ An ! Anþ1 ðcondensationÞ

(1)

Anþ1 ! An þ A ðevaporationÞ

(2)

Am þ An ! Amþn ðcoagulationÞ

(3)

Am ! Amn þ An ðcollapseÞ

(4)

2A þ M ! A2 þ M ðthree-body attachmentÞ

(5)

A2 þ M ! 2A þ M ðdissociationÞ

(6)

Here, the symbol A represents a monatomic molecule or a monomer, An is a cluster consisting of n-monomers (referred to as an “n-cluster”), and M is a molecule of a carrier gas. The rate equations corresponding to the above reactions will be described below. First, the equation for the rate of change of the number density (Z1) of the monomer is expressed as follows: N N X X dZ 1 Z m k 1, m þ Z m nm1, 1  2Z 21 Z b k att þ 2Z 2 Z b vdis ¼ Z 1 dt m¼2 m¼3

(7)

Here, the symbol Zm is the number density of a cluster consisting of m-monomers, Zb is the number density of molecules of carrier gas, and vm1,1, k1,m, katt, and vdis are the rate constants for evaporation, condensation, three-body attachment, and three-body dissociation, respectively. The number N is the maximum size of clusters within the system. The equation for the rate of change of the dimer is similarly expressed as follows: N X dZ 2 ¼ Z 22 k 22  Z 2 Z m k 2m dt m¼1 N X þ Z 4 v22 þ Z m vm2, 2 þ Z 21 Z b k att  Z 2 Z b vdis

(8)

m¼3

Furthermore, the generalized rate equation for the cluster consisting of three or more molecules is derived as follows: n2m X X dZ n n2m Z nm Z m k nm, m  Z n vnm, m ¼ dt m¼1 m¼1 N N  X X   Z n ð1 þ dnm ÞZ m k n, m þ 1 þ dn, mn Z m vn, mn m¼1

(9)

m¼nþ1

In Eq. 9, the first and the third terms on the right-hand side represent an increase by condensation and a decrease of n-clusters by coagulation, respectively. The second and fourth terms likewise represent a decrease by evaporation and an increase by collapse, respectively. Here, dij is the Kronecker delta; in Eq. 9, it enables double counting of the creation and annihilation of n-clusters when clusters of the same size interact with each other.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Jn−1

1

f1 g2

2

f2

3

g3

f3 g4

...

fn-2 gn-1

n−1

fn-1

Jn

n

gn

fn gn+1

n+1

fn+1 gn+2

...

Fig. 1 Liquid droplet model of cluster growth

To use the above-derived equations to calculate the number density associated with cluster formation, the unknown constants that appear in Eqs. 7, 8, and 9 must be determined. The method of determination will be described in the following sections.

Equation for Rate of Change of Critical Nuclei in the Liquid Droplet Model In the liquid droplet model, the nucleation and growth of the atomic cluster can be described as if the cluster has a completely spherical body, as shown in Fig. 1. It may be supposed in Fig. 1 that the growth of a cluster could be based on attachment and detachment of only one molecule. In other words, if Zn is the number density of n-clusters, the rate of change of Zn is expressed by dZ n ¼ J n1  J n dt

ðchange ¼ arrivals at n  departures from nÞ

(10)

In Eq. 10, Jn is the net flux of n-clusters that change into (n + 1) clusters and can be expressed by the following equation: J n ¼ f n Z n  g nþ1 Z nþ1

ðnet flux ¼ visits  returnsÞ

(11)

Here, fn is the rate of attachment of one molecule onto the n-cluster, corresponding to Z1kn,1 in Eq. 9, with dimensions of inverse time. Also, in a similar way, gn is the rate of detachment of one molecule from the n-cluster, corresponding to vn1,1 in Eq. 9. The solution for fi and gi can be derived by using mathematical induction to expand Eq. 11 and then omitting the terms involving Z2 to Zn. If it can be assumed that the net flux of cluster generation is constant, then the following steady condition is true:   dZ n ¼ J n1  J n  0 (12) J 1 ¼ J 2 ¼ . . . ¼ J n J dt If the variable Zei indicates the equilibrium number density of i-clusters, then Eq. 11 becomes the following expression: f n Z en  g nþ1 Z enþ1 ¼ 0

(13)

By using Eq. 13, the variables gi (i = 1 to n) in the solution obtained from Eq. 11, can be eliminated and the following equation was obtained:   ð  Z1 1 1 1 1 Z 1 n dk 1 þ þ ... þ ¼ e J¼ e f n Z en Z 1 f 1 Z e1 f 2 Z e2 Z 1 1 f k Z ek

(14)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

equilibrium

Fig. 2 One n-cluster (right) and n isolated molecules (left)

To obtain the equilibrium number density of n-clusters, Zen, the energy balance between a multiparticle system and a cluster must then be considered. In a system consisting of n isolated molecules and one n-cluster (Fig. 2) in energy states F1 and Fn, respectively, the energy states can be expressed by using molecular partition functions. The equilibrium condition of the n-cluster formed from n isolated molecules is represented by the following equation:   Z en DGn ¼ exp  (15) Z e1 kT Here, k is Boltzmann constant, T is temperature of the intended system, and the variable DGn is the Gibbs free energy change associated with the formation of the n-cluster and is expressed by the following equation: 

Q DGn ¼ kT ln e1 Z1

n



Q  kT ln en Z1

 (16)

Here, Qi is the molecular partition function of i-cluster and occupies a crucial role in considering nucleation and growth of cluster. Therefore, evaluation of Eq. 16 would be necessary to obtain the equilibrium number density, Zen. For that calculation, the value of the molecular partition function of an n-cluster must be determined on the basis of statistical thermodynamics. When the solutions of the normal vibrations and rotational inertia of the partition function in Eq. 16 have been obtained, the equations of nucleation and growth can be set into a system of equations of macroscopic processes by using the solutions. However, there is a simplified method that does not involve evaluating the molecular partition functions. Instead, the energies are rewritten in terms of the chemical potential, m1, of isolated molecules and the Gibbs free energy of the n-cluster, Gn: DGn ¼ nm1 þ Gn

(17)

With respect to the Gibbs free energy Gn, there is a variety of liquid drop models. McClurg [32] has organized the various models in a general formula for Gn: Gn ¼ a1 n þ a2 n

2=3

þ a3 n

1=3

þ a4 lnðnÞ þ

1 X

a5 nð5iÞ=3

(18)

i¼5

In Eq. 18, the constants of a1, a2, a3, a4, and a5 are each determined in a way that is consistent with each model. The explanation of each variable and constant in Eq. 18 is found in the original article, which can

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

be found at the end of this chapter. Under the capillary assumption, an expression involving the potential of bulk state, mb, and the surface tension of the cluster, s, can be used instead of Gn in Eq. 17: DGn ¼ nm1 þ nmb þ 4pr2 s ¼ nDm þ asn2=3

(19) 1=3

Here, Dm represents the difference between m1 and mb, r is the radius of a cluster, and a ¼ ð36pv2 Þ was eventually set, with v representing the volume of one molecule. In Eq. 19, the value of DGn will first increase as the number of molecules (n) constituting the cluster increases, but the value of DGn will begin to decrease after reaching a peak when the effect of the chemical potential difference becomes larger than that of the surface free energy. The critical value is obtained by differentiating Eq. 19 with respect to n and setting the derivative to zero. The number of molecules nc at the critical point is   32 2 s 3 nc ¼ pv 3 Dm

(20)

If DGc indicates the Gibbs free energy associated with formation of the critical cluster, the equilibrium number density of the critical size of the cluster is represented by the following equation:   DGc e e (21) Z nc ¼ Z 1 exp  kT When the critical size is large, the summation of the series in Eq. 14 can be estimated by an integral, as indicated on the right-hand side of Eq. 14. The equilibrium solution for the critical nucleus generation rate is as follows:   DGc e (22) J ¼ K Zel f nc Z 1 exp  kT Here, KZel is generally called the Zel’dovich factor, which is expressed as follows [33]: K Zel

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi  2 e 1 @ DGn ¼  2pkT @n2 n ¼ nc

(23)

The flux J represents the number of critical nuclei generated one unit of volume per unit time and is expressed in an explicit form that can be incorporated into macroscopic equations (e.g., fluid dynamics equations). Equation 22, which was derived from the theory of steady-state transition and equilibrium processes, provides a way to estimate the flux of critical nuclei, and there is still the unknown constant fn to be determined when n = nc. In the next section, Eyring’s transition-state theory [34] will be used to evaluate the rate constant fn.

The Rate Equation of Cluster Growth Cluster growth is considered by applying Eyring’s transition-state theory. When an n-cluster interacts with a monomer, it may become an (n + 1) cluster through an activated complex Anþ1 . The process can be represented by the following equation: A1 þ An $ Anþ1 ! Anþ1

(24)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

As well known in the theory, there is an equilibrium relationship between the original system and the product system Anþ1 , which is represented by using the equilibrium constant K nþ1 in the following equation [35]:   Qnþ1 D  exp (25) K nþ1 ¼ Q1 Qn kT Here, Qnþ1 is the molecular partition function of the activated complex, and D* is the dissociation energy associated with detachment of one monomer from the complex. By introducing a critical state of the activated complex indicated with Qþ nþ1 , we obtain the rate constant fn as follows [35]:   kT Qþ DE nþ1 Z 1 exp  fn ¼ h Q1 Qn kT

(26)

Here, h is Planck constant, and DE is the activation energy that the reaction has to overcome to become an (n + 1) cluster. If we collect the variables into a constant xn, a style of equation familiar in kinetic theory is obtained as follows: f n ¼ xn

P1 1=2

ð2pmkT Þ

an2=3

(27)

where P1 and m are the pressure and the mass of monomer, respectively. The rate constant of evaporation can be derived from Eqs. 13 and 15 as follows:   Z en P1 @DGn 2=3 an exp g nþ1 ¼ e f n ¼ xn (28) Z nþ1 @n ð2pmkT Þ1=2 When the derived rate equations, Eqs. 27 and 28, are substituted into Eq. 11, the number density of each size cluster can be determined, and that leads to the solution for nanoparticle formation.

Size Effect of Nanoparticles In the previous section, the mechanism of nanoparticle formation has been described to enhance understanding of phenomena related to control of nanoparticle size and to facilitate application to actual industrial problems. In the following part of this chapter, some practical examples concerning the effects of nanoparticle size and ways of controlling the size will be introduced.

Synthesizing Size-Selected Nanoparticles The methods for synthesizing nanoparticles are classified as gas-phase processes and liquid-phase processes. The gas evaporation method is popular because it produces nanoparticles from many kinds of materials and facilitates control over environmental conditions during the production. As an example of gas-phase processes, Ward et al. [36] produced b-Mn nanoparticles by placing a tungsten boat containing a small Mn granule inside a chamber with a support tree holding the grids directly above the sample. They found that a pure Mn nanoparticle was obtainable with a liquid nitrogen trap removing moisture content in He gas. At 40 mbar He pressure, they obtained two kinds of nanoparticles (Fig. 3), one in the size range

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Fig. 3 A bright-field TEM image from an area of sample produced at 40 mbar He pressure. The smaller particles that fall into the size range 2–10 nm can be seen isolated across the image (a). The larger particles fall into the size range 12–20 nm and are formed in stringers (b) [36]

2–10 nm, the other in the size range 12–20 nm. The larger nanoparticles were characterized as hollow or doughnut shaped, with a thick outer edge and little or no center. The laser ablation method involving laser irradiation toward a target, evaporation of the target material, and generation of plasma plume is another example of gas-phase processes. Nanoparticles formed in the plasma plume are deposited on a substrate in the processes. Paszti et al. [37] deposited Cu and Ag nanoparticles by this process with a laser fluence of about 10 J/cm2 in an atmosphere of up to 10 mbar Ar gas. Kakati et al. [38] synthesized TiO2 and TiN nanoparticles by supersonic thermal plasma expansion as one other example of gas-phase process. However, this process generally suffers from the fact that the size distribution of the nanoparticles is considerably wide. They noted that the very small residence time of the nanoparticles was a major factor to prevent coagulation of the nanoparticles in the gas phase; possible particle charging by a nonequilibrium electron population was also found to contribute toward reduction of the coagulation of nanoparticles. For liquid-phase processes, how the initial size of nanoparticles impacts the final morphology and configuration of nanostructured materials was investigated by You et al. [39]. Aqueous AgNO3 solution and zinc plate were firstly prepared, and the plate was immersed into the solution for a designed time. Ag nanostructures with different morphologies would grow on the zinc plate through the galvanic replacement reaction at different Ag ion concentrations. According to molecular dynamics calculations, stable amorphous structures appeared when the size of Ag nanoparticles was less than 2.2 nm (Fig. 4). It was clearly found that the initial size of nanoparticles performed an important role by determining the final morphology and configuration of nanostructured materials. Magnetic nanoparticles have been of great interest because of their extensive application in areas such as high-density data storage, biochemistry, hyperthermia, and in vivo drug delivery. Their magnetic properties are size and shape dependent, and the synthesis of well-controlled shapes and sizes of magnetic nanoparticles is therefore important for their applications. Zhang et al. [40] tried to control the size and shape of Fe3O4 nanoparticles by tuning the growth reaction time in a liquid-phase process (Fig. 5).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

a

b 1.5 nm

1.8 nm

2.2 nm

2.8 nm

3.5 nm

4.2 nm

g(r) (a.u)

1.5 nm 1.8 nm 2.2 nm 2.8 nm 3.5 nm 4.2 nm Bulk crystal 3

6

9

12 r (Å)

15

18

Fig. 4 Structure of computer-simulated silver NPs with different sizes in water solution: (a) pair correlation functions, g(r), and (b) structure images. The water molecules surrounding the NPs are not shown here [39]

On the other hand, Iqbal et al. synthesized nanoparticles of lanthanum calcium manganese oxide by inputting citric acid as a liquid-phase method, controlling the size and shape by tuning sintered temperature [41].

Size Effects on Physical Properties The control of nanoparticle size is of interest because some properties of nanoparticle significantly depend on the size. For example, the melting points of nanoparticle are affected by nanoparticle size [42], as is apparent in Fig. 6. Investigating thermal properties of Na nanoparticles, Haberland et al. [43] found that the melting point and latent heat were lower than those of the bulk material for nanoparticles consisting of 135–360 atoms. Especially in the case of nanoparticles consisting of 55–340 atoms, Haberland [44] noted that the melting points were about two-thirds of the bulk melting points (in K), and both the melting points and latent heats fluctuated. There are also interesting phenomena such as premelting [43] and negative heat capacities [45]. Catalytic activity is also affected by nanoparticle size. Bulk Au is inert, whereas Au nanoparticles are very catalytically active. This size dependency has not yet been explained [46]. Joo et al. [47] investigated the effect of Ru nanoparticle size on the catalysis of CO oxidation. They found that the rate of CO oxidation catalyzed by 6 nm Ru nanoparticles was eight times than by 2 nm. Nanoparticles are also used as electrodes of fuel cell which are possibly effective in purification of esgas products in long-duration space travel and conversion of CO in automobile exhaust systems. Geng et al. [48] adopted an approach employed by cyclic voltammetry to measure the activity of electrodes composed of Au nanoparticles on glassy carbon. It was found that the electrodes represented higher activity as the size of nanoparticles became smaller. Silicon is of interest as an anode of Li batteries because it has low discharge potential and is well known to have the highest theoretical charge capacity. However, a problem specific to anode materials is the fact that performance deteriorates as a result of repeated expansions of the materials during charge–discharge cycling. To resolve the problem, Si nanowires were proposed as a novel anode instead of simple Si anode by Chan et al. [49]. They used a vapor–liquid–solid process to synthesize Si nanowires on a stainless steel substrate. Evaluation of the electrochemical properties revealed that the theoretical charge capacity for Si

Page 9 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Fig. 5 TEM images of magnetite nanoparticles with different reaction stages: (a) seeds of 6 nm magnetite nanoparticles; (b) 15 min; (c) 30 min; (d) 45 min; (e) 60 min, after the seed-mediated growth reaction (200  C); (f) 30 min after anneal treatment (300  C) [40]

anodes was reached, and a discharge capacity close to 75 % at the maximum was maintained, with little fading during cycling. In theory, an improved model taking account of diffusion geometry and diffusion length distribution in nanoparticles was proposed to calculate the impedance of a Si anode by Song et al. [50]. When nanoparticles interact with photons, a localized plasmon appears due to electric charge on the surface of the nanoparticles. Applying optical Mie-plasmon spectroscopy for Ag nanoparticles of 2 nm in

Page 10 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Fig. 6 Upper panel: clusters of icosahedral growth pattern. The 2nd, 3rd, and 4th layers are given in yellow, green, and red, respectively. One of the 20 triangular faces is colored in a deeper shade. Lower panel: size dependence of the melting temperature (Tmelt, black), the latent heat of fusion per atom (q, red), and the entropy change upon melting per atom (Ds, blue). The data, given by the open circles, are joined (for N > 92) by splines. Error bars are given only for N above 200, in order to avoid cluttering the figure. The error bars for Tmelt have about the size of the symbol used. The black solid lines, overlapping partially with the blue line, give the calculated entropy change upon melting. The simple hard sphere model gives a surprisingly good fit of the peak shapes [43]

average diameter, Hilger et al. [51] performed experiments which shed some light upon different aspects of these complex interfaces.

Surface Treatment of Nanoparticles Some examples of the size effects of nanoparticles have been introduced. To educe the potential effectiveness and actually control the quality of nanoparticles, it is necessary to treat the surfaces of nanoparticles with nanocoatings. Here, the mechanism of formation of the nanocoatings and the merits of surface treatment are discussed.

Heterogeneous Nucleation The formation of nanocoatings is described by the theory of heterogeneous nucleation. The most important parameter related to the theory is the Gibbs free energy change. Zapadinsky et al. [52] defined this parameter in the two cases: in the first case, the system contains a monomer and a substrate surface, which interacts with the monomer. This interaction is absent in the second case. In the first case, the Gibbs free energy change is defined in terms of DGhom (n) the Gibbs free energy change of an n-cluster resulting from homogeneous nucleation, as follows: DGIhet ðnÞ ¼ ½F het ðnÞ  F hom ðnÞ  ½F het ð1Þ  F hom ð1Þ þ DGhom ðnÞ

(29)

Here, the variable F denotes the Helmholtz free energy, and the subscripts het and hom represent “heterogeneous” and “homogeneous,” respectively. In the latter case, DGhet (n) is formulated as follows:

Page 11 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Fig. 7 (a) Bright-field TEM image of the AA-coated ZnO nanoparticles at low magnification. (b) HRTEM image showing the AA-coated ZnO nanoparticle surfaces at higher magnification. (c, d) HRTEM images of AA-coated ZnO showing the amorphous nature of the AA thin film and the crystal lattices of the ZnO structure [53]

DGIIhet ðnÞ ¼ ½F het ðnÞ  F hom ðnÞ þ DGhom ðnÞ

(30)

Because the equilibrium concentration of an n-cluster can be predicted on the basis of a process similar to homogeneous nucleation, the heterogeneous nucleation and growth on an initial nanoparticle are understood, and the ultimate thickness of nanocoatings is successfully predicted.

Merits of Surface Treatment As an example of nanocoatings, acrylic acid (AA) coatings on ZnO nanoparticles produced by the novel plasma treatment developed by Shi and He [53] are firstly considered. Such a coating can be used in ion exchange experiments for removal of metallic ions in water. Figure 7a–d is the bright-field images of the coated ZnO nanoparticles at various magnifications. Figure 7a, b shows a low-magnification image of a ZnO particle coated with an acrylic acid (AA) film. As can be seen, the coating is uniform over the entire surface of the particle. In the TEM image, it is apparent that although these particles had different diameters, the thickness of the films was the same, the indication being that there was a uniform distribution of active radicals in the plasma chamber. Figure 7c, d is the image at higher magnifications. The uniformity of the AA thin films can be clearly seen in these photographs. The film thickness is about 5 nm. An example of the merits of nanocoatings is the report by Xin et al. [54], who found that the performance of a dye-sensitized solar cell fabricated from a TiO2 nanoparticle film was much improved after the TiO2 nanoparticle film was treated with TiCl4 (Fig. 8).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Current Density, J (mA/cm2)

5

0 0.0 −5

−10 −15

0.2

PCE = 3.86% h = 21 µm; no treatment

0.4

0.6

0.8

1.0 Voltage, V (V)

PCE = 8.35% h = 21 µm; treated with TiCl4 & O2 exposure

−20

Fig. 8 J–V characteristics of DSSCs made after surface treatments with (TiCl4 + O2 plasma) and no treatment sample (Reprinted with permission from [54]. Copyright (2011) American Chemical Society). PCE power conversion efficiency

Pazokifard et al. [55] evaluated silane-treated TiO2 nanoparticles with respect to the self-cleaning properties and photoactivity of an acrylic facade coating. The results showed that both the treated and untreated samples had enough photoactivity. The treated TiO2 nanoparticles were more durable but had less activity than the untreated ones. Addition of an adequate amount of silica-treated TiO2 nanoparticles into the acrylic coatings provided a self-cleaning property in the acrylic facade coatings. Guo et al. [56] made a nanocomposite with alumina nanoparticles and treated the surface with (3-methacryloxypropyl)trimethoxysilane (MPS). The polymeric matrix they used was a vinyl ester resin that consisted of 55 wt% vinyl ester with an average molecular weight of 970 g mol1 and 45 wt% styrene monomers. The treatment resulted in a significant increase in both modulus and strength. The addition of the functionalized nanoparticles had no deleterious effect on the thermal stability of the composite. Hashemi-Nasab and Mirabedini [57] modified the surface of silica nanoparticles with MPS by using a two-step, sol–gel procedure. They evaluated the effects on the modifications of the surfaces of the silica nanoparticles of treatment conditions such as pH, time, and amounts of silane and water. The untreated and MPS-treated silica nanoparticles were used for in situ preparation of silica/styrene–butyl acrylate latex nanocomposites. The results showed that the treatment significantly affected the MPS grafting of nanoparticles as a result of an increase in the rate of silane hydrolysis. Furthermore, the distribution of the treated nanoparticles was better than the distribution of their untreated counterparts. Figure 9 shows TEM micrographs of untreated and MPS-treated silica nanoparticles. Kim et al. [58] used a sol–gel process to synthesize silica nanoparticles and then explored the optimum conditions for treatment of the surface of the synthesized silica nanoparticles with (3-trimethoxysilyl)propyl methacrylate (g-MPS). After treatment of the surface under optimum conditions, the amount of the grafted g-MPS per unit surface area of the silica nanoparticles was nearly the same, regardless of the particle size. Huang et al. [59] have reported that surface treatment of silica nanoparticles with (3-glycidoxypropyl) methyldiethoxysilane improved not only the dispersibility of the silica nanoparticles but also the electrical properties of the composite. These investigators say that surface treatment makes it possible to increase volume resistivity and dielectric strength and to reduce dielectric loss of composites. Dolatzadeh et al. [60] investigated the effect of incorporation of organosilane-modified silica nanoparticles on the electrochemical behavior of the resultant coating material of polyurethane. The studies demonstrated that the modified nanoparticles were very well dispersed in the coating material and

Page 13 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

Fig. 9 TEM images of (a) untreated and (b) MPS-treated silica nanoparticles, (c, d) the thickness of silane on the silica nanoparticle surface [57]

showed that the incorporation of the silica nanoparticles into the polyurethane matrix generally decreased the rate of corrosion of the coated steel substrates.

Conclusion The dynamics of clusters as an early stage of nanoparticle formation have described, and the importance of the role of molecular partition functions has indicated in the description. Use of the molecular partition function facilitates describing the kinetics of cluster formation without the need to distinguish between nucleation and growth, a distinction that must be made with the droplet model. During a nonequilibrium environment like a sudden gas expansion, it is actually important to consider the kinetics at the early stages of nanoparticle formation. As mentioned already, kinetic theory is also important at the initial stage of nanostructure development, which accounts for the characteristics of the secondary structure, the individual nanoparticle. In this chapter, some practical examples were introduced concerning the effects of nanoparticle size and ways of controlling the size. In addition, several studies associated with surface treatment and surface modification were discussed. These treatments were found to be imperative for increasing dispersibility in the solvent and affinity in the matrix.

References 1. G. Cao, Nanostructures & Nanomaterials Synthesis, Properties & Applications (Imperial College Press, London, 2004) 2. R. Kelsall, I. Hamley, M. Geoghegan, Nanoscale Science and Technology (Wiley, West Sussex, 2005)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

3. M. Lu, H. Gong, T. Song, J.P. Wang, H.W. Zhang, T.J. Zhou, Nanoparticle composites: FePt with wide-band-gap semiconductor. J. Magn. Magn. Mater. 303, 323–328 (2006) 4. J. Liqiang, W. Baiqi, X. Baifu, L. Shudan, S. Keying, C. Weimin, F. Honggang, Investigations on the surface modification of ZnO nanoparticle photocatalyst by depositing Pd. J. Solid State Chem. 177, 4221–4227 (2004) 5. H. Keskinen, A. Tricoli, M. Marjam€aki, M. M€akel€a Jyrki, E. Pratsinis Sotiris, Size-selected agglomerates of SnO2 nanoparticles as gas sensors. J. Appl. Phys. 106, 084316 (2009) 6. K. Liao, P. Mao, Y. Li, Y. Nan, F. Song, G. Wang, M. Han, A promising method for fabricating Ag nanoparticle modified nonenzyme hydrogen peroxide sensors. Sensors Actuators B Chem. 181, 125–129 (2013) 7. B. Xie, L. Liu, X. Peng, Y. Zhang, Q. Xu, M. Zheng, T. Takiya, M. Han, Optimizing hydrogen sensing behavior by controlling the coverage in Pd nanoparticle films. J. Phys. Chem. C 115, 16161–16166 (2011) 8. S. Ito, K. Nakaoka, M. Kawamura, K. Ui, K. Fujimoto, N. Koura, Lithium battery having a large capacity using Fe3O4 as a cathode material. J. Power Sources 146, 319–322 (2005) 9. K. Kim, J.H. Park, S.G. Doo, J.D. Nam, T. Kim, Generation of size and structure controlled Si nanoparticles using pulse plasma for energy devices. Thin Solid Films 517, 4184–4187 (2009) 10. K. Kim, J.H. Park, S.G. Doo, T. Kim, Effect of oxidation on Li-ion secondary battery with non-stoichiometric silicon oxide (SiOx) nanoparticles generated in cold plasma. Thin Solid Films 518, 6547–6549 (2010) 11. N.M. Strickland, N.J. Long, E.F. Talantsev, P. Hoefakker, J.A. Xia, M.W. Rupich, W. Zhang, X. Li, T. Kodenkandath, Y. Huang, Nanoparticle additions for enhanced flux pinning in YBCO HTS films. Curr. Appl. Phys. 8, 372–375 (2008) 12. E. Ide, S. Angata, A. Hirose, K.F. Kobayashi, Metal–metal bonding process using Ag metalloorganic nanoparticles. Acta Mater. 53, 2385–2393 (2005) 13. T. Takiya, N. Fukuda, I. Umezu, A. Sugimura, S. Ueguri, H. Yoshida, M. Han, Low temperature bonding of metals by deposition of nanoparticles at the interface. Appl. Phys. Res. 4, 42–47 (2012) 14. K. Wegner, P. Piseri, H.V. Tafreshi, P. Milani, Cluster beam deposition: a tool for nanoscale science and technology. J. Phys. D. Appl. Phys. 39, R439–R459 (2006) 15. Z.H. Wang, D.Y. Geng, Z. Han, Z.D. Zhang, Large critical magnetic field and tunneling anomaly behavior of superconducting carbon-coated Sn nanorods and nanoparticles. J. Appl. Phys. 108, 013903 (2010) 16. S. He, Y. Jing, J.P. Wang, Direct synthesis of large size ferromagnetic SmCo5 nanoparticles by a gas-phase condensation method. J. Appl. Phys. 113, 134310 (2013) 17. L. He, X. Chen, Y. Mu, F. Song, M. Han, Two-dimensional gradient Ag nanoparticle assemblies: multiscale fabrication and SERS applications. Nanotechnology 21, 495601 (2010) 18. S. Lee, H.F. Chen, C.J. Chin, Spectroscopic study of carbonaceous dust particles grown in benzene plasma. J. Appl. Phys. 101, 113303 (2007) 19. E.G. Gamaly, N.R. Madsen, D. Golberg, A.V. Rode, Expansion-limited aggregation of nanoclusters in a single-pulse laser-produced plume. Phys. Rev. B 80, 184113 (2009) 20. M. Nagashima, T. Takiya, S. Furuta, H. Yoshida, Y. Oda, K. Ichimori, S. Ueguri, Fabrication and characterization of ZrO2-Al2O3 films using pulsed laser ablation, in International conference on electronic materials and nanotechnology for green environment, Jeju Island, 21–24 Nov 2010 21. T. Takiya, N. Fukuda, N. Inoue, M. Han, M. Yaga, Y. Iwata, Dynamics of the shock wave accompanied by nanoparticle formation in the PLA processes. Adv. Stud. Theor. Phys. 4, 305–316 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

22. K. Petcharoena, A. Sirivat, Synthesis and characterization of magnetite nanoparticles via the chemical co-precipitation method. Mater. Sci. Eng. B 177, 421–427 (2012) 23. IA. Rahman, V. Padavettan, Synthesis of silica nanoparticles by sol–gel: size-dependent properties, surface modification, and applications in silica polymer nanocomposites – a review. J. Nanomater., Volume 2012, ID132424, 1–15(2012) 24. A. Tabrizi, F. Ayhan, H. Ayhan, Gold nanoparticle synthesis and characterisation. Hacet. J. Biol. Chem. 37, 217–226 (2009) 25. T.T.Q. Hoa, L.V. Vu, T.D. Canh, N.N. Long, Preparation of ZnS nanoparticles by hydrothermal method. J. Phys. Conf. Ser. 187, 012081 (2009) 26. T. Takiya, M. Han, M. Yaga, Thermodynamics of nanoparticle formation in laser ablation, in Thermodynamics Interaction Studies-Solids, Liquids and Gases, ed. by J.C. Moreno-Pirajan (InTech, Rijeka, 2011), pp. 123–146 27. P.G. Hill, Condensation of water vapour during supersonic expansion in nozzles. J. Fluid Mech. 25, 593–620 (1966) 28. J. Feder, K.C. Russell, J. Lothe, G.M. Pound, Homogeneous nucleation and growth of droplets in vapours. Adv. Phys. 15, 111–178 (1966) 29. G.K. Schenter, S.M. Kathmann, B.C. Garrett, Dynamical nucleation theory: a new molecular approach to vapor–liquid nucleation. Phys. Rev. Lett. 82, 3484–3487 (1999) 30. H.P. Godfried, I.F. Silvere, Raman studies of argon dimers in a supersonic expansion. II. Kinetics of dimer formation. Phys. Rev. A 27, 3019–3030 (1982) 31. B.K. Rao, B.M. Smirnov, Cluster growth in expanding copper vapor. Mater. Phys. Mech. 5, 1–10 (2002) 32. R.B. McClurg, R.C. Flagan, Critical comparison of droplet models in homogeneous nucleation theory. J. Colloid Interface Sci. 201, 194–199 (1998) 33. D. Kashchiev, Nucleation: Basic Theory with Applications (Butterworth-Heinemann/Elsevier, Oxford, 2000) 34. H. Eyring, The activated complex in chemical reactions. J. Chem. Phys. 3, 107 (1935) 35. R. Zhang, A. Khalizov, L. Wang, M. Hu, W. Xu, Nucleation and growth of nanoparticles in the atmosphere. Chem. Rev. 112, 1957–2011 (2012) 36. M.B. Ward, R. Brydson, R.F. Cochrane, Mn nanoparticles produced by inert gas condensation. J. Phys. Conf. Ser. 26, 296–299 (2006) 37. Z. Pászti, Z.E. Horváth, G. Petõ, A. Karacs, L. Guczi, Pressure dependent formation of small Cu and Ag particles during laser ablation. Appl. Surf. Sci. 109–110, 67–73 (1997) 38. M. Kakati, B. Bora, S. Sarma, B.J. Saikia, T. Shripathi, U. Deshpande, A. Dubey, G. Ghosh, A.K. Das, Synthesis of titanium oxide and titanium nitride nano-particles with narrow size distribution by supersonic thermal plasma expansion. Vacuum 82, 833–841 (2008) 39. H. You, F. Chen, S. Yang, Z. Yang, B. Ding, S. Liang, X. Song, Size effect on nanoparticle-mediated silver crystal growth. Cryst. Growth Des. 11, 5449–5456 (2011) 40. L. Zhang, R. He, H.C. Gu, Synthesis and kinetic shape and size evolution of magnetite nanoparticles. Mater. Res. Bull. 41, 260–267 (2006) 41. M.Z. Iqbal, S. Ali, M.A. Mirza, Effect of particle size on the structural and transport properties of La0.67Ca0.33MnO3 nanoparticles. CODEN JNSMAC 48, 51–63 (2008) 42. M. Schmidt, J. Donges, T. Hippler, H. Haberland, Influence of energy and entropy on the melting of sodium clusters. Phys. Rev. Lett. 90, 103401 (2003) 43. H. Haberland, T. Hippler, J. Donges, O. Kostko, M. Schmidt, B. von Issendorff, Melting of sodium clusters: where do the magic numbers come from? Phys. Rev. Lett. 94, 035701 (2005)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_15-1 # Springer International Publishing Switzerland 2015

44. H. Haberland, Melting of clusters, in Atomic Clusters and Nanoparticles Les Houches Session LXXIII 2–28 July 2000, ed. by C. Guet. Les Houches – Ecole d’Ete de Physique Theorique, vol. 73 (Springer, Heidelberg, 2001), pp. 29–56 45. M.D. Agostino, F. Gulminelli, P. Chomaz, M. Bruno, F. Cannata, R. Bougault, F. Gramegna, I. Iori, N. Le Neindre, G.V. Margagliotti, A. Moroni, G. Vannini, Negative heat capacity in the critical region of nuclear fragmentation: an experimental evidence of the liquid–gas phase transition. Phys. Lett. B 473, 219–225 (2000) 46. B.R. Cuenya, Synthesis and catalytic properties of metal nanoparticles: size, shape, support, composition, and oxidation state effects. Thin Solid Films 518, 3127–3150 (2010) 47. S.H. Joo, J.Y. Park, J.R. Renzas, D.R. Butcher, W. Huang, G.A. Somorjai, Size effect of ruthenium nanoparticles in catalytic carbon monoxide oxidation. Nano Lett. 10, 2709–2713 (2010) 48. D. Geng, G. Lu, Size effect of gold nanoparticles on the electrocatalytic oxidation of carbon monoxide in alkaline solution. J. Nanoparticle Res. 9, 1145–1151 (2007) 49. C.K. Chan, H. Peng, G. Liu, K. McIlwrath, X.F. Zhang, R.A. Huggings, Y. Cui, High-performance lithium battery anodes using silicon nanowires. Nat. Nanotechnol. 3, 31–35 (2008) 50. J. Song, M.Z. Bazant, Effects of nanoparticle geometry and size distribution on diffusion impedance of battery electrodes. J. Electrochem. Soc. 160, A15–A24 (2013) 51. A. Hilger, T. von Hofe, U. Kreibig, Recent investigations of size and interface effects in nanoparticle composites. Nova Acta Leopold. Neue Folge 92, 9–19 (2005) 52. E. Zapadinsky, A. Lauri, M. Kulmala, The molecular approach to heterogeneous nucleation. J. Chem. Phys. 122, 114709 (2005) 53. D. Shi, P. He, Surface modifications of nanoparticles and nanotubes by plasma polymerization. Rev. Adv. Mater. Sci. 7, 97–107 (2004) 54. X. Xin, M. Scheiner, M. Ye, Z. Lin, Surface-treated TiO2 nanoparticles for dye-sensitized solar cells with remarkably enhanced performance. Langmuir 27, 14594–14598 (2011) 55. S. Pazokifard, M. Esfandeh, S.M. Mirabedini, M. Mohseni, Z. Ranjbar, Investigating the role of surface treated titanium dioxide nanoparticles on self-cleaning behavior of an acrylic facade coating. J. Coat. Technol. Res. 10, 175–187 (2013) 56. Z. Guo, T. Pereira, O. Choi, Y. Wang, H.T. Hahn, Surface functionalized alumina nanoparticle filled polymeric nanocomposites with enhanced mechanical properties. J. Mater. Chem. 16, 2800–2808 (2006) 57. R. Hashemi-Nasab, S.M. Mirabedini, Effect of silica nanoparticles surface treatment on in situ polymerization of styrene–butyl acrylate latex. Prog. Org. Coat. 76, 1016–1023 (2013) 58. J.W. Kim, L.U. Kim, C.K. Kim, Size control of silica nanoparticles and their surface treatment for fabrication of dental nanocomposites. Biomacromolecules 8, 215–222 (2007) 59. X. Huang, Y. Zheng, P. Jiang, Influence of nanoparticle surface treatment on the electrical properties of cycloaliphatic epoxy nanocomposites. IEEE Trans. Dielectr. Electr. Insul. Soc. 17, 635–643 (2010) 60. F. Dolatzadeh, S. Moradian, M. Mehdi Jalili, Influence of various surface treated silica nanoparticles on the electrochemical properties of SiO2/polyurethane nanocoatings. Corros. Sci. 53, 4248–4257 (2011)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Size-Dependant Optical Properties of Nanoparticles Analyzed by Spectroscopic Ellipsometry Kalyan Kumar Chattopadhyay* and Nirmalya Sankar Das Thin Film and Nanoscience Laboratory, Department of Physics, Jadavpur University, Kolkata, West Bengal, India

Abstract Spectroscopic ellipsometry, is a very power full tool for accurately investigating the optical properties of nanostructured materials in thin film form. In this chapter, the effect of dimensions on the properties of various nanoparticles including metal oxides, sulphides etc., have been discussed and reviewed. Basic principles of optical characterization using spectroscopic ellipsometry are presented. Results of ellipsometric studies of nanoparticles in thin film form for the determinations of various optical constants like band gap, absorption coefficient, extinction coefficient, refractive indices etc., and their variation with wavelength are presented. Strengths and weaknesses of the ellipsometric techniques compared with other optical techniques are also discussed.

Keywords Nanoparticles; Ellipsometry; Band gap; Refractive index

Introduction Low-Dimensional Systems and Quantum Confinement Before looking into the broad detail of this chapter, let us have a look on the brief history of development of nanoscience and technology in Table 1. However, the history of thin film and ellipsometry is even older which is summarized in Table 2. Shape and dimension of materials, especially of nanostructures, play key roles to control their electronic and optical properties. Scientists have devoted much effort in the last few decades to know the dimensional variety of small system and to establish clear relationship between their various properties with size. The motions of the free carriers in low-dimensional systems are restricted to two, one, or zero dimensions. The concept of density of states (which may be defined as the number of states per unit energy interval per unit volume that is available to charged carriers at each energy level) was studied in detail to properly describe low-dimensional systems. Without going to the detail of mathematical calculations starting from the Schrödinger equation, the density of states can be expressed in the following general form: N ðE ÞdE / E =2 1 dE d

d ¼ 1, 2, 3

(1)

Here d is the dimensionality.

*Email: [email protected] Page 1 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

E is the energy of electrons and holes, from the bottom of the conduction band for electrons and from the top of the valence band for holes. N(E) is function of energy. This function N(E) is a smooth square root function of energy for 3D systems and results in a quasicontinuous energy spectrum; N(E) is constant for 2D system (i.e., quantum well) and represents a step function. This function is p1ffiffiEffi proportional to 1D (quantum wire) system, and the energy spectrum exhibits singularities near the band edges. This can be demonstrated in Fig. 1. Due to well-known Coulomb interaction, the coupled electron–hole pairs in a material form excitons. Excitonic Bohr radius is defined as the distance between the electron and the hole within an exciton. If the electrons are confined in a potential well, then their energy levels En are quantized. The electronic structure of crystals is modified when the sizes of the nanoparticles are comparable to that of Bohr excitonic radius (rB) of those materials:

Table 1 Brief chronology of development of Nanoscience and nanotechnology Year 1959 1974 1980 1981

Development Richard Feynman delivered his lecture on “There’s Plenty of Room at the Bottom” which conceptually opened up the new area of science related to low-dimensional materials Prof. Norio Taniguchi first used the term “nanotechnology” Prof. K. E. Dexlar elaborated the significance of nanotechnology Scanning tunneling microscopy emerged as the first experimental technique to characterize nanomaterials

Reference [1] [2] [3] [4]

Table 2 Brief chronology of development of Ellipsometry

dN/dE ∼ E1/2

E

2D

dN/dE ∼ const

E

N(E)

3D

N(E)

Polarization of light was discovered by Prof. E. L. Malus Wave theory of light was established by Prof. A. J. Fresnel Vaporization and film deposition was first reported by Grove (1852) and Pl€ucker (1858) Maxwell’s electromagnetic field theory was developed Ellipsometry was first used by Drude Rothen first used the term “ellipsometer” Ellipsometer was first commercially developed and automated with computers

N(E)

1808 1823 1852–1858 1873 1888 1945 1980

1D

[5] [6] [7,8] [9] [10] [11]

dN/dE ∼ E −1/2

E

Fig. 1 Density of states N(E) for charge carriers as a function of the dimensionality of the semiconductor: (3D) threedimensional semiconductor, (2D) quantum well, (ID) quantum wire

Page 2 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

  h2 e 1 1 rB ¼ 2  þ  pe me mh where e is the permittivity of the sample, me is the effective mass of electron, and mh is the effective mass of hole in the nanomaterial. These phenomena are equivalent to the simple example for a particle of mass m in an infinite square well potential of width L in one dimension: ( 0 f or jxj  L=2 : V ðxÞ ¼ 1 f or jxj  L=2 Solving Schrödinger equation with these potentials, the allowed energy levels for the particle in the well can be obtained as En ¼

n2 h2 8mL2

ðwhere n ¼ 1, 2, 3, . . .



The energy of these levels is inversely proportional to the square of the size of the well. For bulk material, the well size is large and therefore the energy level spacing tends to zero and hence no size dependency occurs. In case of lower-dimensional system, the width of the well decreases, the spacing between the energy levels increases and as a result, the particle is strongly bounded by the well. This phenomenon is known as quantum confinement. Strong quantum confinement effects take place if the values of particle radius (r) in the low-dimensional systems are less than excitonic Bohr radius (r < rB). Reversely, if the particle is weakly bound by the nucleus, i.e., if particle radius (r) is greater than Bohr radius (r > rB), the weak quantum confinement effects occur. This effect is important because with the occurrence of quantum confinement effect, properties of material become tunable, and this effect is typically found in sufficiently low-dimensional systems, i.e., nanoparticles.

Zero-Dimensional System: Nanoparticles/Quantum Dots

In the first section, the energies of systems with three, two and one dimensions and the quantum confifinement have been discussed. Now, systems with lower dimensions, i.e., zero-dimensional systems will be focused. Theoretical calculations show that the function N(E) drastically changes for systems in case of zero-dimensional systems or quantum dots. We have already discussed that quantum confinement effect dominates if the excitonic Bohr radius is comparable to the dimension of particle. Quantum dots are generally considered to contain a limited number of elementary electronic charges, such as valance band holes or conduction band electrons. In this case, N(E) is proportional to 1/E and the energy spectrum is represented by a d function as presented in Fig. 2. It is generally observed quantum confinement effect is dominant for particles having dimension less than 10 nm. Nanoparticles synthesized by various methods possess dimension in this range and therefore are the topic of our interest. However, it is better to address quantum dots or nanoparticles as quasi-zerodimensional systems rather than zero-dimensional systems. In the next section, some typical forms of such quantum dots will be discussed.

Page 3 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

“0 D” N(E)

dN/dE ~ δ(E)

E

Fig. 2 Density of states N(E) for a (0D) quantum

Thin Films of Nanoparticles During the early research on nanotechnology, nanoparticles were named as ultrafine particles [12], and very little knowledge about the synthesis size control of nanoparticles was there. However, with the advancement of instrumental facility and basic scientific knowledge on the size control of materials, several physical and chemical techniques were developed to synthesize nanoparticles. Thin film synthesis has emerged as one of the most convenient techniques to obtain regularly sized nanoparticles on prefabricated matrices or substrates. A thin film is defined as a low-dimensional material created by condensing, one-by-one, atomic/molecular/ionic species of matter. In other words, thin films are the thin material layers ranging from fractions of a nanometer to several micrometers in thickness. Thin films are often consisting of nanoparticles having dimensions of different ranges. Several reports are available regarding synthesis of thin films of nanoparticles of various materials [13–16]. In early 1995, a pioneering work by Murray et al. [17] demonstrated the synthesis of thin film quantum dots. The composite thin films of quantum dots of different materials were also reported later [18]. It was also observed that various optical and electrical properties of the nanoparticulate thin films can be easily tuned by simply varying the particle dimensions [19, 20]. For example, optical emission generally blue shifts with decreasing particle size of ZnO quantum particle thin films [21]. However, detail studies on correlation of nanoparticle dimension and their optical properties require efficient characterization tools and advanced instruments like high-resolution transmission electron microscope (HRTEM), atomic force microscope (AFM), dynamic light scattering (DLS), various fluorometers, UV–visible (UV–Vis) spectrophotometers, etc. Along with these tools, a spectroscopic ellipsometric study has emerged as a very efficient tool to characterize thickness and optical properties of nanoparticle thin films. Details about this tool will be discussed in the next section.

Basics of Ellipsometry: Theory and Instrumentation Theory and Basic Principle Spectroscopic ellipsometer deals with the polarized light. Before proceeding further, let us briefly discuss about the polarization phenomena. When the electric field of an electromagnetic wave is oriented in a specific direction, that wave is called as polarized wave. Polarization of light waves may occur as liner polarization, right circular polarization, and elliptical polarization. Ellipsometer is designed to deal with elliptically polarized light [22]. When an electromagnetic wave is incident on a medium, one part of it transmits through the medium and one part gets reflected. The polarization state of the wave is a key Page 4 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Fig. 3 Different types of polarization

controlling factor to determine what fraction of the wave will be reflected. One can assign two basic types of polarization states as parallel (p) and perpendicular (s) depending upon the orientation of the electric vector with respect to the plane of incidence. Complex reflectances rp and rs are defined as the ratios of the amplitudes and phases of the reflected and incident p- and s-polarized electric fields. The intensityindependent ratio of the p- to the s-polarized component of such a wave is termed the polarization state. In case of linear polarization, p- and s-polarized components are in phase. Circular polarization refers to the polarization in which case the phases of p- and s-polarized differ by 90 , but their amplitudes are equal. The geometric terms refer to the locus of the p and s (or y and x) components of the electric field when plotted in the complex plane, and the general polarization state is called as elliptical. The fraction of reflected light depends on the complex refractive index, the angle of incidence, and some basic characteristics of the medium, and here the nanoparticles and their properties modified due to size effects play an important role in ellipsometric analysis (Fig. 3). The medium, i.e., nanoparticles or quantum dots, can be investigated by determining the ratio of reflected and incident intensities Irefl/Iinc = R = |r|2. In other words, since rp and rs are different, the complex reflectance ratio r = rp/rs, which is equal to the ratio of reflected and incident polarization states, can also be determined. This is what the ellipsometry deals with. The ratio r is traditionally expressed in terms of angles c and D as in the equation below: r¼

rp ¼ tan ceiD rs

The reflectance spectrum, r(E), for normal incidence is described in terms of n(E) and k(E) as follows:

Page 5 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Ambient Nanoparticle+ambient Layer of Nanoparticle Substrate

Fig. 4 Schematic of ellipsometric modeling

rðE Þ ¼

ðnðE Þ  1Þ2 þ k ðE Þ2 ðnðE Þ þ 1Þ2 þ k ðE Þ2

The real (e1(E)) and imaginary (e2(E)) parts of dielectric constants are related as e1 ðE Þ ¼ n2 ðE Þ  k 2 ðE Þ,

and

e2 ðE Þ ¼ 2nðE Þk ðE Þ

The spectra are recorded in a user-defined energy range. The ellipsometric angle c and phase difference D are recorded at a definite incidence angle. Where n is the real part of the complex refractive index, A, B, and C are constants. As the signal received by the ellipsometer contains information regarding the path difference traveled by the incident electromagnetic wave, ellipsometry is also a major technique to determine the thickness of nanoparticle layers. However, the optical constants of the nanoparticles will be mainly discussed. The size of the nanoparticles appreciably affects the energy gap, refractive index, and extinction coefficients which can be properly analyzed by fitting the ellipsometric data, i.e., by theoretically simulating the variation of angles c and D with energy and fitting the same with experimental data. The fitting of ellipsometric data is performed considering a multilayer model which includes the base layer of substrate, pure compact layer of nanoparticles, layer of nanoparticles plus ambient at rough interface, and infinitely thick layer of ambient; the schematic of the fitting structure is shown in Fig. 4.

Instrumental Detail Ellipsometer consists of a source (a combination of deuterium and halogen is generally used), a polarizer, and a quarter wave plate which provide a state of polarization which can be varied from linearly polarized light to elliptically polarized light to circularly polarized light by varying the angle of the polarizer. The beam is reflected off the layer of interest and then analyzed with the analyzer. The operator changes the angle of the polarizer and analyzer until a minimal signal is detected. This minimum signal is detected if the light reflected by the sample is linearly polarized, while the analyzer is set so that only light with a polarization which is perpendicular to the incoming polarization is allowed to pass. The angle of the analyzer is therefore related to the direction of polarization of the reflected light if the null condition is satisfied. In order to obtain linearly polarized light after reflection, the polarizer must provide an optical retardation between the two incoming polarizations which exactly compensates for the optical retardation caused by the polarizationdependent reflections at each dielectric interface. Since the amplitude of both polarizations was set to be equal, the ratio of the amplitudes after reflection equals the tangent of the angle of the analyzer with respect to the normal. The schematic diagram of the instrument is presented in Figs. 5 and 6.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Detector

Source

Analyzer Polarizer Nanoparticle Film Substrate

Fig. 5 Schematic of ellipsometer

Fig. 6 Ellipsometer instrument

Fitting Procedure and Dispersion Relations

In the fitting procedure, firstly, the values of c and D were simulated putting probable values of the quantities like thickness and fractional volume of the host for the intermediate two layers. It was observed that the thickness was the most important parameter affecting the fitting procedure. After an appreciable fitting was achieved (i.e., when the experimental and simulated curves of c and D considerably matched), then the dispersion relation was selected for further refined fitting. Several models are available for this purpose, like: • Cauchy equations Bn C n þ þ  l2 l4 Bk C k k ðlÞ ¼ Ak þ 2 þ 4 þ    l l nðlÞ ¼ An þ

where An, Bn, Ak, etc., are fitting parameters. • Sellmeier relations (with exponential extinction coefficient) 

nðlÞ ¼ An þ k ðlÞ ¼ 0

or

Bn l2 l2 C 2n

1=2

h  i1 B3 B2 k ðlÞ ¼ nðlÞ B1 l þ l þ l3

where An, Bn, A1, etc., are fitting parameters. Page 7 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

• Lorentz oscillator (single oscillator) Al2   n k ¼1þ 2 l  l20 þ gl2 = l2  l20 pffiffiffi A g l3 2nk ¼  2 l2  l20 þ gl2 2

2

• Forouhi–Bloomer equations (single term)  2 q X Ai E  E g k ðE Þ ¼ 2 i¼1 E  Bi E þ C i q X Boi E þ C oi nðE Þ ¼ nð1Þ þ 2 i¼1 E  Bi E þ C i

where



Ai B2i 2  þ E g Bi  E g þ C i Boi ¼ Qi 2

B Ai  2 i C oi ¼  2E g C i Eg þ Ci Qi 2 1=2 1 Qi ¼ 4C i  B2i 2

There are some physical constraints, usually valid for semiconductors and insulators in the region of normal dispersion [23]: 1. 2. 3. 4.

n(l)  1 and k(l)  0 for all l. n(l) and k(l) are decreasing functions of l. n(l) is convex (which translates into n00 (l)  0). There is an infliction point linfl such that k(l) is convex if l  linfl and concave if l < linfl.

The Cauchy equations take into account the first three constraints, provided all the fitting constants are positive. This model is good for transparent semiconductors like SiO2, Al2O3, Si3N4, etc. At wavelengths well above the critical wavelength, the Sellmeier relation for n(X) also complies with the first three constraints. This model is applicable for transparent materials and for almost all wide bandgap semiconductors. Forouhi–Bloomer model is effective to describe the refractive index dispersion of materials at energies higher than the bandgap. It is to be noted that the nature of fitting enhances when higher order parameters are taken into account. The following figure (Fig. 7) presents a flowchart of the ellipsometric fitting procedure.

Optical Constants of Semiconductor Nanoparticles: Measurement by Ellipsometry Nanoparticles of various materials exhibit different optical properties. They can be optically characterized by UV–Vis spectrophotometer and by spectroscopic ellipsometry. We will now briefly highlight some of these optical constants of the materials and discuss how to analyze them with ellipsometric measurements.

Absorption Coefficient Absorption of light (or any electromagnetic wave) occurs whenever the light wave is incident upon a medium which is a nanoparticulate thin film in our case. The absorption coefficient a describes the decay Page 8 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Taking 4 layer / 3 layer model for fitting

Loading the experimental data

Putting of probable values of thickness and fractional volume Putting different values of thickness and fractional volume Simulating ψ and Δ Inferior fitting

Good fitting with experimental data

Choosing different dispersion relation

Choosing proper dispersion relation

Putting different values of parameters of dispersion relation

Putting the parameters of dispersion relation

Inferior fitting Best fitting of the experimental and simulated curves

Obtaining the values for n and k

Fig. 7 Ellipsometer fitting flow chart

of the irradiance due to energy dissipation [24]. Alternatively absorption coefficient describes how far an electromagnetic wave of a specific wavelength can penetrate through a medium before being absorbed. An electromagnetic wave will be poorly absorbed by nanoparticles having low absorption coefficient. This is an important property of the material because it determines how much materials will be required for a desired absorption such as in solar cells. a is represented by the following expression: a¼

4pk l

where l is the wavelength of the incident electromagnetic wave and k is the extinction coefficient. The inverse of a describes as the penetration depth. The next sections describes how to determine a for nanoparticles from ellipsometric studies.

Extinction Coefficient Extinction coefficient is another very important optical parameter regarding nanoparticles. When an electromagnetic wave passes through a medium of particles, attenuation of the wave takes place. This attenuation is referred to as extinction [25], and the extinction coefficient is defined as k¼

E ext I 0s

where Eext is the rate of reduction of energy of the incident EM wave and I0 and s correspond to intensity of the incident wave and cross section of the nanoparticles, respectively. It is therefore clear that extinction coefficient is directly related with scattering of light by nanoparticles and obviously with the size of the nanoparticles.

Page 9 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Refractive Index Refractive index is probably the most important optical constant of a material which can be analyzed using spectroscopic ellipsometry. Refraction of an EM wave by a medium is referred to as the change of direction of propagation of the wave due to the presence of the medium. The complex refractive index N has two pats, the real and the imaginary part, and expressed as N ¼ n þ ik where n is the real part and k is the damping constant. n demonstrates the change in the phase velocity of the EM wave due to the presence of the nanoparticles within the medium, and k represents the change in the amplitude of the EM wave [26]. If the density of the nanoparticles in a specific medium is very low, then it is quasi-transparent for the incident EM wave, and here a value of N is almost equal to n in this case. But for a considerable assembly of nanoparticles (thin film or other forms), both n and k have nonzero values. It is also to be noted that in most of the cases, n and k depend upon the wavelength of the incident EM wave. Since spectroscopic ellipsometry is a very effective tool to measure the optical properties in a wide range of wavelength, the variation of both n and k with wavelength can be obtained by analyzing spectroscopic ellipsometric results. The section “Fitting Procedure and Dispersion Relations” describes how to determine n and k by fitting ellipsometric data using various dispersion models.

Dielectric Function Dielectric function or dielectric constant is an important parameter which describes the EM wave propagating through a nanoparticulate thin film. It basically correlates the electrical and optical properties of the nanoparticles on which the EM wave is incident upon. The complex refleflctance ratio p is already mentoined in the section “Theory and Basic Principle.” This parameter is included in the basic theory of ellipsometry. Now the complex dielectric function is related with p by the following expression [26,27]:

1r sin2 F tan2 F þ sin2 F e¼ 1þr where F is the angle of incidence of the EM wave. The complex dielectric function is also expressed as a combination of a real and imaginary part: e ¼ e1 þ ie2 where e1 = n2 – k2 and e1 = 2nk. n and k are symbolizing their usual meaning described in previous sections. However, it is also to be mentioned that like n and k, e1 and e2 are also wavelength-dependent parameters. Analyzing ellipsometric data, variation of both of them can be obtained directly.

Energy Gap Energy gap (alternatively termed as bandgap) is one of the elementary properties of nanoparticles. The simplest definition of bandgap is the energy gap which is forbidden for electrons to reside. The energy difference between the bottom of the conduction band and the top of the valance band is referred to as the bandgap. However, it must be mentioned that with other factors, energy gap is dependent upon the temperature and hence it is better to mention the bandgaps of nanoparticles at a specific temperature. The band structure and energy gap are different for semiconductor, insulator, and conducting nanoparticles. For insulators, the energy gap is large, the conduction and valance bands generally overlap

Page 10 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

in the case of conductors, and semiconductors have small nonzero bandgaps. However, electrical and optical bandgaps differ a bit. Electrical bandgap is considered in cases when an electron is added to the lowest unoccupied molecular orbital, LUMO, or removed from the highest occupied molecular orbital, HOMO, in a molecular species. If a system is excited by photon, the optical bandgap is considered. In this case, a strongly bound electron–hole pair is created by transferring an electron from the ground state to an excited state, in other words, from HOMO to LUMO. Due to this Coulomb interaction, optical bandgap is generally smaller than the electrical energy gap. The bandgap of the nanoparticles can be easily determined using ellipsometric data. After determining a and k by fitting ellipsometric data, the bandgap can be determined using the following relation [28]: E  Eg ¼

pffiffiffiffiffiffi Ea

where E is the energy and Eg is the bandgap of the nanoparticles. Refractive index and bandgap are also correlated by Moss rule [29, 30] which is expressed as follows: n4 ¼ constant The bandgap can be easily determined from the k spectra as the absolute minima of k spectra derived from ellipsometric fitting procedure typically represent the bandgap of the nanoparticles.

Origin of Size Dependencies of Optical Properties This section will discuss various examples of variation of optical bandgap with particle size and try to explain the reasons. A number of models are used to explain the correlation between the optical bandgap and the particle dimension. Effective mass approximation (EMA) has been employed by several research groups to explain the bandgap variation with particle dimension. The bandgap of a semiconductor can be stated as the energy required to create an electron–hole pair such that the Coulomb attraction in between them is negligible [30, 31]. It can be expressed by first writing down the Hamiltonian term for the nanoparticle: 

 ħ2 2 ħ2 2 e2 þ polarzation terms ∇  ∇  H¼ 2me e 2mh h e0 jre  rh j By solving the eigenvalues of the Hamiltonian, one can write down the energy E for the nanoparticles as EðQDÞ ¼ E g ðbulkÞ þ

p2 ħ2 e2  1:786  0:248 E RY e R 2mR2

where 1 1 1 ¼ þ  m me mh and m*e and m*h are the effective masses of electrons and holes, respectively, e is the permittivity, and R is the radius of the nanoparticles. In general, it may be assumed from the above model that the energy bandgap is inversely proportional to the particle dimension. However, it is also found that this model fits Page 11 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

well for nanoparticles with diameter 2.5–4 nm [32]. For particle diameter below that, some discrepancies between the models and the experimental results may occur. Actually, while solving the above equation, the value taken for the effective mass is crucial. The values of effective masses are different for excited and non-excited electrons, and hence, the nature of size dependency of the bandgap calculated from this model also changes with particle dimensions. Bandgap variation of most of the semiconductor nanoparticles is generally explained with this model. The variation of bandgap and other optical properties with particle dimension is explained by employing tight-binding (molecular orbit) model and electron-shell model for simple metal nanoparticles and clusters [33]. In this case, firstly, crystallites are considered without dangling orbitals. These orbitals create localized states in the gap. The dangling orbitals are considered to be saturated by molecules of a colloidal system. Secondly, crystallites are built up by connecting the successive shells of first-nearest neighbors. Now, if the band gap for very small particles or quantum dots is calculated, the binding energy is required to be determined. Hence only the first term of the previous equation is related to the bandgap and others can be neglected. Thus, the Coulomb attraction can be assimilated to the binding energy. Thus the calculation of bandgap does not depend upon the effective masses, and the uncertainty regarding the effective mass values can be avoided resulting in precise values of bandgap as a function of particle dimension only [34]. Not only the optical bandgap, the luminescence properties also vary considerably with particle dimension. When the dimension of the nanoparticles is reduced, a high surface-to-volume ratio is achieved. If the surface-to-volume ratio occurs in nanoparticles, then larger density of dangling bands is expected. As mentioned earlier, the presence of large density of dangling bond in a crystal surface can change a state more localized due to splitting of the state out of the border of the bandgap. In many cases, surface states are responsible for luminescence. Therefore, with increase of surface states, the emission intensity corresponding to these states also increases. Wang et al. [35] established a direct relationship between the crystallite size and the emission intensity by the following expression: I PL / 1=R2 where IPL is the emission intensity and R is the crystallite size. Not only the emission intensity, the emission lifetime is also correlated with the particle dimension. It is well known that the lifetime of emission is directly related to the rate of population of the excited states. Again, the number of photo-carriers nex in the surface states in a crystallite is directly proportional to the number of atoms on the surface ns as reported by Wang et al. [36]. According to them, the number of such surface states is related with crystallite size by the following relation: ns / 1=R where R is the dimension of the crystallite. In order to explain this more clearly, let us consider the fact that photoluminescence lifetime at room temperature strongly depends on the size of the emitting nanoparticles. The lifetime becomes longer with the increment in particle size. Therefore if high excitation power is applied, photoluminescence contributed from larger particles is more easily saturated than that from smaller particles. Hence, if a system of distribution of various particle sizes is considered, with higher excitation power, particles smaller in size will contribute more to the emission spectra than the higher dimension particles. This results in higherenergy shift of the photoluminescence peak. This effect may be avoided by selecting excitation power in such a range the PL intensity is proportional to the excitation power [37].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Along with the bandgap, luminescence properties and other optical parameters like extinction coefficient, refractive index, etc., are found to vary with the nanoparticle dimension. Scaffardi et al. [38] illustrated this fact in their report. According to them, damping constant g for the free electron contribution is expected to increase because of additional collisions with the boundaries of the particles which can be expressed as gfree ðRÞ ¼ gbulk þ C

vF ; R

where R is the radius of the nanoparticle and VF is the velocity of free electron. Thus, the damping factor indirectly affects the refractive indices of the nanoparticles. In addition to all the above examples of origin of size dependency. The moderation of density of states due to size of the nanoparticles may be taken into account. The electronic density of states which controls the elementary properties of matter is different for nanoparticles of different dimensions. Scaffardi et al. also discussed that small particles are supposed to have higher spacings between electronic states and hence they should have smaller density of states. Depending upon this idea, they developed a correction factor or proportionality factor which was expressed as follows: Qsize ¼ Qbulk ½1  expðR=R0 Þ where R is the particle dimension and R0 is the scale factor. This factor takes care of the contribution from bound electrons to the dielectric function. In a bulk material, the energy required to add or remove an electron is called the work function of the same. Taking the lower-dimensional system, for example, in a molecule, the corresponding energies, electron affinity, and ionization potential, respectively, are not equivalent. Nanocrystals can be considered to be intermediary system. In this case, the difference between the two energies, which is called the charging energy, is small [39]. Let us say that charging energy X is not the electronic energy gap; rather, this may be considered as Coulombic energy. It is well known that Coulombic states are similar for all nanocrystals like metals or semiconductors. But the electronic states are appreciably different for metals, semiconductors, and insulators. Rao et al. [39] proposed in their work related to metallic nanoparticles that the charging energies follow a scaling law which can be expressed as X = A + B/d, where A and B are constants, which are characteristic of the metal and d is the particle diameter. In conclusion of this section, it can be summerized that there are two approaches for explaining the origin of size dependencies of optical properties of nanoparticles, i.e., classical approach and quantum confinement theory. Quantum confinement theory considering the effective mass approximation predicts positive, size-dependent energy shift and that shift will be proportional to 1/R2. On the other hand, classical physics also proposes a positive energy shift, but the same will be proportional to 1/R. The classical physics approach involves the dielectric properties of spheres. Several attempts were made to predict this size-dependent variation via computational simulations. Those theoretical simulations were performed on band structure in general nanoparticles to achieve more accurate predictions of the allowed photon transitions between two energy states for quantum dots of a particular size. But the results describing E versus R were not fully satisfying as they did not explain experimental results to large extent. However, most of the experimental results show that particle dimension R is correlated to energy shift having a relation proportional to 1/R. It should be mentioned here that moderation of electronic band structure with size plays the key role to change the optical properties.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Some Results of Size-Dependent Optical Properties Analyzed by Spectroscopic Ellipsometry Preparation of nanoparticle samples for ellipsometric characterization is very important for obtaining accurate results (optical parameters and film thickness). Samples are generally prepared in forms of thin films (i.e., nanoparticles embedded in perfectly reflecting substrate) or they are embedded in other matrices. Samples may be prepared both in physical and chemical routes. However, there are some general precautions which should be taken care of while preparing the samples: 1. Nanoparticles should be evenly distributed on the substrate/matrix; otherwise, so much information will be contributed by the substrate that signals containing the information of the nanoparticles will be merely at noise level. If the sample is in the form of a nanoparticulate thin film, then the film should be continuous for proper characterization. 2. The sample’s roughness should be at least below the value of particle dimension. 3. If the sample is a thin film, then the substrate should be perfectly reflecting (i.e., metal foil, silicon substrate). However, if a glass or transparent substrate is used, then the back of the substrate should be blackened to ensure that no signal comes from the sample holder. 4. The sample’s thickness should be below one micron to achieve accuracy up to angstrom order. Those conditions are easily achieved in the case of physical deposition techniques. However, in case nanoparticles are in powder form and synthesized via chemical methods, then they can be modified by simply depositing them on a cleaned substrate using dispersion technique in appropriate solvent/media. The next section will demonstrate a synthesis technique as an example. Up to now, we have discussed several features of nanoparticles and their density of states, and we tried to focus on the ellipsometric determination of the size-dependent optical properties and discussed the theoretical background. Now some experimental results analyzing size-dependent optical properties with spectroscopic ellipsometry will follow. Since spectroscopic ellipsometer has been proved as an effective tool to characterize nanoparticles, a huge number of scientific reports have been published on these topics. Among the metallic nanoparticles, Beyene et al. [40] reported their work on in situ ellipsometry on growth and plasmonic properties of gold nanoparticles deposited on silica matrix. According to them, a redshift of the plasmon resonance absorption peak occurred as the nanoparticles increase in size. As discussed earlier, they also considered multilayer model with SiO2/Au as main fitting zones. It is described in Fig. 8 that the resonance peaks are redshifted with increasing deposition time or, in other words, with increase in particle size. They explained that as a result of increase in size, the interparticle spacing increased and as a consequence, the overlapping induced dipole field around the neighboring particles increased. This field is responsible for plasmon resonance absorption which increased with particle size. In a similar system (Si QD on SiO2), Wei et al. [41] showed that the dielectric function is strongly dependent on average particle size. They employed Bruggeman effective medium approximation and a Gauss–Lorentz oscillator model to fit ellipsometric data (Fig. 9). The variation of dielectric function (both real and imaginary parts) was also analyzed by them, and they found almost the same results as previous groups [40]. The effect of size on the dielectric function and resonance was also studied by ellipsometry for semiconductor nanoparticles. Tonova et al. [42] reported the effect of Ga nanoparticle dimension on the optical properties studied via ellipsometry. They used Maxwell–Garnett effective medium theory to fit ellipsometric data which is presented in Fig. 10. Page 14 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

Imaginary dielectric function (e2)

140 10 min 20 min 30 min 40 min 50 min 60 min 70 min 80 min 90 min 100 min 110 min 120 min 130 min 140 min 150 min

120 100 80 60 40 20 0

Real dielectric function (e1)

60 40 20 0 −20 −40 −60 −80 −100 0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Photon energy (eV)

Fig. 8 Real-time evolution of the dielectric function of the top Au layer as function of the deposition time [40]

3nm

400

90

200

60

0

30

−200

0

400

90

200

60

0

30

Δ (degree)

ψ (degree)

5nm

−200

0 8nm

90

400

60

200

30

0 −200

0 400

800 600 Wavelength (nm)

400

600 800 Wavelength (nm)

Fig. 9 Measured ellipsometric angles (left) and (right) for 3 nm (open squares), 5 nm (open diamonds), and 8 nm (open circles) nanocrystals compared to fits (solid curves) [41]

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015

a 0.30

tan(ψ)exp tan(ψ)fit

0.25

tan(ψ)

0.20 0.15 0.10 0.05 1.0

b

1.5

2.0

2.5

3.0 3.5 Energy(eV)

4.0

4.5

5.0

5.5

0.6 cos(Δ)exp cos(Δ)fit

0.4 0.2

cos(Δ)

0.0 −0.2 −0.4 −0.6 −0.8 −1.0 −1.2 1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

Energy(eV)

Fig. 10 Experimental (solid line) and best-fit (dashed line) ellipsometric spectra [42]

3.4

fit: Γ = 1.58 + 8.47 / R

3.2

Γ (eV)

3.0 2.8 2.6 2.4 2.2 2.0 4

6

8

10

12

14

16

R (nm)

Fig. 11 Variation of the electron damping parameter with particle size [42]

A resonance peak shifted to higher photon energies with the decrement in particle size. Along with that, they determined the damping factor from ellipsometric measurement, and it was found that the electron damping factor decreased with increase in particle size (Fig. 11). However, they explained the size effects

Page 16 of 24

80 70 ψ (degrees)

60 50 40

Exp65° Cal65° Exp70° Cal70° Exp75° Cal75°

30 20 10 0 200 300 400 500 600 700 800 900 Wavelength (nm)

Δ (degrees)

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_16-1 # Springer International Publishing Switzerland 2015 220 200 180 160 140 120 100 80 60 40 20 0 −20

Exp65° Cal65° Exp70° Cal70° Exp75° CAL75°

300 400 500 600 700 800 900 1000 Wavelength (nm)

Fig. 12 Experimental and calculated data for C and D for the composite thin film with embedded nc-Si particles having an average size of about 6 nm [43]

by the predictions of the classical size theory for the optical properties of small particles and claimed that the obtained value of the Fermi velocity in their work was in good agreement with previous results. More direct studies on optical properties of various nanoparticles were reported by Feng et al. [43] at 2007. They worked on Si–SiO2 composite nanoparticle thin film and employed multilayer fitting structure. In their studies, the effective medium approximation (EMA) with the four-parameter Lorentz oscillator model was used to fit ellipsometric data which are presented in Fig. 12. According to their analysis, the real part of complex refractive index increased in value as the particle size increased. They also showed the variation of extinction coefficient and dielectric function of the Si–SiO2 system varied considerably with particle size. But according to them, the volume fraction of Si nanoparticles within the matrix was more dominant factor than the quantum confinement effect to control the optical parameters. Their results are summarized in Fig. 13. In addition to standard ellipsometric measurement procedures, Hong et al. [44] added another important work in this topic regarding Rayleigh–Mie scattering ellipsometry. They synthesized and analyzed the growth process of a-C:H nanoparticles in Ar–C2H2 and Ar–CH4 plasmas by means of in situ Rayleigh–Mie scattering ellipsometry. They used the ellipsometric data to determine complex refractive index, mean particle radius, and particle size distribution of a-C:H nanoparticles. They found that, in both synthesis procedures, small nanoparticles, having radius 2,000

Pressure (bar) 6 4,000 to ~13,000 3,000 3,700 40,000 500,000

a

Note: Partially adopted from Byrappa and Yoshimura [1]. The work conditions might vary and depend on materials and reaction solutions

operating temperatures and pressures in Table 1. The working conditions of autoclaves vary for different materials, including glass, quartz, and high-strength alloys. Temperature, pressure, and corrosive resistance of reactor materials are the most important parameters for the reactor selection. For safety, pressures generated in a sealed vessel should always be estimated and controlled below the strength of autoclave materials.

Fundamental Mechanisms of Crystal Growth via the Hydrothermal/Solvothermal Process Material synthesis through hydrothermal/solvothermal methods is a crystallization process directly from solutions that usually involve two steps: crystal nucleation and subsequent growth. By controlling processing variables, such as temperature, pH, reactant concentrations, and additives, the final products could be fabricated with desired particle sizes and morphologies. The phenomena underlying the size and morphology control through tuning the process variables are the overall nucleation and growth rates, which depend on supersaturation [19]. The term supersaturation is defined as the ratio of the actual concentration to the saturation concentration of the species in the solution [20]. Although the presence of myriad species in the hydrothermal/solvothermal solution makes it difficult to determine the exact reaction equilibria, several thermodynamic models have been established to calculate the solubility of the species that exist in hydrothermal/solvothermal systems, especially in aqueous solutions [3, 21–26]. For instance, Shock and coworkers proposed a revised Helgeson-Kirkham-Flowers (HKF) model [8], and the solubilities of hundreds of inorganic compounds in aqueous solution have been calculated over wide ranges of conditions (25–1,000
C, 0.1–500 MPa) based on the HKF model [5–8]. Page 3 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Fig. 2 Schematic representation of crystal growth mechanism under the hydrothermal/solvothermal environment

Other researchers subsequently proposed further revised HKF models to calculate the solubility more precisely [27–30]. From the revised HKF model, the equilibrium constant K of species in solution could be calculated as follows (Eq. 1) [30]: 2

lnKT , r ¼ lnKT r , rr 

DH0T , rr þ bð1  r Þ3 þ aDoT r , rr Tr



þ

DoT r , rr 1 1 eT r , rr RT



R



1 1   T Tr



  DoT , r 1 1  e RT (1)

where r* is a density ratio of water (density at actual conditions/density at reference conditions (25
C and 0.1 MPa)); a is a constant, 6.385  105 K1; e is the dielectric constant of water; o is the parameter determined by reaction system; the subscript “r” refers to the reference state; and b is a reaction-dependent constant. The reaction-dependent constant is determined as follows (Eq. 2):   (2) b ¼ l1 DC 0P, T r , rr þ l2 DoT r , rr þ l3 where DC 0P, T r , rr is the heat capacity. l1, l2, and l3 are 97.66 K, 2  104 K1, and 3.317  102 J mol1, respectively. It is obvious from the above equations that the solubility of species in solution strongly depends on the properties of the solvents, including their density and dielectric constant (the dielectric constant is discussed further in section “The Effect of Other Factors”). Nucleation occurs when the solubility of the solute exceeds its limit in the solution (i.e., when the solution becomes supersaturated). The reaction is irreversible; the solute precipitates into clusters of crystals that can grow to macroscopic size [31]. Following nucleation, the crystals grow sequentially or concurrently via a series of processes involving the incorporation of growth units, which have the same composition as crystal entities but possess the same or different structures, from the bulk solution into the existing crystal entities and causing increased sizes. These different processes can be roughly categorized into four steps: transport of units through solution, attachment of units to the surface, movement of units on the surface, and attachment of units to growth sites. The schematic representation of widely recognized mechanisms of crystal growth via hydrothermal/solvothermal methods is shown in Fig. 2. However, there are a lot of debates on the crystal growth mechanisms under hydrothermal/solvothermal conditions, including identifying the growth unit attached to the surface of crystal entities and controlling steps in the crystal growth process. For instance, Schoeman proposed that the growth unit of a zeolite crystal was probably an anionic silicate species, most likely a monomer [32]. Other researchers have proposed that it is also possible that nanoparticles (NPs) are also growth units of zeolite crystal under hydrothermal conditions [33, 34]. To contribute to crystal growth, each growth unit would require its own sequence of governing steps.

Page 4 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

100

80

ε

60

40

0

500 M 250 Pa

20

20

100 70 4 50 25 30 0 0.1

0

100

200

300 t / ºc

400

500

Fig. 3 The static dielectric constant of water as function of temperature with various pressures (Reproduced with permission from Uematsu and Franck [35]. Copyright 1981, American Institute of Physics) Table 2 Properties of commonly used hydrothermal/solvothermal solvents Solvent water Ethylenediamine Methanol Ethanol Toluene Ethanolamine

Formula H2O H2NCH2CH2NH2 CH3OH CH3CH2OH C7H8 HOCH2CH2NH2

Critical temperature (
C) 374 319.9 239.2 241.1 320.6 398.25

Critical pressure (MPa) 22.1 62.1 8.1 6.1 4.2 8

References [35] [40] [41] [41] [42] [43]

As an abundant, low-toxic liquid with a high dielectric constant, water is the most widely used solvent in the hydrothermal/solvothermal process, and hydrothermal chemistry has been widely investigated. The critical temperature and pressure of water are 374
C and 22.1 MPa, respectively. The properties of water vary with the temperature and pressure, especially above the critical point. For instance, as shown in Fig. 3, the dielectric constant of water is 78 at room temperature, which is favorable for the dissolution of polar salts. With increasing temperature and decreasing pressure, the dielectric constant of water decreases to ~10 in the critical region and above the critical point drops dramatically to between 2 and 10 [35]. According to Eq. 1, the dramatic change in the dielectric constant results in a remarkably reduced solubility of solute species, leading to high supersaturation in the solution, and thus facilitates the nucleation growth of crystals. From another aspect, the low dielectric constant allows the dissolution of organic species in the supercritical water, where they act as additives to control the crystal nucleation and growth. Similar trends could also be observed for solvothermal solution systems. Nonaqueous organics have also been widely utilized as solvents in the solvothermal fabrication process, which is analogous to the hydrothermal process. The organic solvents commonly used in solvothermal processes include methanol [36], 1,4-butanediol [37], toluene [38], and amines [39]. Their physicochemical properties are summarized in Table 2. As an alternative to the hydrothermal process, the solvothermal process can make the reactions occur at relatively low temperatures and pressures, and most importantly, the solvothermal process can handle precursors that are sensitive to

Page 5 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Table 3 The brief summary of hydrothermal/solvothermal technique Time 1845–1950 1950–1980

1980–1990 >1990

Research highlights Mineral synthesis (especially quartz with large size and high yields), natural conditions mimic Phase diagrams of aqueous systems with hightemperature and pressure, novel, and advanced materials Material sciences, advanced ceramic powders, physical chemistry of hydrothermal solutions Engineering of hydrothermal process, emergence of solvothermal

Typical equipment Morey autoclaves, flat closures, welded closure Autoclaves with improved sealing: Tuttle-Roy, welded closures, modified Bridgman General autoclaves with Teflon or alloy linings Diverse reactors designed for specific requirements, such as batch reactors, flow reactors

Representative references [54–58] [59–69]

[9, 70–81] [22, 82–103]

water [44]. In addition, the products derived from the solvothermal process are free from foreign anions [45, 46], and morphology [47] or crystal phase control [48] is easily realized.

The Effect of Other Factors Several other factors can significantly affect the crystal nucleation and growth of nanomaterials during hydro-/solvothermal syntheses, such as additives [49], precursors [50, 51], reaction time [52], and filling factor (the ratio of the volume filled with solution to the total reactor volume) [53]. The evolution of hydrothermal/solvothermal technique has been briefly summarized in Table 3.

Synthesis of Nanomaterials via Hydrothermal and Solvothermal Methods Nanostructured materials with controllable size, shape, crystallinity, and tunable surface functionalities have attracted extensive research attention due to their unique optical, electronic, magnetic, mechanical, and chemical properties, which are derived mainly from the quantum confinement effect and large surface-to-volume ratios. The hydrothermal and solvothermal synthetic methods are considered to be among the most promising approaches to preparing nanomaterials. These methods possess many advantages, such as producing a large amount of nanomaterials at a relatively low cost and yielding highly crystalline nanocrystals (NCs) with well-controlled dimensions. Hydrothermal and solvothermal methods can be combined with microwaves and magnetic fields for semicontinuous synthesis of materials having much improved reproducibility and high quality. In this section, the hydrothermal and solvothermal methods employed to prepare oxides; Group II–VI, III–V, and IV NPs; metal-organic frameworks (MOFs); and transitional-metal NPs will be described and summarized.

Metal Oxides Nanoparticles Nanostructured metal oxides are attractive materials that, because of their unique properties, are widely applied in catalytic, ceramic, electrical, optical, and other fields. The properties of metal oxides directly determine their practical applications. Compared with the hydrothermal process, the solvothermal process could produce metal oxides that are smaller and have a narrower size distribution, and they could be produced at a lower temperature [44]. Extensive work has been reported in the preparation of numerous nanostructured metal oxides, such as Al2O3, CuO, Fe2O3, NiO, ZrO2, TiO2, BaTiO3, and SrTiO3, through both hydrothermal and solvothermal processes [19, 104–112]. Common metal oxides obtained through those processes are summarized in Tables 4 and 5. TiO2 is selected as a representative binary metal oxide

Page 6 of 28

Hydrated cerium chloride, octadecylamine, ethylenediamine Zn(NO3)2●6H2O, NaOH (10 Ma)

Hf metal chips ZrCl4, NH4OH, KF/NaOH/LiCl/KBr

Fe(NO3)3●9H2O, Poly(N-vinyl-2pyrrolidone) Copper acetate Al(NO3)3●9H2O, NH4OH, camphorsulfonic acid

CeO2

HfO2 ZrO2

a-Fe2O3

a

Concentration of KOH or NaOH used in the solution

CuO Al2O3

ZnO

Starting materials TiO2 nanopowder, NaOH (15 Ma) MnSO4●H2O, (NH4)2S2O8

Compound TiO2 MnO2

N, N-dimethylformamide Ethanol H 2O

H2O + ethanol + ethylenediamine H 2O H 2O

H2O + ethanol

Solvent H 2O H 2O

3–9 nm ~28 nm in diameter, ~460 nm in length

30–50 nm

Particles size 30–80 nm in diameter 5–20 nm in diameter, 2.5–4 mm in length 40–50 nm in diameter, 0.3–2 mm in length 46 nm in diameter, 1.54 54 mm mu;m in length 25–35 nm 15–20 nm

Table 4 Representative binary metal oxides obtained through hydrothermal/solvothermal process

Nanoparticle Nanotube

Monoclinic nanoparticle Tetragonal and monoclinic nanoparticle Quasicubic nanoparticle

Nanorod

Nanorod

Morphology Nanowire Nanowire

[118] [119]

[117]

[115] [116]

[89]

[114]

References [113] [92]

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Page 7 of 28

TiO2 powder, KOH (10 M)

Nb2O5 powder, KOH

Ta2O5 powder, NaOH

Nb2O5, NaOH

GaCl3, HCl, Zn metal powder

Ba metal, zirconium isopropoxide isopropanol Li metal, niobium ethoxide

K2Ti6O13

KNbO3

NaTaO3

NaNbO3

ZnGa2O4

BaZrO3

LiNbO3

Starting materials Ti[OH(CH3)2]4, Ba(OH)2●8H2O

Compound BaTiO3

Benzyl alcohol

Benzyl alcohol

H 2O

H 2O

H 2O

H 2O

Solvent Ethanol + 2-methoxyethanol + acetic acid H 2O

Table 5 Typical ternary metal oxides achieved via hydrothermal/solvothermal process

20–50 nm

2–3 nm

10 nm

100 nm–3 mm

Nanowire

10 nm in diameter, 500 nm–2 2 mm mu; m in length 60 nm in diameter, 6 6 mm mu;m in length 200 nm

Nanoparticle

Cubic nanoparticle Polyhedron particle Spherical nanoparticle Nanoparticle

Nanowire

Morphology Nanoparticle

Particles size 5–37 nm

[125]

[125]

[124]

[123]

[123]

[122]

[121]

References [120]

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Page 8 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

to demonstrate the effect of the hydrothermal/solvothermal process on the properties of metal oxides. These properties include the crystallinity, crystal phase, morphology, and particle size, which crucially determine the further applications of final metal oxides. Extensive studies have been made to prepare nanostructured TiO2 through hydrothermal/solvothermal processes. Formation of TiO2 goes through two steps regardless of the solvents used: (1) the formation of titanium hydroxides via a hydrolysis reaction and (2) the formation of titania via a dehydration/condensation reaction. The hydrolysis and condensation reactions might take place in series in a highly diluted solution. However, it is quite difficult to separate these two reactions in a concentrated solution. The

Particle number (%)

20

Average = 5.4 nm

15 10 5 0 3 4 5 6 7 8 Diameter (nm)

2 20 nm

9 10

Particle number (%)

Average = 6.0 nm 30 25 20 15 10 5 0 2

3

4

20 nm

5 6 7 8 Diameter (nm)

9 10

Particle number (%)

Average = 8.9 nm 20 15 10 5 0 5

7 8 9 10 11 12 Diameter (nm)

6

20 nm

Average = 7.0 nm

Particle number (%)

30 25 20 15 10 5 0 20 nm

3

4

5

6 7 8 9 10 11 Diameter (nm)

Fig. 4 (continued)

Page 9 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Fig. 4 Transmission electron microscope (TEM) images of TiO2 obtained in the solvothermal process with various TiCl4/ acetone (AC) ratios and operating temperatures. The TiCl4/AC used was 1/90 (a), 1/30 (b, d), 1/15 (c), 1/10 (e, g), and 1/7 (f). The operating temperature used is 110
C (a, b, c, e, f), and 140
C (d, g). The graphs in the column on the right indicate the particle size distribution obtained from the TEM images shown on the left (Reproduced with permission from Wu et al. [133]. Copyright 2007, American Chemical Society)

condensation reaction inevitably occurs with excessive OH groups [126], leading to the formation of clusters, polymers, or NCs of titania. These clusters are the embryos of titania crystals that can further grow into large particles during the subsequent heat treatment [112]. The properties of the final titania products can be tuned via adjusting the processing parameters. The presence of a mineralizer is one of these important parameters. HNO3 has been reported to be a better mineralizer in the hydrothermal process to obtain monodispersed NPs with homogeneous composition than NaOH, KOH, HCl, HCOOH, or H2SO4 [127]. The mineralizer concentration also greatly affects the phase and morphology of hydrothermal titania products. Under hydrothermal conditions, the phase and morphology of titania will transfer from rutile nanorods to anatase NPs, brookite nanoflowers, dititanate nanosheets, and trititanate nanoribbons sequentially, as the pH is varied from highly acidic (6 M HCl) to highly alkaline (10 M NaOH) [128] or KOH [129], with tetrabutyl titanate or TiCl4 being used as the precursor. When titania powders are the precursors and NaOH is the mineralizer, only sodium titanate nanotubes could be produced; increasing the concentration of NaOH can further enhance the nanotube to unreacted titania particle ratio [130, 131]. Interestingly, after ion-exchange treatment of the sodium titanate nanotubes, the H-titanate nanotubes are transformed to anatase NPs with rhombic shape when the pH > 1 and turned into rutile nanorods with two pyramidal ends when the pH < 0.5 [131]. Another crucial factor is solvent. Water is the solvent in the hydrothermal process and usually incorporates into the resultant titania product. However, the hydroxyl contents from a water-based ambient condition could be eliminated by replacing the water with organic solvents [132]. In addition, it could be easy to control phase and morphology by merely adjusting the ratio of Ti precursors and organic solvents. For instance, a low TiCl4/acetone (AC) ratio (1/10) resulted in rutile TiO2 nanofibers when TiCl4 was the precursor and AC was Page 10 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

the solvent used in a solvothermal process (Fig. 4) [133]. The employment of organic solvents is also beneficial if the intent is to dope anions into the titania phase [134, 135]. Additives that act as structure-directing agents during the crystal growth are also crucial factors in the hydro-/solvothermal process. For instance, anatase TiO2 NPs can be transformed from an irregular spherical shape to a rod-like shape in a solvothermal process if acetic acid is introduced to the solution. The anisotropic growth of the titania crystal was attributed to the attachment of acetic acid to the crystal plane [136]. Depending on the precursors and solvents used, the additives could change the phase and morphology of final titania products. For instance, in the ethanol/TiCl4 solvothermal system, rutile nanofibers or nanorods were observed with f = 1, where f is defined as the volume ratio between ethanol and acetic acid. A mixed anatase-rutile phase was obtained when 0.33 < f < 10, and pure anatase NPs were produced in the rest of the f region [137]. The morphology evolved from the submicrometer aggregates to microspheres and eventually to submicrometer aggregates by decreasing the f [137]. Some additives can also function as a solvent, especially in a multiple-solvent system. For instance, anatase nanotubes, nanosheets, nanorods, and nanowires could be obtained in a solvothermal solution containing aqueous NaOH ethanol [138], aqueous NaOH-ethylene glycol, or polyethylene glycol [139, 140]. This makes it difficult to distinguish additives from solvents and to further identify the role of additives, solvents, and mineralizers and thus leads to an ambiguous crystal growth mechanism.

Group II–VI Nanoparticles Group II–VI semiconducting nanomaterials have potential applications in the optoelectronic and energy industries. These nanomaterials include ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, and HgTe as well as their doped and ternary compounds. Nanospheres of ZnS composed of 4 nm hexagonal NCs can be solvothermally synthesized in ethylene glycol using a single precursor, Zn(NCS)2(C5H5N)2, and an 80 % filling factor [141]. The nanospheres grow larger with increasing reaction temperature, reaching a size of 200, 350, and 450 nm in a 12 h reaction period at 160
C, 180
C, and 200
C, respectively. Polycrystalline Mn-doped ZnS nanospheres can be synthesized in oleic acid using ZnCl2, MnCl2, and sulfur powders as the precursors at 180
C for 60 h. These large (100 nm) nanospheres are actually aggregates of many tiny (10 nm) crystalline ZnS NPs [142]. Besides spheres (0-D), nanoplatelets (2-D) and nanorods (1-D) of ZnS can also be prepared hydrothermally or solvothermally [143, 144]. Cubic ZnSe and ZnTe NPs (NPs) can be synthesized via a solvothermal method that uses precursors that are less toxic than those used in the traditional chemical vapor deposition method [143]. The sources for Zn can be Zn(CH3COO)2, ZnSO4, or Zn powders, and the precursors for Se and Te are elemental Se and Te powders or Na2SeO3 and Na2TeO3. Common solvents for the synthesis include ethylenediamine, ammonia, triethylamine, and hydrazine, and the pH usually maintains at 9–10. For example, crystalline ZnSe NCs can be synthesized by heating Zn and Se powders in a 1:1 ratio in a 90 % filled Teflon-lined autoclave at 120
C for 6 h [145]. These nanomaterials consist of a mixture of NPs, short nanorods, and nanocubes with broad size distributions. ZnSe nanorods with more controllable morphology can be obtained by solvothermal reaction of ZnSO4 and Se in triethylamine with the presence of the reducing agent KBH4. The width of the nanorods is mostly between 30 and 70 nm [146]. ZnSe nanorods can be synthesized by heating Zn and Te powders in a 1.1:1 ratio in a 70 % filled Teflon-lined autoclave at 170
C for 16 h. The nanorods are very uniform with a typical width of ~50 nm [147]. Highly uniform CdS spheres can be obtained using an ethylene glycol solvothermal method. Cd(NO3)2 and thiourea are used as precursors, and polyvinylpyrrolidone (PVP) is employed as a capping agent [148]. A stainless steel autoclave lined with polytetrafluoroethylene (PTFE) is used as the reactor, and the filling factor is 70 %. The CdS NPs grow from 150 to 450 nm if the reaction time is increased from 5 to 75 min at 140
C [148]. The NP size also increases with increasing Cd2+ concentrations. For example, the particle size increases from 100 to ~400 nm when the total concentration of Cd2+ ions is increased from Page 11 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Counts (a.u.)

600

400

200

30 nm

0 10

20

30

40

50

60

2q/degrees

Fig. 5 X-ray diffraction and selected-area electron diffraction (SAED) (left) and transmission electron microscope image (right) of the thioglycolic acid-stabilized CdTe nanocrystals (Reproduce with permission from Zhang et al. [145]. Copyright 2003, John Wiley and Sons)

0.02 to 0.2 M while maintaining the temperature, time, and concentration of capping agents at 140
C, 8 h, and 0.2 M, respectively [148]. In contrast, the NP size reduces with increasing PVP concentration, from 310 to 210 nm, when PVP increases from 0.05 to 0.5 M. These PVP molecules might function as nucleation sites during crystal growth. Higher PVP concentrations mean more available nucleation sites, which mitigate particle growth and result in smaller particles [148]. This method can also be applied to other sulfides, such as HgS, Ag2S, and Bi2S3 [148]. Thioglycolic acid and dithiol glycol can also be used as S sources for the synthesis of CdS NPs via hydrothermal or solvothermal methods [149, 150]. Highly crystalline cubic zinc-blende CdTe has been obtained by the hydrothermal reaction of CdCl2 and NaHTe in the presence of stabilizing agents such as thioglycolic acid, 3-mercaptopropionic acid, or 1thioglycerol and at temperatures ranging between 100
C and 180
C (Fig. 5) [145, 147]. The rate of crystal growth is faster at higher temperature, as confirmed by both powder X-ray diffraction (XRD) and the red shift of the absorption spectra. Longer reaction time results in a larger crystal size and a larger red shift in their photoluminescence spectra due to the Ostwald ripening effect. In contrast, higher reactant concentration favors nucleation and produces smaller crystals. Although mercury chalcogenides possess some unique properties and can be applied to sensors, photoelectronic devices, and transducers, but because the toxicity of mercury is high, research on these materials is very rare compared with the research on other II–VI compounds [151]. Traditional wet chemistry methods can also be utilized to grow II–VI NPs with well-controlled shapes and sizes [143, 151], but hydrothermal and solvothermal methods have the advantage of one-pot synthesis without the need of post-synthetic annealing to crystallize the NPs and thus provide greater potential for scale-up.

Group III–V Nanoparticles Group III–V nitrides, arsenides, and phosphides are very important direct band-gap semiconductors that have broad applications in optoelectronic devices such as light-emitting diodes, lasers, photodetectors, and optical amplifiers. The most important III–V compound is GaN, which has been commercially used in the LED bright-display panels. The breakthrough in solvothermal synthesis of GaN was first reported by Xie et al. [152]. Polycrystalline GaN with a mixture of hexagonal and rock salt phases can be produced by a benzene solvothermal reaction of GaCl3 and Li3N at 280
C for 6–12 h in a silver-lined stainless steel autoclave with a filling factor of 75 %. The chemical reaction is shown in Eq. 6: GaCl3 þ Li3 N ! GaN þ 3LiCl

(3)

Page 12 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

The LiCl salt is a by-product and can be removed by ethanol rinsing. The total yield is up to 80 %, and GaN shows an average diameter of 32 nm. However, no quantum effect is observed because the size is much larger than its Bohr exciton radius (11 nm). This novel benzene solvent method can be carried out at much lower temperature than that required in traditional methods. For example, hexagonal GaN is synthesized at around 900
C by traditional gas-phase reaction between Ga metal and ammonia gas. GaCl3 and NaN3 can also be used to synthesize GaN NPs in tetrahydrofuran (220
C) or toluene (260
C) via a solvothermal method [153]. It is a time-consuming reaction (2–4 days), and extreme caution should be exercised during the reaction because the metal azides are thermally unstable and shock sensitive. The product is a mixture of NPs and nanorods. The NPs have wide diameter distribution, from 20 nm to several hundred nanometers. The reaction mechanism is shown in Eqs. 4 and 5: GaCl3 þ 3 NaN3 ! GaðN3 Þ3 þ 3NaCl

(4)

GaðN3 Þ3 ! GaN þ 4N2

(5)

GaN NPs having a diameter of several hundreds of nanometers can also be synthesized using anhydrous ammonia as a solvent (Table 5) [154]. The anhydrous ammonia is condensed into a quartz tube containing the reactants, and the tube is flame sealed. The pressure in the quartz tube is balanced with water held in an exterior pressure vessel at a pressure of about 10,000 psi. The temperature gradient along the tube is 10
C/cm. Metal Ga, GaI2, or GaI3 can be used as Ga sources. Additives such as NH4I, NH4Cl, or NH4Br are required to generate GaN with Ga as the source. Temperature is critical in the synthesis of GaN when this ammoniathermal method is used. No GaN can be obtained below 250
C. When the growth temperature is below 300
C, only cubic phase and amorphous GaN NPs can be produced, and they are only deposited on the bottom of the tube reactor. In contrast, above 440
C, most products are composed of hexagonal GaN, and they are deposited on the middle wall of the tube. As-synthesized cubic GaN can be transformed to hexagonal GaN by annealing above 440
C. GaI2 or GaI3 can also be used as the Ga source. The detailed experimental conditions are listed in Table 6. GaI2 will disproportionate into Ga and GaI3 immediately in ammonia. Gallium imide-iodide (Ga-NH-I) can be prepared by reaction of GI3 with KNH2 in ammonia. When it is used as a precursor, only cubic GaN NCs can be obtained. However, this experiment is highly non-reproducible, probably due to an uncontrollable introduction of impurities like Si grease or poly (dimethylsiloxane) in the imide synthesis reaction [154]. GaN NPs with a very narrow size distribution (the average diameter is ~4 nm) can be synthesized via a toluene solvothermal method at 240
C if Ga cupferron [Ga(C6H5N2O2)3] (a metal-organic complex) is used as the Ga source and hexamethyldisilazane (HMDS) [(CH3)3SiNHSi(CH3)3] is used as the nitriding reagent [155] with a filling factor of 30 %. The diameter increases from 4 to 12 nm with decreasing Ga cupferron/HMDS by five times. It is believed that the Ga cupferron is first decomposed into Ga2O3 NPs, which then react with the HMDS at high temperature to form GaN NPs as shown in the following equation (Eq. 6): GaO1:5 þ ðCH3 Þ3 SiNHSiðCH3 Þ3 ! GaN þ ðCH3 Þ3 SiOSiðCH3 Þ3 þ 1=2 H2 O

(6)

With the presence of the capping reagent cetyltrimethylammonium bromide (CTAB), the diameter can be further reduced to 2.5 nm with a narrower size distribution (from 1 to 5 nm). If the Ga cupferron is replaced with GaCl3 as shown in Eq. 7, the Ga NPs become larger with a wider size distribution (from 5 to 15 nm):

Page 13 of 28

b

Fill Temp pgm., C (16.67 h unless mmol (%)a noted) Exp Reactants (mg) NH3 (I) No acid, or a small amount of NH4I 1 Ga (20) 19.2 58 495 2 Ga (33), NH4I 19.7 61 413 (2.5) 3 Ga (18), NH4I 20.1 59 506 (3.5) (II) ~0.5 M equiv of NH4I, temperature varied 4 Ga (22), NH4I  66 204 (23) Above tube Reheat 261 Above tube Reheat 298 5 Ga (27), NH4I 19.7 64 318 (26) 6 Ga (26), NH4I 19.7 64 349 (26) 7 Ga (31), NH4I 19.2 60 383 (32) 8 Ga (31), NH4I 19.2 57 406 (30) 9 Ga (29), NH4I 19.2 62 425 (29) 10 Ga (31), NH4I 19.7 65 430 (31) 11 Ga (28), NH4I 19.2 63 446 (28) 12 Ga (27), NH4I 19.2 64 448 (28) 13 Ga (22), NH4I  61 470 (16) 14 Ga (20), NH4I 19.2 60 497 (20)




Nothing Nothing

  29 19 17 21

ow pdr, 55 % h-GaN ow pdr, 50 % h-GaN ow pdr, 65 % h-GaN ow pdr, 75 % h-GaN ow pdr, 75 % h-GaN ow pdr, 80 % h-GaN

Nothing

Nothing

Nothing

22

or dep, 100 % c-GaN

or dep, 80 % c-GaN

yl dep, 100 % c-GaN yl cls, 100 % c-GaN

Nothing

Nothing

Nothing Nothing Nothing

yl dep, 90 % c-GaN

Nothing

Middle of tubec

 

No reaction

9

No reaction 24

yld (mg)d

yl pdr + Ga metal tan pdr, 95%c-GaNe tan-wh pdr, 55 % c-GaN + Ga metal ow pdr, 65 % h-GaN

gr pdr, 85%h-GaN

ow pdr, 95 % h-GaN

bottom of tubec

Products: appearance, X-ray analysis, and yield

Table 6 Experimental data for the solvothermal synthesis of GaN nanocrystals from Ga metal and Ga iodides precursors [154]

19

21

1.0

3

4

yld (mg)a

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Page 14 of 28

29

GaI2 (100)

19.5

62

(III) 1 M equiv of NH4I 15 Ga (30), NH4I 19.7 64 (60) 16 Ga (70), NH4I  64 (140) (IV) 0.5 M equiv of NH4I, fill varied 17 Ga (25), NH4I 12.8 42 (25) 18 Ga (28), NH4I 22.4 72 (28) (V) Multistep temperature programs 19 Ga (42), NH4I 19.7 59 (38) 20 Ga (31), NH4I 19.2 59 (30) 21 Ga (19), NH4I 18.3 62 (18) 22 Ga (37), NH4I 19.2 60 (39) 23 Ga (28), NH4I 19.7 58 (28) (VI) NH4Cl or NH4Br mineralizer 24 Ga (25), NH4Cl 19.8 63 (9) 25 Ga (40), NH4Cl 13.0 41 (13) 26 Ga (20), NH4Br 20.1 64 (20) 27 Ga (28), NH4Br 19.7 66 (19) (VII) GaI2 or GaI3 precursor 28 GaI2 (100) 19.4 ~60 ow pdr, 60 % h-GaN

ow pdr, 80 % h-GaN

466

435 (64 h)

ow pdr, 80 % h-GaN

ow pdr, 65 % h-GaN

455

350; 25; 455

ow pdr, 100 % h-GaN

454

ow pdr + or cls, 65 % h-GaNg

405; 455

ow pdr, 100 % h-GaN

Nothing

360; 510

453

ow pdr, 50 % c-GaN



306 (40 h); 25; 455 350; 455

ow pdr, 80 % h-GaN

305 (48 h); 25; 410

ow pdr, 100 % h-GaN

461

10

4

2

3

5

ub- or dep 90 % c-GaN lb- gr dep 60 % hGaN gr dep, 100 % hGaN

gn dep, 100 % c-GaN ow dep, 60 % hGaN yl + gr cls, 80 % c-GaN yl + gr cls, 70 % hGaN

>8

10

or cls, 100 % c-GaN yl + wh cls,85 % hGaN or + gr cls, 95 % c-GaN

gr dep, 95 % h-GaN

Nothing

or dep, >95 % c-GaN or cls, c-GaN

yl-or cls, 75 % c-GaN

8

31

13

3

ow pdr 85 % h-GaN

459

14 gr cls, h-GaNf

ow pdr, 100 % h-GaN

514

453

(continued)

14

15

13

15

12

0.2

3.5

10

40

5

21

0.1

6.5

0.9

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Page 15 of 28

GaI3 (200)

33

20.1

mmol NH3 19.2 19.2 19.2 66

Fill (%)a 61 64  491

Temp pgm.,
Cb (16.67 h unless noted) 416 419 466 Nothing

bottom of tubec or pdr, 100 % c-GaN or-tan pdr, 80%c-GaN gr pdr, 60 % h-GaN

yld (mg)d 6 11 17

Products: appearance, X-ray analysis, and yield Middle of tubec Nothing Nothing or dep, >95 % c-GaN or dep, 100 % c-GaN

12

6

yld (mg)a

a

pdr powder, dep. deposit, cls clusters of crystals,  datum not available, or orange, yl yellow, gr gray, gn green, wh white, ow off-white, ub upper band, lb lower band Fraction of volume filled with solid and liquid at room temperature b Actual temperatures measured in thermowell at least 3 h after heating begins (typically ~50
C below furnace setting). The furnace on time at each temperature is 16.67 h unless noted otherwise c Percentages are indicate the fraction of crystalline GaN in the cub and hex form: only d Isolated yield. Not measured for all experiments e May contain an amorphous product f Tube burst from excess H2 pressure when exterior counterpressure was relieved g C–GaN clusters may have fallen from above

Reactants (mg) GaI3 (80) GaI3 (100) GaI3 (273)

Exp 30 31 32

Table 6 (continued)

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Page 16 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

GaCl3 þ ðCH3 Þ3 SiNHSiðCH3 Þ3 ! GaN þ 2SiðCH3 Þ3 Cl þ HCl

(7)

Metal-ion-doped GaN NPs can be synthesized using a similar method with slightly different precursors. For example, ferromagnetic Mn-doped GaN with potential applications in spintronics can be synthesized by using (Ga1xMnx) (C6H5N2O2)3(1x)+2x as the precursor [156]. 3 % Mn-doped GaN NCs can be obtained by the reaction of (Ga0.97Mn0.3)(C6H5N2O2)2.97 with HMDS in toluene in a 30 % filled Swagelok autoclave at 350
C for 20 h. Average diameter of as-synthesized NPs is about 4 nm with a size distribution between 2 and 8 nm. Apparently, the introduction of dopants can significantly affect the crystallinity of the NPs, and post-synthetic annealing is required to obtain crystalline NPs as confirmed by powder XRD. However, the size increases to 18 nm after being annealed at 500
C in NH3 gas for 3 days. It seems that the amount of Mn doping does not affect the size of the NPs because 3 % and 5 % Mn-doped GaN NPs have the same size (4 nm) under the same synthetic conditions. The size of NPs increases to 6 nm when GaCl3, MnCl2, and HMDS are used as the reactants. The same method can also be used to synthesize 10 nm 5 %–10 % in-doped GaN NPs with (Ga1xInx) (C6H5N2O2)3 as the precursor [157]. Other metal nitrides, such as NbN, ZrN, HfN, and Ta3N5, can also be prepared through a similar strategy. Using TaCl5, ZrCl4, HfCl4, and NbCl5 as the metal precursor and LiNH2 as the nitriding reagent, crystalline NPs of Ta3N5, ZrN, HfN, and NbN of variable sizes can be prepared through a benzene solvothermal reaction at 550
C for 24 h [158]. However, only amorphous NPs are observed below 450
C. The methods for the synthesis of other nitrides, phosphides, and arsenides are similar to the abovementioned ones (see Table 7).

Group IV Nanoparticles The most important Group IV NPs include those containing carbon, silicon, and germanium. Carbonbased NPs include carbonaceous and composite carbonaceous NPs (i.e., carbon modified with magnetic, optical, catalytic, or other materials). Carbonaceous and composite carbonaceous nanomaterials have broad applications in environmental remediation, catalysis, bioimaging, and drug delivery and in the manufacture of lithium ion batteries, fuel cells, and sensors [164]. The focus is on low temperature hydrothermal methods used to synthesize carbonaceous NPs (high-temperature hydrothermal methods, which can be used to synthesize advanced carbon structures such as carbon nanotubes, activated carbon, carbon thin films, and graphite, but they are not the focus of this chapter.). The hydrothermal precursors for carbon NPs can be sugar, glucose, cyclodextrins, fructose, sucrose, cellulose, and starch, all of which are biocompatible and relatively cheap [165]. The morphology of carbon NPs tends to be spherical. Reaction temperature is critical in formation of carbon spheres. No carbon spheres are obtained below 140
C. In contrast, with 0.5 M glucose as the C source and a 160
C Table 7 Synthesis of other III–V nanomaterials using hydrothermal and solvothermal methods Compound BN [159]

Size of NPs (nm) 150

InP [160] InAs [161] GaP [162] GaAs [163]

Solvent BBr3

Surfactant N/A

8

Morphology Hollow hexagon sphere Sphere

Ammonia

12 2–48 20–50

Sphere Sphere Sphere

Xylene Benzene H 2O

Potassium stearate N/A N/A N/A

Temperature (
C) 400–450

Time (h) 6–12

140

8–12

150 300 180–190

48 0–24 24

Precursors BBr3, NH4Cl, and NaNH2 InCl3, NBH4, and elemental P InCl3, AsCl3, Zn Na3P, GaCl3 As2O3, metal Ga, H2SO4

Page 17 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

reaction temperature, carbon spheres of 200, 500, 800, 1,100, and 1,500 nm in diameter can be produced after a reaction time of 2, 4, 6, 8, and 10 h, respectively. The growth of these NPs consists of dehydration, condensation, polymerization, and aromatization processes. The presence of metal ions and metal oxides such as Fe3+ and Fe2O3 can significantly catalyze the process of carbonization of carbon precursors. The reaction temperatures usually range from 150
C to 350
C, and the reaction time is between 4 and 24 h. Depending on the precursors, the sizes of the NPs vary from 100 nm to several micrometers. Porous carbon NPs can be prepared on mesoporous or nonporous silica templates. After the NPs are deposited on the templates, the templates are selectively etched away (Fig. 6). Surface wettability plays an extremely important role. If the surface of the templates cannot be wetted by the precursor, no porous carbon NPs can be obtained [166, 167]. In addition, when the triblock copolymer Pluronic F127 is used as a template and phenolic resol is used as a carbon source, more-uniform mesoporous carbon NPs can be produced. The reaction can be tuned by varying the reagent concentration to produce NPs whose sizes range from 20 to 140 nm. For example, carbon NPs of 140 nm and 20 nm can be synthesized through a hydrothermal reaction at 130
C in a solution of phenol and water in ratios of 1:200 and 1:450, respectively [168]. Although this method is elegant, the cost is too high for practical large-scale applications. Similarly, this one-pot hydrothermal method can be extended to the synthesis of composite carbonaceous NPs by simply mixing the metal precursors or metal oxide NPs (e.g., Ag, Pd, Se, Fe3O4,

a Mesoporous Templates NH4HF2

very hydrophobic hydrothermal carbonisation

Macroporous casts

NH4HF2

medium hydrophobic hydrothermal carbonisation

Mesoporous hollow spheres

Si-100

Mesoporous microspheres


6

dehydroxilated

NH4HF2 + Nanoparticles

6-10 nm released noncoherent carbon spherules

b Non-porous Templates NH4HF2

ic

ob

ph

o dr

r Ve

y yh

Macroporous casts

hy med dro ium ph Mono 1500 ob ic

NH4HF2

Hollow spheres

Fig. 6 Schematic representation of the hydrothermal carbonization process using silica templates with different polarities, resulting in the formation of various carbon morphologies (Reproduced with permission from Titirici et al. [166]. Copyright 2007, John Wiley and Sons) Page 18 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

SnO2) with a carbon source [167]. Alternatively, such composite materials can be prepared via a postsynthetic treatment of as-synthesized hydrothermal carbonaceous NPs. Silicon and germanium are highly important semiconductors due to their broad applications in the electronic and optoelectronic industries. Solvothermal and hydrothermal methods to grow Si and Ge NPs are extremely challenging and often require very high temperature to initiate crystallization. Ge NPs with poor crystallinity can be synthesized by decomposition of tetraethylgermanium in organic solvents or superfluidic solvents such as CO2 with and without surfactants at high temperature. The surfactants have three functions: (1) forming inverse micelles to guide nucleation and crystal growth (size control), (2) morphology control of the Ge NPs (shape control) by selective adsorption on certain crystal planes, and (3) stabilizing nanoscale particles (stability control) by reducing the surface energy of NPs through surface adsorption on those NPs. Ge nanocubes of 100 nm edge length can be synthesized using a hexane solvothermal method with a surfactant additive, heptaethylene glycol monododecyl ether (C12E7) [169]. Equimolar amount of GeCl4 and phenyl-GeCl3 is used as the Ge precursors, and metallic Na dispersed in toluene is employed as the reducing reagent. The mixture is heated at 280
C for 3 days in a Parr 4750 reactor without stirring or shaking. The filling factor is about 65 %. NaCl, a by-product, can be removed by vigorous rinsing with ethanol, water, and hexane. The as-synthesized Ge nanocubes are highly crystalline with a diamond cubic structure (a = 5.655 Å), as confirmed by both powder XRD and high-resolution TEM. These 100 nm nanocubes are composed of multiple smaller nanocubes, which are connected to each other through the surface-adsorbed surfactant molecules. When the surfactant is changed to pentaethylene glycol ether (C12E5), a mixture of spherical, triangular, and hexagonal Ge NPs is produced with diameters ranging from 15 to 70 nm (Fig. 7) [170]. The shape of Ge NPs can be tuned by controlling surfactant amount. For example, only Ge spheres with diameters between 6 and 35 nm are yielded if the amount of surfactant is reduced by three times (1.8 ml to 0.6 ml). The yield of Ge 1.8 mL C12E5

80 mL hexane

Inverse micelle solution containing 1.8 mL C12E5

a

b

c

d

0.6 mL phenylGeCl3 0.6 mL GeCl4

Inverse micelle solution containing 1.8 mL C12E5, 0.6 mL phenyl -GeCl3, 0.6 mL GeCl4

5.6 mL Na (25% dispersion in toluene)

Inverse micelle solution containing 1.8 mL C12E5, 0.6 mL phenyl-GeCl3, 0.6 mL GeCl4, 5.6 mL Na (25% dispersion in toluene)

Stirring for 30 min, then sealing in a 125 mL Parr reactor

Heating in furnace at 280 °C for 72 h

Washing with hexane, alcohol and distilled water

Drying in an vacuum oven at 60 °C for 12 h

Products

Fig. 7 Diagram showing the fabrication method to obtain Ge nanocubes (left); Right: (a) transmission electron microscope (TEM) images of the Ge nanocrystals; (b) selected-area electron diffraction pattern of Ge nanocrystals; (c) high-resolution TEM image of spherical and (d) triangular Ge nanocrystals. (Reproduced with permission from Wang et al. [170]. Copyright 2005, Institute of Physics) Page 19 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

NPs is mainly affected by the reaction time. Extending the reaction time from 4 to 12 h enhances the yield from 35 % to 54 %. However, the size and crystallinity of these NPs are independent of the reaction time, probably due to the presence of the capping surfactant molecules. Other Group IV NPs, such as Si, can also be synthesized using such a solvothermal method [171].

Transition Metal Nanoparticles Metallic NPs possess many unique optical, electronic, and magnetic properties that can be applied to catalysts, sensors, and memory devices. Although wet chemistry methods (with reducing agents and capping surfactants) can be used for controllable synthesis of metal NPs, hydrothermal and solvothermal methods provide better control of morphology and crystallinity. Usually, the NPs are deposited or loaded onto a support material to increase their reactivity and recyclability. Extremely small (1.7 nm) Pt particles have been synthesized using an ethylene glycol solvothermal method at basic conditions [172]. The ethylene glycol functions both as the solvent and as a reducing agent; H2PtCl6.6H2O serves as the Pt precursor. The mixture was heated to 433 K for 3 h [172]. The ethylene glycol solvothermal method can also be utilized to grow Ag NPs [173]. In a typical procedure, AgNO3 is added into a double-walled digestion vessel that has an inner Teflon liner and an outer high-strength shell. Then, appropriate amounts of toluene, ethylene glycol, and dodecylthiol (thiol) are added into the vessel in that order. The solvothermal reaction is carried out at 160
C to 170
C for 3 h in a microwave digestion system. The Ag NPs have a very regular spherical shape and an average diameter of ~10 nm. The thiol functions as a complexing reagent, and the ethylene glycol is a mild reducing agent. Decreasing the ethylene glycol/thiol ratio from 3 to 1.5 can dramatically change the morphology of the Ag NPs from spherical to rectangular with a slightly reduced diameter (6–10 nm). Pt NPs can also be synthesized using a dimethylformamide (DMF) solvothermal method in a sealed PTFE-lined reactor vessel [174]. The metal precursor is platinum (II), 2,4-pentanedionate (Pt(acac)2), and DMF works as a mild reducing agent and solvent. The reaction mixture is heated in a furnace to 200
C for 24 h. The same DMF solvothermal method can also be employed to grow Ag and Au NPs. Besides ethylene glycol and DMF, other reducing agents (e.g., NaBH4, N2H4, NH2OH, and ethanol) can also be used to grow transition metal NPs. Bimetallic-alloy NPs can also be synthesized using the aforementioned method (Table 8) [174]. The only difference is that two metal precursors are added simultaneously. For instance, the DMF solvothermal method can be used to generate platinum-nickel alloy NCs. The metal precursors for Pt Table 8 Metal content and Rietveld analysis of PtxNi1x alloy nanoparticles, reproduced with permission from [174]. Copyright 2012, American Chemical Society

0.5

Analyzed metal content wt % wt % Pt/Ni Pt Ni molar ratio 23 11.8 0.6

1

25

8.5

0.9

1.5

27

4.8

1.7

2

27

3.8

2.1

3

29

2.7

3.2

Reactant Pt/Ni molar ratio

XRD-derived values Lattice Ni mole parameter fraction (Å) 3.7939 0.33 3.7368 0.47 3.8292 0.24 3.7529 0.43 3.8556 0.17 3.7840 0.35 3.8636 0.15 3.7976 0.32 3.8427 0.20

Pt mole fraction

Phase wt %

0.77 0.53 0.76 0.57 0.83 0.65 0.85 0.68 0.80

37 63 40 60 32 68 61 39 100

Average crystallite size (nm) 3.8 6.1 6.7 6.7 4.0 7.4 3.1 5.9 5.5

Page 20 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

and Ni are platinum (II) 2,4-pentanedionate and nickel (II) 2,4-pentanedionate, respectively. In a typical reaction, the Pt and Ni acetylacetonates are dissolved in DMF to yield concentrations of 30 mM Pt(acac)2 and 10 mM Ni(acac)2. The reaction mixture is heated in a furnace to 200
C for 24 h. The reaction is incomplete below 200
C due to the slow decomposition of Ni(acac)2 at that temperature. As-synthesized Pt3Ni NPs are highly crystalline and have diameters ranging from 11 to 13 nm. Variations in the ratio of the two precursors result in the synthesis of PtNi bimetallic-alloy NPs having various compositions and slight differences in diameter, as shown in Table 8. The same strategy can be used to prepare other bimetallic-alloy NPs (e.g., Pt-Co and Pt-Fe).

Metal-Organic Framework Nanoparticles In the past two decades, MOFs have attracted enormous research attention due to their potential applications for hydrogen storage [172], gas separation [173], catalysis [175], bioimaging [176], drug delivery [177, 178], sensors [179], and proton exchange membranes [180]. MOFs constitute a class of hybrid nanoporous crystalline materials consisting of metals and bridging organic linkers with pore sizes ranging from 0.4 to 6 nm [177]. MOFs are commonly synthesized through hydrothermal and solvothermal methods. Compared with the synthesis of Group II–VI and III–V NPs, the pressure and temperature used for MOF NP synthesis are much milder to avoid decomposition of organic ligands. Herein, only the synthetic methods for MOF NPs for biomedical applications are extensively discussed, mainly because such NPs are highly desirable. For other applications, thin film (gas separation) or bulk form (gas storage) shows superior performance:

(a) Crystal growth without a surfactant template MOF NCs can be grown via a simple, straightforward solvothermal method. For instance, Fe(III) MOF NCs with a framework formula of Fe3-(m3-O)Cl(H2O)2(BDC)3 (MIL 101; BDC = terephthalic acid) can be synthesized by simply microwave heating a solution of equal-molar FeCl3 and BDC in DMF at 150
C (Fig. 8) [181]. The microwave heating produces smaller particles with high reproducibility. The synthesized NPs are octahedral and have an average diameter of ~200 nm. The NPs are highly crystalline as confirmed by powder XRD, and the Langmuir surface area ranges from 3,700 to 4,535 m2/g [181]. The MOF NPs can be functionalized with dye molecules for cell imaging or anticancer prodrugs for cancer therapies. However, these functionalized NPS are chemically unstable in a physiological environment. That limitation can be overcome by post-synthetic coating of the MOF NPs with a layer of silica [181]. (b) Crystal growth with surfactant template Surfactant additives used in solvothermal and hydrothermal methods can form micelles, which functions as templates to guide the growth of NPs with controlled size, shape, and crystallinity. For example, highly paramagnetic Gd(III) MOF NPs can be synthesized via a surfactant-assisted hydrothermal method with or without microwave heating. To synthesize [Gd2(bhc)(H2O)6] MOF NPs (bhc = mellitic acid), CTAB/1-hexanol/n-heptane microemulsions are first added with an aqueous mellitic acid methylammonium salt and an aqueous GdCl3 solution. Then they are loaded into a Teflon-lined Parr reactor and heated to 120
C for 18 h to yield the NPs [182]. The MOF NPs have to be purified by repeated centrifugation at high speed and re-dispersion in an ethanol solution to completely remove surfactant impurities. As-synthesized MOF NPs are highly crystalline with a block shape (25  50  100 nm), and the yield is very high (84.4 %). Hydrothermal growth is beneficial for obtaining highly crystalline NPs compared to the traditional wet chemistry growth. When the reaction is carried out at room temperature, only amorphous Gd MOF NPs can be obtained because the nucleation rate is too rapid and dominates the NP growth. Page 21 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

Fig. 8 Scanning electron microscope (SEM) images of (a) Fe3(m3-O)Cl(H2O)2(BDC)3 nanoparticles, (b) Fe3(m3-O)Cl (H2O)2(BDC)3 nanoparticles incorporated with 17.4 mol % NH2-BDC, (c) nanoparticles shown in image (a) loaded with 1,3,5,7-tetramethyl-4,4-difluoro-8-bromomethyl-4-bora-3a,4a-diaza-s-indacene dye molecules and (d) nanoparticles shown in image (a) loaded with c,c,t-[PtCl2(NH3)2(OEt)(O2CCH2CH2CO2H)] anticancer prodrug (Reproduced with permission from Taylor-Pashow et al. [181]. Copyright 2009, American Chemical Society)

Instead, using a 400 W microwave to heat the Teflon reactor to 60
C produces final NPs that possess a nanorod shape with lengths up to several micrometers and widths ranging from 100 to 300 nm. The MOF NPs obtained under microwave heating have a formula of [Gd2(bhc)(H2O)8](H2O)2 instead of [Gd2(bhc)(H2O)6]. When the temperature is increased to 120
C under 400 W microwave heating, the NPs are octahedral with larger diameters (1–2 mm). The synthesized Gd(III) MOFs can be applied to magnetic resonance imaging [182]. Similar hydrothermal methods can be employed to obtain Mn(II), Eu(III), and Tb(III) MOF nanomaterials [183, 184]. The microwave heating, reaction temperature, and water-to-surfactant ratio have significant impacts on the morphology of these synthesized MOF NPs. Lower temperature and a larger water-to-surfactant ratio lead to the growth of nanorods, whereas higher temperature and microwave heating result in shorter nanorods or octahedral NPs.

Surface Treatment of Nanoparticles Using Hydrothermal and Solvothermal Methods and its Effect on Their Physicochemical Properties Inorganic NPs have potential applications in various fields, including electronics, energy storage, catalysts, hybrid materials, and biomedical applications [185–188] due to their unique “quantum size effect” [189]. However, the practical application of inorganic NPs is hindered by the severe aggregation resulting from their high surface area [190] and poor dispersion in organic solvents owing to the hydroxyl groups on their surfaces [191]. These issues could be addressed by modifying the surfaces of the NPs. Among the various methods that are available for modifying the surface of NPs, the hydrothermal and Page 22 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_17-1 # Springer International Publishing Switzerland 2015

solvothermal processes are among the most promising techniques to improve the dispersibility and compatibility between inorganic NPs and organic solvents [192–195]. For instance, NH2 and –CHO groups can be successfully grafted onto the surface of AlOOH NPs through in situ surface modification via a hydrothermal process [188] that makes the hydrophilic surface of AlOOH NPs hydrophobic, resulting in modified AlOOH NPs that disperse well in solvents [188]. In the presence of caprylic acid and n-butylamine, ZnO/TiO2 hybrid NPs show reduced agglomeration and enhanced dispersibility [192]. Successful surface modifications of other inorganic NPs via a hydrothermal process, including Fe3O4 [194] and BaTiO3 [196], have also been reported.

Conclusion Hydrothermal and solvothermal techniques have been widely adopted as classic methods for the fabrication of inorganic and metal-organic nanomaterial, including oxides; Group III–V, II–IV, and VI elements; MOFs; and transitional metals. These techniques could be utilized to synthesize organic NPs, provided that the organic chemicals will not be decomposed at such high temperatures and pressures. However, methods to synthesize organic NPs are still under development and are limited by the stability of organic compounds. Additionally, organic NPs can be readily synthesized via a traditional wet chemistry method with or without the assistance of surfactants. Due to the unlimited combinations of metal ions and bridging organic ligands for MOF compounds, it would be worth exploring the MOF NP synthesis via hydrothermal and solvothermal methods. Such research could yield very interesting discoveries in the coming decades.

References 1. K. Byrappa, M. Yoshimura, Handbook of Hydrothermal Technology (William Andrew, Norwich, 2001) 2. K.F.E. Schafthaul, Gelehrte Anzeigen Bayer. Akad. 20, 557 (1845) 3. K. Byrappa, T. Adschiri, Progr. Cryst. Growth Character. Mater. 53, 117 (2007) 4. Z.L. Wang, Adv. Mater. (Weinheim, Germany) 15, 1497 (2003) 5. H.C. Helgeson, D.H. Kirkham, Am. J. Sci. 274, 1089 (1974) 6. H.C. Helgeson, D.H. Kirkham, Am. J. Sci. 276, 97 (1976) 7. H.C. Helgeson, D.H. Kirkham, G.C. Flowers, Am. J. Sci. 281, 1249 (1981) 8. E.L. Shock, E.H. Oelkers, J.W. Johnson, D.A. Sverjensky, H.C. Helgeson, J. Chem. Soc. Faraday Trans. 88, 803 (1992) 9. W. Dawson, J. Am. Ceramic Soc. Bull. 67, 1673 (1988) 10. I. Sunagawa, K. Tsukamoto, K. Maiwa, K. Onuma, Progr. Crystal. Growth Character. Mater. 30, 153 (1995) 11. B.E. Etschmann, W. Liu, D. Testemale, H. Mueller, N.A. Rae, O. Proux, J.L. Hazemann, J. Brugger, Geochim. Cosmochim. Acta 74, 4723 (2010) 12. C. Gerardin, M. Haouas, C. Lorentz, F. Taulelle, Magn. Reson. Chem. 38, 429 (2000) 13. S.R. Higgins, C.M. Eggleston, G. Jordan, K.G. Knauss, C.O. Boro, Mineral. Mag. 62A, 618 (1998) 14. K. Kawamura, H. Nagayoshi, T. Yao, Anal. Chim. Acta 667, 88 (2010) 15. J.E. Maslar, W.S. Hurst, W.J. Bowers Jr., J.H. Hendricks, Corrosion (Houston, TX, United States) 58, 739 (2002)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Advances in Spray Drying Technology for Nanoparticle Formation Tin Wui Wonga,b* and Philipp Johnc a Particle Design Research Group, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia b Non-Destructive Biomedical and Pharmaceutical Research Centre, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia c BÜCHI Labortechnik AG, Flawil, Switzerland

Abstract The biggest societal impact of pharmaceutical nanotechnology is related to “nanomedicine,” a promising new drug delivery mode which provides a higher therapeutic efficacy than conventional dosage forms due to increased drug bioavailability. Spray drying is commonly used in the pharmaceutical industry to convert a liquid phase (solution, emulsion, suspension, slurry, paste, or melt) into a dry, solid powder. In conventional spray drying, a feed product is atomized into a fine spray and dried by a hot inlet air stream. The contact between the hot inlet air stream and spray causes evaporation of solvent and drying of the spray into solid product in a single-step process. The widespread research investigation of nanoparticles as a mode of drug delivery has translated to the late development of spray drying technique with advancement focuses on atomization mechanism to produce discrete dried nanoparticles. This chapter describes spray drying processes and processors for particle production from micro- to nanoscale and highlights advantages of using spray drying as the process of nanoparticle manufacture, characteristics of spray-dried nanoparticles, and limitations of spray drying in drug targeting device manufacture.

Keywords Drug targeting; Nanoparticle; Nanotechnology; Spray drying

Introduction Drug delivery system can be designed in solid, liquid, and gaseous dosage forms. Formulation of solid dosage form generally requires drying. The process of drying has a strong bearing on the density, porosity, friability, strength, hardness, compressibility, product disintegration, dispersibility, rheological property, adhesiveness, drug content, particle size, shape, stability, crystallinity, drug-excipient migration, drugexcipient polymorphism, drug dissolution, drug bioavailability, and other biological responses of a solid dosage form [67]. In the development of solid dosage form, the process of drying can be accomplished by a number of technologies, namely, oven/tray, fluidized bed, band, turbo tray, centrifugation, pneumatic, cyclone, drum, vacuum, filter, freeze, and spray drying methods. Spray drying receives a widespread application in pharmaceutical and nutraceutical industries to transform solution, suspension, emulsion, liposome, elixir, and slurry or even paste into a dry solid powder [31, 10, 37, 64, 35, 34, 27]. It has been adopted to produce solid dosage form which is sensitive to the thermal, humidity, and/or mechanical condition of the immediate environment. Examples of such are

*Email: [email protected] Page 1 of 16

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Table 1 Spray-dried pharmaceutical and nutraceutical dosage forms Dosage form Inhalation Dry powder aerosol

Lipid-polymer hybrid nanoparticles Microencapsulated nanoparticles Inclusion complexes Liposome

Oral Redispersible oil-inwater emulsion Microencapsulated Radix salvia miltiorrhiza nanoparticles Injection Casein-based micelles Solid lipid nanoparticles Others Redispersible nanocapsules

Drug

Excipient

References

Albuterol sulfate Bacteriophage

Mannitol, L-leucine, poloxamer 188 Trehalose, lactose, dextran

Immunoglobulin Plasmid pEGFP-N1 Levofloxacin

Mannitol Chitosan, leucine, lactose Poly(lactic-co-glycolic acid), soy bean lecithin, polyvinyl alcohol, L-leucine Poly(lactide-co-glycolide), trehalose, lactose, mannitol Poly (lactic-co-glycolic acid), mannitol g-Cyclodextrin

Son et al. [56] Vandenheuvel et al. [62] Sch€ule et al. [55] Mohajel et al. [39] Wang et al. [66]

siRNA Rifampicin Beclomethasone dipropionate Superoxide dismutase CAF01

Dipalmitoylphosphatidylcholine, trehalose, sucrose, lactose Dimethyldioctadecylammonium bromide, a,a0 -trehalose-6,60 -dibehenate, lactose, trehalose

Jensen et al. [30] Ohashi et al. [43] Cabral-Marques and Almeida [8] Lo et al. [37] Ingvarsson et al. [27]

5-Phenyl-1,2dithiole-3-thione Radix salvia miltiorrhiza

Maltodextrin, sodium caseinate, fractionated coconut oil Gelatin, sodium carboxymethylcellulose

Dollo et al. [15]

Flutamide -

Casein, genipin Cetyl palmitate, glyceryl behenate, calcium behenate, poloxamer 188, mannitol, lactose, trehalose, sorbitol, glucose, mannose

Elzoghby et al. [19] Freitas and M€uller [23]

-

Polycaprolactone, caprylic/capric triglyceride, sorbitan monostearate, mannitol, lactose, maltodextrin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose

Tewa-Tagne et al. [60]

Su et al. [58]

inclusion complex, solid dispersion, formulated bacteriophage, antibody, Lactobacilli rhamnosus GG, vaccine, as well as chitosan-plasmid complexes [55, 8, 39, 68, 27, 45, 62]. The spray-dried particles are deemed to be a vehicle that can increase the drug dissolution and bioavailability of poorly water-soluble drugs [15, 41]. In addition, they are widely investigated as pulmonary drug delivery system for the treatment of chronic pulmonary infection, cystic fibrosis, and asthma [47, 52, 1, 16]. Examples of spray-dried pharmaceutical and nutraceutical dosage forms are summarized in Table 1. With reference to pharmaceutical and nutraceutical applications, the adoption of spray drying technology as the processing tool in product development brings about several advantages as follows [25, 64, 49, 46]:

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

1. Both thermal labile and non-labile substances can be processed with low risks of physicochemical degradation due to fast drying rate and use of moderate drying temperature. 2. Dried particles of controlled size, shape, crystal form, moisture content, porosity, and other specific properties can be produced. 3. Both fast-release and sustained-release particles can be designed through appropriate formulation and processing approaches. In the case of sustained-release particle design, large molecular weight and slowly biodegradable polymers such as poly(lactide), poly(lactide-co-glycolide), polycaprolactone, carbomer, methacrylate copolymer, chitosan, hyaluronan, cellulose derivative, and cross-linked protein are used. 4. Spray drying is a single-pot continuous process which denotes simplicity and ease of operation. 5. Low operation cost, energy efficient, and speedy. 6. Spray dryer can be designed in different production capacities and production rates. 7. Spray drying can be carried out using aqueous or organic solvent through appropriate dryer design and choice of process layout (open cycle vs. close cycle). 8. Spray drying can be further developed into new processing technology to meet the stability and other quality requirements of a product. Examples of technology derived from spray drying are superheated steam spray dryer, two-stage horizontal spray dryer, and spray freeze dryer.

Spray Dryer Principally, a spray dryer constitutes of four instrumentation zones: atomization, drying, collection, and waste filtration (Fig. 1). The atomization zone consists of a nozzle which functions to break down a liquid feed into fine droplets and disperse them in a flowing air stream for drying, with the aid of a compressed gas. The drying zone is made of air intake system, heater, drying chamber, and aspirator where the air will be filtered and heated to the required temperature and move to contact with the sprayed droplets to elicit

Fig. 1 Schematic diagram of a spray dryer (Image is provided by BÜCHI)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

heat and mass transfer for drying to take place. This zone is equipped with temperature sensors at both inlet and outlet of air of the drying chamber. The collection zone is installed with a separator to collect the intended particles into a container. The unintended particles and wet air are introduced into waste filtration zone to avoid particle leakage into the immediate environment and recycle the air, if necessary, via removing its wetness by means of heating prior to the next cycle of drying process. Depending on atomizer design and size of droplets formed, the dimension of the drying chamber may have its diameterto-length ratio varied from 1 to 5 or higher [45].

Spray Drying Process Spray drying proceeds through atomizing a liquid feed into a fine spray followed by its contact with a stream of hot air to remove the solvent (Fig. 1) [14, 46, 6, 45]. The dried particles are then entrained in the drying air. They exit the drying chamber and are collected and separated from the gas stream by a cyclone separator and/or less commonly an electrostatic precipitator, textile filter, and scrubber. The spraying of liquid feed is accompanied by the formation of millions of micrometer-sized droplets. These droplets have a large specific surface area. They experience a very short drying time due to effective heat and mass transfer between the droplets and hot air. Organic solvent may be used in the preparation of liquid feed [14]. In such cases, nitrogen drying gas is employed to provide an inert environment to the drying chamber. There are three types of product-air flow pattern in spray drying process, namely, cocurrent, countercurrent, and mixed flow (Fig. 2) [46, 45]. Cocurrent configuration is widely adopted as the product-air flow pattern, whereas countercurrent flow design is used in the processing of nonthermal labile substances. Using mixed flow design, the droplet spray zone is located at the bottom of the dryer. The liquid feed is sprayed upward and has flow reversal under the influences of gravity and downward drying gas flow. The mixed flow design is suitable for use to spray dry coarse droplets which are provided with a long

Fig. 2 Product-air flow patterns in a spray drying process (Image is provided by BÜCHI)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Table 2 Spray-dried particle size as a function of formulation and processing variables [14, 6, 21, 45] Variable Formulation

Processing

Parameter Organic solvent instead of aqueous solvent as processing liquid Matrix substance concentration decreases in liquid feed Surface tension of liquid feed decreases Viscosity of liquid feed decreases Density of liquid feed decreases Spray air flow rate increases Spray air density increases Liquid feed rate decreases Atomization energy increases: increase rotating wheel/disk atomizer speed, nozzle pressure, sonication frequency

Outcome Particle size decreases Particle size decreases Particle size decreases Particle size decreases Particle size decreases Particle size decreases Particle size decreases Particle size decreases Particle size decreases

path to travel in chamber in order to complete their removal of solvent prior exiting to the collection chamber. The drying gas may pass through the chamber once before it is vented as waste or be recycled through condensation and heating prior to introducing into the same chamber [14, 45]. The latter can lead to the formation of particles with different physicochemical properties from those of undergoing singlepass process. It is practiced when the nitrogen gas is used in spray drying of products carrying organic solvent, toxic, or oxygen-sensitive constituents [6, 45].

Atomization Broadly, a spray dryer is constituted of feed pump, atomizer, air heater, air disperser, drying chamber, collection chamber, cyclone, and waste filter. The size of dried particles produced by spray drying process is a function of formulation variables such as viscosity, surface tension, solid load, and its geometry characteristics, in addition to processing parameters of the spray dryer. Table 2 summarizes formulation and processing variables which can lead to a reduction in the size of spray-dried particles. The size of droplets and dried particles is critically dependent on the design and operational principle of the atomizer. An ineffective atomizer is expected to translate to the formation of large particles with a broad size distribution. In addition, the spray drying process using such atomizer can be characterized by a low throughput when only liquid feed with low matrix substance concentration or viscosity is used to avoid the growth in size of the product. Many different types of spray nozzle are available for atomization of liquid feed, namely, ultrasonic, rotary (spinning), pneumatic, and pressure (hydraulic) atomizers [63, 14, 46, 21, 45]. Rotary atomizer uses centrifugal energy where a high-speed rotating wheel/disk breaks down the liquid feed into droplets. Pressure atomizer operates through forcing the liquid feed through an orifice under pressure to disintegrate into droplets. In the case of ultrasonic atomizer, the liquid feed passes through the nozzle installed with sonic generator to break up the liquid into droplets. This atomizer is suitable for fine droplet formation typically below 50 mm. The pneumatic atomizer is available as two-fluid and three-fluid denominations. The two-fluid nozzle receives a widespread application where the liquid feed and compressed air are passed separately into the nozzle head to form spray via kinetic impact of compressed gas onto the liquid feed. This nozzle is useful in pharmaceutical applications due to its ability to process high-viscosity liquid feeds. A recent innovation attempts to transform the two-fluid nozzle into a fourfluid nozzle spray system [43]. In the latter, the nozzle is equipped with two liquid feed and two gas passages. This allows drug and excipients to be dissolved in separate solvent systems. The nozzle design simplifies the process without the need to dissolve drug and excipients in a same solvent of which may be Page 5 of 16

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Fig. 3 Characteristics of two-fluid nozzle with external and internal mixing modes (Image is provided by BÜCHI)

difficult due to their differences in solvent affinity. It is also envisaged that such spray system can be used in processing of materials that exhibit incompatibility physically and/or chemically. Two-fluid nozzle can produce fine droplets and is easy to be installed in the spray dryer. In order to achieve fine droplet formation, two types of two-fluid nozzle have been designed: internal and external mixing [24]. The external mixing two-fluid nozzle composes of concentric tubes (Fig. 3). The fed liquid passes from the inner tube and is sheared by the air flow from the outer tube into fine droplets. The shear rate varies at different locations of a liquid stream. This leads to broad droplet size distribution. In order to produce fine droplets with a narrow size distribution, the diameter of the inner tube shall be as small as possible. The diameter of the inner tube shall be less than 0.2 mm, and the flow ratio of air to liquid feed shall be kept at about 2.6 in order to produce droplets of 10 mm in size. Using such equipment and process design, fine droplets are produced nonetheless at the expense of the productivity of a spray drying process. Internal mixing two-fluid nozzle mixes both air and liquid feed before spray. The primary droplets blown off from nozzle collide with each other to further break down into smaller droplets. Reproducibly small droplets however are not attainable when liquid feed with high matrix substance concentration or viscosity is concerned. Fine dried particles may be produced via spray drying process. However, the ability to collect these particles dictates the success of a spray drying process. Cyclone separator is commonly used as a particle collector (Fig. 1). Its inner surfaces are coated with nano-sized antistatic film to reduce particle adhesion onto the wall and thus increase the product yield (BUCHI Labortechnik AG [5, 6]). Using cyclone separator, the separation of particles from the continuous gas stream is based upon the difference in density between these two phases [45]. The dried particles and gas stream are subjected to an accelerating flow field in a rotating vortex in cyclone. The dense dried particles exhibit a lag in velocity when compared to the gas stream. The high velocity gas stream forces the dried particles to the wall of the cyclone and down to a cone section where the gas stream reverses its flow direction and leaves the cyclone via vortex finder. Larger dried particles are separated and collected. Smaller particles are on the other hand entrained in gas stream and leave the cyclone vortex. The collection of smaller dried particles can be accomplished with the use of a high acceleration flow field. At low cyclone acceleration flow fields, fine particles may be produced, but they may not be able to be collected for use.

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The size of dried particles is related to the size of droplets formed from the atomization process. The relationship of these two-dimension parameters can be expressed by the following equation [14]:   1=3  Dparticle  Ddroplet  xsolid  rdroplet =rparticle (1) where Dparticle = diameter of dried particle, Ddroplet = diameter of atomized droplet, xsolid = solid content of liquid feed, rdroplet = density of liquid feed, and rparticle = density of dried particle. Correlations between droplet size, solution properties, and nozzle geometry are available in the literature and can be used to guide nozzle selection. One empirical equation which relates the droplet size with atomizer attributes and liquid feed properties is given as below [40]: Ddroplet ¼ Kf  Qn  ra  sb  mc




(2)

where Kf = excitation equipment constants such as centrifugal force, frequency, pressure, and compressed air velocity, Q = liquid feed flow rate, n = power constant of liquid feed flow rate, r = liquid feed density, s = liquid feed surface tension, m = liquid feed viscosity, and a, b, and c are power constants of liquid feed properties. An optimal combination of nozzle choice and operating condition, liquid feed properties, and particle collection system render both fine dried particles production and retrieval possible in a single-pot spray drying process.

Development of Nanomedicine Nanotechnology receives a widespread application in semiconductor, manufacturing, and biotechnology industries [26]. Its biggest societal impact in pharmaceutical application is related to its use in design of nanomedicine, a promising new therapeutic form to improve medical efficacy via resolving the poor drug bioavailability status. Pharmaceutical nanoparticles can be described as solid colloidal particles with sizes below 1,000 nm [26, 20, 36, 13, 35, 34]. Examples of nanocarrier are liposome, polymeric micelle, dendrimer, nanosuspension, nanoemulsion, nanosphere, and nanotube [13, 38]. The nanoparticles can be used to deliver polypeptides, proteins, vaccines, nucleic acids, and genes [36]. Active pharmaceutical ingredients can be adsorbed, encapsulated, or covalently attached to the surface/ into the matrix of nanoparticles [28, 57, 26, 51, 48]. Owing to small size and large specific surface area of nanoparticles, they can further improve the dissolution of poorly water-soluble drugs, enable drug targeting, enhance bioavailability, reduce dose and associated toxicity, and enhance transcytosis across epithelial and endothelial barriers to affect intracellular drug delivery when compared to microparticles (Fig. 4) [26, 22, 34, 48]. Nanoparticles can enhance drug stability and efficacy and enable sustained delivery [64, 4]. They can avoid rapid clearance by phagocytes, thereby leading to prolonged drug circulation in the body. The nanoparticles can penetrate cells and target organs such as the liver, spleen, lung, spinal cord, and lymph. Its element of drug targeting is mainly exploited in the treatment of solid tumors, cardiovascular diseases, and immunological diseases [59, 3, 22, 17]. Nonetheless, manufacturing of nanomedicine can be complex and additional hurdles are expected in the development for clinical usage. A number of processing approaches can be adopted to produce nanoparticles. They are emulsion crosslinking, polyelectrolyte complexation, precipitation, phase separation, in situ polymerization, spray drying, emulsion-droplet coalescence, ionic gelation, and reverse micellation techniques [4, 33, 12]. The nanoparticles can be prepared by bottom-up and top-down approaches [42]. The top-down approach

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015 Improve dissolution of poorly watersoluble drugs

Enable drug targeting

Enhance drug bioavailability Nanoparticles

Enhance particle transcytosis and intracellular drug action

Reduce drug dose and toxicity

Fig. 4 Roles of nanoparticles as nanomedicine

involves primarily a size reduction process via milling, cutting, etching, or high-pressure homogenization. The bottom-up approach uses growth, aggregation, or assembly of atoms to build the particles. It enables design and construction of nanoparticles of specific geometries. Nevertheless, random movement of atoms needs to be controlled to ensure formability of nanoparticles in a reproducible manner [26, 42]. Unlike the top-down approach, the bottom-up system is deemed to be less destructive to the materials undergoing the formative process of nanoparticles. It thus is favorable in pharmaceutical application where the physicochemical instability of both drug and excipient can have negative impacts on the biological performance of an active. Spray drying has been utilized as a process to dry the preformed nanoparticles, namely, Radix salvia miltiorrhiza nanoparticles, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, and siRNAloaded poly(D, L-lactide-co-glycolide) nanoparticles [23, 60, 58, 30, 66]. In most cases, microparticles are fabricated through mixing the preformed nanoparticles with additional excipients prior to process of spray drying. The additional excipients are required to provide the microparticles with regular spherical shape or redispersibility to reconstitute the nanoparticles. They can function to keep the nanoparticles from aggregation in the microparticulate domain [40]. The prevention of nanoparticle aggregation may also be achieved through using low-pressure-assisted spray drying technique. Under the circumstances of low pressure, the solvent of sprayed droplets evaporates rapidly. The evaporated solvent generates pressure in droplets, thus promoting nanoparticle deaggregation. Spray drying of preformed nanoparticles is not the only option in the preparation of nanomatrices. Nanoparticles can also be fabricated and harvested directly using spray drying technique where evaporation of solvent from the sprayed droplets is accompanied by the precipitation of a small mass characterized by nanoscale geometry. Nanospray dryer is the recent advancement of the related technology [35, 34, 40, 46, 2]. The procedure of nanospray drying process is largely identical to that of spray drying method. The formation of nanoparticles is dependent on judicious choice of atomizer and particle collector design. The nanospray dryer is equipped with vibration mesh atomization technology which breaks up the liquid feed to form individual droplets of a very narrow size distribution (3–15 mm) and enables the formation of droplets smaller than those generated by spray dryer (Fig. 5). The dried powder is submicron particles with a narrow size distribution and produced at a high yield. Principally, the atomizer of a nanospray dryer is made of a piezoelectric crystal which induces vertical movement of the spray head (Fig. 6). The spray head is installed with a thin perforated mesh (4.0, 5.5, or 7.0 mm) that functions to generate and release fine droplets via an extrusion process, thereby generating the aerosol and dried Page 8 of 16

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Fig. 5 Schematic diagram of a nanospray dryer (Image is provided by BÜCHI)

Fig. 6 Operation of vibration mesh atomization technology (Image is provided by BÜCHI)

nanoparticles thereafter. The design of atomizer is critical as nanoparticle production via mere lowering the drug, and/or excipient content in a liquid feed is deemed to result in poor production rates. With reference to 100 nm particles, the typical 5 mm sprayed droplets must contain less than 0.0008 % dried mass, and this is impractical in industry practice. The cyclone separator has a mass-dependent particle cut off of approximately 2 mm. In conjunction with the use of vibrating mesh atomizer to produce nanoparticles, the mass independent electrostatic particle collector is thus used instead to harvest the formed product (Fig. 5). Using electrostatic collection mechanism, high yields between 70 % and 95 % are obtainable for small batch production in the range of 30–500 mg unlike traditional cyclone separator [53].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Nanospray drying technology has been employed in fabricating particles for inhalation drug delivery, processing of nanotherapeutic, generation of polymeric nanoparticles, encapsulation of nanoemulsion, and formulation of novel pharmaceutical excipients and nanocrystals [35, 7, 34, 53, 54]. Nanospray drying of emulsion with globules smaller than 100 nm can lead to non-aggregated submicron particles. The spray-dried particles are redispersible in water without a significant increase in size. Nanospray drying of excipients such as arabic gum, whey protein, polyvinyl alcohol, modified starch, and maltodextrin provides particles with size distribution mainly below 1 mm scale, attaining sizes as low as 350 nm for arabic gum processed at 0.1 % solid concentration. Nanospray drying of poorly water-soluble drugs, namely, furosemide, aids to increase its specific surface area for dissolution. In addition, rapid evaporation of solvent from ultrafine drug solution droplets can exert a control over the drug crystal morphology and its associated physicochemical properties. Nanospray drying of protein such as b-galactosidase is possible with its storage enzymatic stability upkept through the use of a larger spray cap size to minimize shear stress incurred on protein during spraying, in addition to the avoidance of use of ethanol and process the liquid feed at low temperatures.

Compare and Contrast Conventional Versus Nanospray Dryers The nanospray dryer is built with piezoelectric-driven vibrating mesh and electrostatic particle collector to produce fine particles in low quantity and high yield. The typical yield of a conventional spray drying process is between 50 % and 70 %, whereas nanospray drying can end with a yield as high as 90 % [2]. The maximum liquid feed viscosity allowable in nanospray drying is 10 cps, a level much smaller than conventional spray drying which can accommodate a liquid viscosity of 300 cps. This is partly transcribed from the use of liquid feed with a low solid content to avoid nanoparticulate aggregation into microparticles during the spray drying process. Both conventional and nanospray dryers have their unique roles in particle fabrication. The latter is characterized by engineering features which emphasize on the production of nano- or submicron particles with controlled and narrow size distribution. The particles prepared from both spray drying technologies are primarily adopted a matrix structure. The preparation of a reservoir system remains a great challenge when spray drying is concerned. A reservoir is made of a matrix with surfaces coated by the intended materials. Its design is crucial when this additional coat is required to modulate the drug release from a core matrix. With respect to site-specific drug delivery, the attachment of targeting ligands onto the surfaces of a matrix allows the host receptor to recognize the dosage form. The drug action will be restricted to the targeted tissue, thereby reducing unnecessary adverse effects to the surrounding healthy cells. Attachment of targeting ligands onto a spray-dried matrix has yet to be possible or executed in situ during the spray drying process.

Drug Targeting Drug targeting is ideally accompanied by reduced drug concentration in normal tissue, minimum drug release during transit, and maximum drug release at the target site. The use of nanoparticles as a targeting device may be achieved via passive or active mode of drug delivery. Passive targeting refers to accumulation of nanoparticles at the target site due to enhance permeability and retention effect [38]. An example of such event is related to leaky vasculature and incomplete lymphatic system surrounding tumors of soft tissue and epithelial cell origin. The leaky vasculature is formed as a consequence of rapid and defective angiogenesis [65]. The size of endothelial pores varies from 10 to 1,000 nm [11]. Page 10 of 16

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Table 3 Targeting ligands for tumor-specific drug delivery [11, 32, 50, 61, 65] Targeting ligand Folate

Receptor site Folate receptor

Galactosamine Hyaluronan Transferrin Anti-HER-2 Anti-HER-2 monoclonal antibody Anti-EGRF monoclonal antibody Anti-Flk1 monoclonal antibody Anti-VEGF monoclonal antibody RGD peptide

Asialoglycoprotein receptor CD44 receptor Transferrin receptor HER-2 receptor HER-2 receptor EGRF receptor VEGFR-2 VEGF Integrins (avb3)

Anti-VCAM-1 GPLPLR Anti-MT1-MMP Fab NGR Urokinase plasminogen activator

VCAM-1 MT1-MMP MT1-MMP Aminopeptidase N Urokinase plasminogen activator receptor

Organ/tissue site Breast, lung, kidney, ovary, colon, brain, myelogenous leukemia cancer Liver, melanoma Ovarian cancer cell, glioma Breast cancer, glioma

K1735-M2 and CT-26 tumor, liver cancer Melanoma, breast cancer, pancreatic/ renal orthotopic tumor Colon cancer Colon cancer, neuroblastoma

Colon cancer, breast cancer

For efficient extravasation from the fenestrations of the endothelial tissue, the nanoparticles shall have sizes below 400 nm. Active targeting requires the nanoparticles being decorated with biochemical moiety, namely, monoclonal antibody, leptin, transferrin, folic acid, or others. Table 3 presents the lists of ligands used for tumor-specific drug delivery system design. The drug delivery is facilitated through specific recognition of nanoparticles via the surface-decorated ligand by diseased site that expresses biomarkers that distinguish such site from the surrounding healthy tissues [11, 65, 38]. Although nanoparticles can be passively accumulated in tumor tissue as a result of enhanced permeation retention effects, internalization of nanoparticles and thus drug delivery can be greatly improved by the attachment of a high-affinity targeting ligand on the matrix and ligand with innate ability to activate receptor-mediated endocytosis. Through receptor-mediated endocytosis processes, the tumor cells can be directly killed against cells at their periphery. The attachment of ligand onto the surfaces of sprayed dried nanoparticles poses two challenges: 1. The technology to have ligand coated onto the nanoparticles in the same process of spray drying has yet to be developed. 2. Coating of ligand onto the surfaces of nanoparticles, is possible, may largely mediate via non-covalent bonding. Thus, it is highly probable that the ligand may leach out of the matrix, and this negates the biorecognition element of the ligand-tagged system. So far, only competitive surface adsorption has been exploited as the mode of forming an apparent coat encapsulating the core substance of spray-dried particles [18, 29]. The competitive adsorption is a common phenomenon of formulations containing a mixture of surface-active species. The formation of coated particles by spray drying process is accompanied by surface adsorption of surface-active species at the air-liquid interface of the drying droplets. The average lifetime of droplet surfaces is estimated to range between 0.1 and 1.0 s in a laboratory dryer. The transport and attachment of coating material in a drying droplet are strictly limited by the time scale, in addition to the physicochemical nature of substances which are largely surface active and can be undesirable with reference to pharmaceutical and biomedical applications. Page 11 of 16

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

Conclusion With reference to nanospray drying technology and its use in design of ligand-tagged nanoparticles, future endeavors shall focus on spray dryer instrument design and more specifically nozzle geometry invention. It is envisaged that the possibility to coat ligands via covalent bonding to the surfaces of sprayed droplets will lead to a revolutionary approach in particle manufacture. The use of nanospray drying technology in the preparation of ligand-tagged nanoparticles, if successful, is deemed to be highly desirable as spray drying is characterized by high process and product quality reproducibility, ease of instrument operation, and efficient product harvest attributes. It can broaden the application spectrum of spray drying process. In addition to fabrication of tumor-specific nanoparticles, the matrices may be coated for the purpose of controlled drug release; enhanced powder flow and stability; organ-specific delivery, namely, brain delivery using polysorbate, transferrin receptor-binding antibody (OX26), lactoferrin, cell-penetrating peptide, melanotransferrin, or peptidomimetic monoclonal antibody as ligand [44, 9]; as well as prevention of reticuloendothelial uptake via polyethylene glycol grafting to prolong nanoparticle’s systemic circulation and therapeutic effect [11, 65].

Acknowledgments The authors wish to thank Micheal Whelehan, Stefanie Meyer, and the Ministry of Science, Technology and Innovation (Nanofund) for technical support.

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28. K.A. Janes, P. Calvo, M.J. Alonso, Polysaccharide colloidal particles as delivery systems for macromolecules. Adv. Drug Deliv. Rev. 47, 83–97 (2001) 29. M. Jayasundera, B. Adhikari, P. Aldred, A. Ghandi, Surface modification of spray dried food and emulsion powders with surface-active proteins: a review. J. Food Eng. 93, 266–277 (2009) 30. D.M.K. Jensen, D. Cun, M.J. Maltesen, S. Frokjaer, H.M. Nielsen, C. Foged, Spray-drying of siRNA-containing PLGA nanoparticles intended for inhalation. J. Control. Release 142, 138–145 (2010) 31. C.K. Kim, Y.S. Yoon, J.Y. Kong, Preparation and evaluation of flurbiprofen dry elixir as a novel dosage form using a spray-drying technique. Int. J. Pharm. 120, 21–31 (1995) 32. S.A. Kularatne, P.S. Low, Targeting of nanoparticles: folate receptor, in Cancer Nanotechnology, Methods in Molecular Biology, ed. by S.R. Grobmyer, B.M. Moudgil, vol. 624 (Springer, New York, 2010), pp. 249–265 33. A. Kumari, S.K. Yadav, S.C. Yadav, Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf. B Biointerfaces 75, 1–18 (2010) 34. S.H. Lee, D. Heng, W.K. Ng, H.-K. Chan, R.B.H. Tan, Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy. Int. J. Pharm. 403, 192–200 (2011) 35. X. Li, N. Anton, C. Arpagaus, F. Belleteix, T. Vandamme, Nanoparticles by spray drying using innovative new technology: the B€ uchi nano spray dryer B-90. J. Control. Release 147, 304–310 (2010) 36. Z. Liu, Y. Jiao, Y. Wang, C. Zhou, Z. Zhang, Polysaccharides-based nanoparticles as drug delivery systems. Adv. Drug Deliv. Rev. 60, 1650–1662 (2008) 37. Y.L. Lo, J.C. Tsai, J.H. Kuo, Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase. J. Control. Release 94, 259–272 (2004) 38. S.E. McNeil, Unique benefits of nanotechnology to drug delivery and diagnostics, in Characterization of Nanoparticles Intended for Drug Delivery, Methods in Molecular Biology, ed. by S.E. McNeil, vol. 697 (Springer, New York, 2011), pp. 3–8 39. N. Mohajel, A. Roholamini Najafabadi, K. Azadmanesh, A. Vatanara, E. Moazeni, A. Rahimi, K. Gilani, Optimisation of a spray drying process to prepare dry powder microparticles containing plasmid nanocomplex. Int. J. Pharm. 423, 577–585 (2012) 40. A.B.D. Nandiyanto, K. Okuyama, Progress in developing spray-drying methods for the production of controlled morphology particles: from the nanometer to submicrometer size ranges. Adv. Powder. Technol. 22, 1–19 (2011) 41. L.M. Nolan, L. Tajber, B.F. McDonald, A.S. Barham, O.I. Corrigan, A.M. Healy, Excipient-free nanoporous microparticles of budesonide for pulmonary delivery. Eur. J. Pharm. Sci. 37, 593–602 (2009) 42. N.A. Ochekpe, P.O. Olorunfemi, C. Ndidi, Nanotechnology and drug delivery part 1: background and applications. Trop. J. Pharm. Res. 8, 265–274 (2009) 43. K. Ohashi, T. Kabasawa, T. Ozeki, H. Okada, One-step preparation of rifampicin/poly(lactic-coglycolic acid) nanoparticle-containing mannitol microspheres using a four-fluid nozzle spray dryer for inhalation therapy of tuberculosis. J. Control. Release 135, 19–24 (2009) 44. J.C. Olivier, Drug transport to brain with targeted nanoparticles. NeuroRx ® J. Am. Soc. Expt. Neurother. 2, 108–119 (2005) 45. A. Paudel, Z.A. Worku, J. Meeus, S. Guns, G.V.D. Mooter, Manufacturing of solid dispersions of poorly water-soluble drugs by spray drying: formulation and process considerations. Int. J. Pharm. 453, 253–284 (2013)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_18-1 # Springer International Publishing Switzerland 2015

46. S.H. Peighambardoust, A. Golshan Tafti, J. Hesari, Application of spray drying for preservation of lactic acid starter cultures: a review. Trends Food. Sci. Technol. 22, 215–224 (2011) 47. G. Pilcer, F. Vanderbist, K. Amighi, Preparation and characterization of spray-dried tobramycin powders containing nanoparticles for pulmonary delivery. Int. J. Pharm. 365, 162–169 (2009) 48. L. Plapied, N. Duhem, A. des Rieux, V. Préat, Fate of polymeric nanocarriers for oral drug delivery. Curr. Opin. Colloid Interface Sci. 16, 228–237 (2011) 49. E.M. Radman, T.W. Wong, Effects of microwave on drug release responses of spray-dried alginate microspheres. Drug Dev. Ind. Pharm. 36, 1149–1167 (2010) 50. M. Rothdiener, J. Beuttler, S.K.E. Messerschmidt, R.E. Kontermann, Antibody targeting of nanoparticles to tumor-specific receptors: immunoliposomes, in Cancer Nanotechnology, Methods in Molecular Biology, ed. by S.R. Grobmyer, B.M. Moudgil, vol. 624 (Springer, New York, 2010), pp. 295–308 51. A.K. Sailaja, P. Amareshwar, P. Chakravarty, Chitosan nanoparticles as a drug delivery system. Res. J. Pharm. Biol. Chem. Sci. 1, 474–484 (2010) 52. F. Sansone, R.P. Aquino, P. Del Gaudio, P. Colombo, P. Russo, Physical characteristics and aerosol performance of naringin dry powders for pulmonary delivery prepared by spray-drying. Eur. J. Pharm. Biopharm. 72, 206–213 (2009) 53. K. Schmid, C. Arpagaus, W. Friess, Evaluation of a vibrating mesh spray dryer for preparation of submicron particles. Respir. Drug Deliv. Eur. 2, 323–326 (2009) 54. K. Schmid, C. Arpagaus, W. Friess, Evaluation of the Nano Spray Dryer B-90 for pharmaceutical applications. Pharm. Dev. Technol. 16, 287–294 (2011) 55. S. Sch€ ule, W. Frieb, K. Bechtold-Peters, P. Garidel, Conformational analysis of protein secondary structure during spray-drying of antibody/mannitol formulations. Eur. J. Pharm. Biopharm. 65, 1–9 (2007) 56. Y.-J. Son, P. Worth Longest, M. Hindle, Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: effect of spray drying process conditions on aerosol performance. Int. J. Pharm. 443, 137–145 (2013) 57. K.S. Soppimath, T.M. Aminabhavi, A.R. Kulkarni, Biodegradable polymeric nanoparticles as drug delivery devices. J. Control. Release 70, 1–20 (2001) 58. Y.L. Su, Z.Y. Fu, J.Y. Zhang, W.M. Wang, H. Wang, Y.C. Wang, Q.J. Zhang, Microencapsulation of Radix salvia miltiorrhiza nanoparticles by spray-drying. Powder Technol. 184, 114–121 (2008) 59. J.C. Sung, B.L. Pulliam, D. Edwards, Nanoparticles for drug delivery to the lungs. Trends Biotechnol. 25, 563–70 (2007) 60. P. Tewa-Tagne, S. Briancon, H. Fessi, Preparation of redispersible dry nanocapsules by means of spray drying: development and characterisation. Eur. J. Pharm. Sci. 30, 124–135 (2007) 61. V.P. Torchilin, Passive and active drug targeting: drug delivery to tumors as an example, in Drug Delivery, Handbook of Experimental Pharmacology, ed. by M. Schafer-Korting, vol. 197 (Springer, New York, 2010), pp. 3–53 62. D. Vandenheuvel, A. Singh, K. Vandersteegen, J. Klumpp, R. Lavigne, G.V.D. Mooter, Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections. Eur. J. Pharm. Biopharm. 84, 578–582 (2013) 63. H. Vega Mercado, M. Marcela Gongora Nieto, G.V. Barbosa Canovas, Advances in dehydration of foods. J. Food Eng. 49, 271–289 (2001) 64. R. Vehring, Pharmaceutical particle engineering via spray drying. Pharm. Res. 25, 999–1022 (2008)

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65. M. Wang, M. Thanou, Targeting nanoparticles to cancer. Pharmacol. Res. 62, 90–99 (2010) 66. Y. Wang, K. Kho, W.S. Cheow, K. Hadinoto, A comparison between spray drying and spray freeze drying for dry powder inhaler formulation of drug-loaded lipid-polymer hybrid nanoparticles. Int. J. Pharm. 424, 98–106 (2012) 67. T.W. Wong, C.L. Law, A.S. Mujumdar, Drying of pharmaceutical products, in Guide to Industrial Drying: Principles, Equipment and New Developments, ed. by A.S. Mujumdar (Three S Colors, Mumbai, 2008), pp. 201–221 68. D.Y. Ying, J. Sun, L. Sanguansri, R. Weerakkody, M.A. Augustin, Enhanced survival of spray-dried microencapsulated Lactobacillus rhamnosus GG in the presence of glucose. J. Food Eng. 109, 597–602 (2012)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

The Development and Characterization of Stimulus-Sensitive Nano-/ Microparticles for Medical Applications Jyothi U. Menona,b, Dat X. Nguyena,b and Kytai T. Nguyena,b* a Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA b Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, TX, USA

Abstract Stimulus-responsive polymers, also known as “smart,” “intelligent,” and “environment-responsive” polymers, are a rapidly emerging class of materials that can respond to minor changes in environmental parameters such as pH, temperature, light, electric and magnetic field, salt concentration, and mechanical stress. This response is generally in the form of reversible transitions in shape, conformation, and/or hydrophilicity of the polymer. Nano-/microparticles prepared using smart polymers are of interest as their drug release characteristics can be modulated in response to external stimuli. This aids in controlling the release of encapsulated payloads until the particles reach the desired site. This book chapter attempts to summarize current research in the development of “smart” micro- and nanoparticles for various biological applications. It will also cover various parameters involved in smart particle preparation including polymers, surfactants, and methods used in nano-/microparticle formulation as well as surface modification and characterization of nano-/microparticles. Further, we will discuss recent research in dualstimulus-responsive and theranostic particles for multiple therapies. The future scope of these particles and hurdles to overcome for translation to clinical research will also be briefly discussed.

Keywords Stimuli; Temperature; pH; Responsive; Electric; Light; Nanoparticles

Abbreviations AAm AFM AH Azo CMC CTAB DAH DI DLS DMAB DNA DOX

Acrylamide Atomic force microscopy Allylamine Azobenzene Critical micelle concentration Cetyltrimethylammonium bromide Dodecylamine hydrochloride Deionized Dynamic light scattering Didodecyldimethylammonium bromide Deoxyribonucleic acid Doxorubicin

*Email: [email protected] Page 1 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

dT-DMAEMA/HEMA EDX EGFR FDA FVB GPC HA LCST LTSLs MALDI-TOF MS MDR mPEG MPs MRI MSPC NIR NMR NPs PAMAM PCL PCS PDEAM PEG PEO PLGA PMA PNIPAAm/PNIPAM/ PNIPA PPy PVA QELS RAFT RF SD SDS SEM SQUID TEM TEMED UCST UV VSM XPS ZWC

Dithiolated dimethylaminoethyl methacrylate/(hydroxyethyl) methacrylate Energy-dispersive X-ray spectroscopy Epidermal growth factor receptor Food and Drug Administration Friend virus B-type Gel permeation chromatography Hyaluronic acid Lower critical solution temperature Lyso-lipid thermosensitive liposomes Matrix-assisted laser dissociation–ionization time-of-flight mass spectrometry Multidrug resistance Monomethyl ether PEG Microparticles Magnetic resonance imaging 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphatidylcholine Near infrared Nuclear magnetic resonance Nanoparticles Polyamidoamine Poly(e-caprolactone) Photon correlation spectroscopy Poly(N,N-diethylacrylamide) Polyethylene glycol Polyethylene oxide Polylactic-co-glycolic acid Polymethacrylates Poly(N-isopropylacrylamide) Polypyrrole Polyvinyl alcohol Quasi-elastic light scattering Reversible addition–fragmentation chain transfer Radio frequency 4-Sulfonic diphenylamine Sodium dodecyl sulfate Scanning electron microscopy Superconducting quantum interference device Transmission electron microscopy Tetramethylethylenediamine Upper critical solution temperature Ultraviolet Vibrating sample magnetometer X-ray photoelectron spectroscopy Zwitterionic chitosan

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

Introduction In the race for miniaturization of equipment and technology to impart greater accuracy and specificity, scientists have developed the field of “nanomedicine” for controlled delivery of therapeutic agents to the site of interest. Nanomedicine is essentially an area of study involving the use of nanotechnology to diagnose and treat diseases at the molecular level. This research area is better than conventional treatment methods due to its attractive properties such as improved solubility and bioavailability of the drug, specific targeting of diseased organs, reduced drug toxicity due to the use of lower dosages, as well as multifunctionality for diagnosis and therapy [1, 2]. The past few decades have seen an increasing interest in the development of biocompatible nanocarriers as drug delivery devices. A wide variety of nanocarriers ranging from liposomes and micelles to emulsions and multifunctional polymeric nanoparticles (NPs) are available today for various drug delivery applications. Polymeric microparticles (MPs) and nanoparticles (NPs) have immense potential as drug delivery vehicles since their parameters can be manipulated and modified according to the desired application. However, the need for accurate and controlled therapy as well as recent advances in nanomedicine led to the development of stimulus-responsive/“smart”/“intelligent” polymer-based MP/NP systems where the polymer plays an active role in the accurate delivery and release of the drug [3]. Smart polymers respond to changes in external stimuli such as temperature, pH, light, magnetic field, and so on by undergoing dissociation or rapid and reversible phase transition. This phase transition usually involves change in properties of the polymeric MPs/NPs from hydrophilic to hydrophobic or vice versa, resulting in rapid release of the encapsulated drug within the diseased cell, leading to cell death (Fig. 1). This chapter attempts to briefly review some of the different types of stimulus-responsive polymers being studied today for micro-/nanoparticle synthesis, their methods of formulation and characterization, as well as the challenges to overcome in order to bring them into clinical trials. Some of the recent works on stimulus-sensitive micro- and nanoparticles for controlled drug delivery have also been summarized in Table 1.

Common Stimulus-Sensitive Polymers Used in Microparticle (MP)/ Nanoparticle (NP) Synthesis Stimulus-responsive polymers are polymers with the unique property of demonstrating sharp phase/ property changes in response to environmental stimuli such as temperature, pH, light, electric and magnetic fields, as well as biochemical signals. Drug delivery vehicles synthesized using these polymers

Fig. 1 Diagrammatic illustration of drug release by stimulus-sensitive NPs within the targeted cell resulting in cell death Page 3 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

Table 1 Brief summary of various stimulus-responsive NPs developed for diagnosis and treatment of different diseases Polymer used Nanoparticles Chitosan/heparin

Stimulus

Therapeutic agent

Application

References

pH

–

[8]

Hyaluronic acid

pH

Insulin

PNIPAAm–AAm–AH (core), PLGA (shell) P(NIPAAm-co-PAA) liposomes HPHEEP-Azo micelles

Temperature

Curcumin, doxorubicin

Temperature UV and visible light Electrical

Doxorubicin –

Temperature, magnetic Sugar Temperature, pH

–

Anti-Helicobacter pylori therapy Oral insulin delivery for insulin-dependent diabetes Targeted melanoma therapy Cancer therapy Controlled drug release Sensors (e.g.: enzymatic biosensors, immunosensors) Targeted prostate cancer treatment Sensor device Transdermal delivery

pH

Insulin

Eudragit P-4125 F (methacrylic acid, methyl acrylate, and methyl methacrylate copolymer)

pH

Low molecular weight heparin (enoxaparin)

Magnetic nanoparticles coated with poly(N-isopropylacrylamide-coaminoethylmethacrylate) (PNIPAMco-AEMH) Poly(N-isopropylacrylamide-coallylamine) (PNIPA–AH) shell, PLGA core

Temperature

DNA

Temperature

Chitosan, concanavalin A, and dextranbased composite MPs PEG–peptide microgels

Glucose

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) Insulin

Enzyme (trypsin) Temperature, pH

IgG, DNA, polystyrene NPs Fibroblast growth factor-2 (FGF-2)

4-Sulfonic diphenylamine–pyrrole NPs

PNIPAAm–AAm–AH NPs PNIPAm–phenylboronic acid NPs P(NIPAM-co-AAc) nanogels Microparticles Poly(ester amide) MPs

Poly(N-isopropylacrylamide-co-propyl acrylic acid-co-butyl acrylate) (p (NIPAAm-co-PAA-co-BA)) microspheres

–

– Caffeine

Oral insulin delivery Oral delivery to colon to treat inflammatory bowel disease Nucleic acid extraction, purification, concentration Cell isolation and expansion, nonchemical detachment Self-regulated insulin delivery Pulmonary drug delivery Controlled protein delivery to ischemic tissues

[9]

[19] [138] [26] [32]

[41] [44] [131]

[139] [140]

[141]

[142]

[143] [45] [144]

can be used for a wide range of medical applications to provide accurate, stimulus-sensitive therapy (Fig. 2). This section reviews the most common stimulus-responsive polymers in use as micro-/ nanocarriers for drug delivery.

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Fig. 2 Schematic of application of stimulus-sensitive nanoparticles following administration

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

pH-Responsive Polymers pH-responsive polymers are a newly emerging area of study used in a wide array of medical applications ranging from delivering drugs to the acidic stomach lumen and tumor microenvironment to intracellular drug delivery [4]. The acidic milieu of the stomach (pH 1.5–2.5) consists of a hostile environment for microbial pathogens that can cause food- and waterborne diseases [5]. However, certain microorganisms such as Helicobacter pylori can survive the harsh acidic conditions of the stomach and adhere to the cell–cell junctions between gastric mucous cells to cause peptic ulcers [6]. Antibiotics required for treating this disease must therefore be able to retain their activity in acidic gastric juice as well as permeate the mucous layer to reach the bacteria for an effective treatment. Chitosan is a naturally derived pH-responsive polymer with multiple attractive properties such as biocompatibility, mucoadhesiveness, abundance, and biodegradability, among others [7]. Lin et al. [8] have recently developed pH-responsive NPs using chitosan and heparin for anti-H. pylori therapy. Chitosan and heparin can form stable polyelectrolyte complexes between the pH range of 1.2 and 6.5 and will break apart at higher pH and release the encapsulated agents. The developed NPs (130–300 nm in diameter) were stable at a pH of 1.5–2.5, thereby protecting encapsulated drugs from the damage due to gastric juices. Further, the particles were cytocompatible with human gastric mucosa cells (AGS) up to 1 mg/ml concentration, while in vivo studies on Balb/c mice demonstrated that the NPs could penetrate the cell–cell junctions and interact with H. pylori infection sites. pH-sensitive hyaluronic acid (HA) has also been used to develop NPs for oral insulin delivery [9]. The 182.2 nm-sized NPs showed less than 10 % insulin release at pH 1.2 and more than 80 % release at 6.8 pH, thereby demonstrating their pH sensitivity. These particles could permeate through the intestine of diabetic rats and showed greater hypoglycemic effects than oral delivery of insulin solution alone [9]. In addition to oral drug delivery, pH-sensitive polymer-based NPs can also be used in the delivery of therapeutic agents to tumors, which exhibits an extracellular pH (6.0–7.0) lower than that observed in normal tissues (~7.4) [10]. Chitosan NPs encapsulating the anticancer drug 5-fluorouracil (FU) had an average size of 243.1
17.9 nm and showed significant pH-dependent swelling and drug release at a pH of 5 than at other tested pH [11]. Recently, a doxorubicin (DOX)-encapsulated NP system consisting of dithiolated dimethylaminoethyl methacrylate/(hydroxyethyl) methacrylate (dT-DMAEMA/HEMA) and gold NPs aided in greater release of DOX at pH 5.5 (44 % release) in 8 h than at pH 7.4 (15 % release) [12]. Other pH-responsive polymers used in the development of nanocarriers for cancer treatment include other polymethacrylates (PMA) [13], methacrylic acid [14], acrylic acid [15], and poly(vinylpyridines) [16]. pH-sensitive polymers also play a very important role in intracellular drug delivery. Endosomes within the cells maintain an acidic environment (pH 5–6) which is beneficial for delivery of various drugs and genes. DMAEMA/HEMA NPs encapsulating DNA and labeled with quantum dots were synthesized by You et al. [17] for gene delivery applications. The NPs demonstrated higher DNA release at pH 5.5, which is in the endosomal pH range, than those at pH 6.5 and 7.4. These particles were also successfully endocytosed by HeLa cells in a time-dependent manner. Some of the pH-responsive nanocarriers developed recently for drug delivery applications have been summarized in Table 2.

Thermosensitive Polymers Temperature-sensitive NPs are an emerging class of biomaterials that have been receiving widespread attention for the past several decades. These polymers have the unique property of undergoing rapid and reversible phase transitions in response to changes in temperature. Some polymers become hydrophobic above a certain temperature (lower critical solution temperature, LCST), while others demonstrate hydrophilicity above a designated temperature (upper critical solution temperature, UCST) [18]. The LCST or UCST of the polymer can be maintained at 37  C for accurate drug delivery at body temperature or increased to 40–45  C for dual therapy by combination of drug delivery with hyperthermia (inducing Page 6 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

Table 2 pH-sensitive nanoparticles used in drug delivery applications Polymer Chitosan and heparin Hyaluronic acid

Size (nm) 130–300 182.2

Encapsulated agent – Insulin

References [8] [9]

5-FU DOX DNA Cisplatin DOX

Applications Anti-H. pylori therapy Oral insulin delivery for diabetes treatment Anticancer therapy Breast cancer treatment Gene delivery Cancer treatment Cancer treatment

Chitosan dT-DMAEMA/HEMA DMAEMA/HEMA PDEA–PEG Poly(methacrylic acid)–polysorbate 80-grafted starch Polymethacrylic acid–PEG–chitosan PEG, calcium phosphate

243.1 186.4 200 81.9 310 330 79.8

Metoprolol tartrate DOX

Oral drug delivery Cancer treatment, imaging

[75] [133]

[11] [12] [17] [51] [53]

Table 3 Temperature-sensitive nanoparticles used in drug delivery applications Polymer PLGA core, PNIPAAm–AAm–AH shell

Size (nm) 296

Encapsulated agent DOX, curcumin

P(NIPAAm-co-PAA) PNIPAAm–AAm–AH

93.3–131.7 243.1

DOX –

Poly(2-isopropyl-2-oxazoline)

37–41

–

mPEG–PLGA PNIPAM

50–100 350

Teicoplanin DOX

PAMAM, PDLLLA, PEG PNIPAM, PFV

203–1,027 24

Camptothecin –

Hydroxypropyl cellulose PNIPAM-2-acrylamido-2-methyl-1propanesulfonic acid

160–250 293–408

Curcumin TNF-a, IL-6

Applications Melanoma-targeted therapy Cancer therapy Prostate cancer treatment Thermosensitive drug carrier Osteomyelitis treatment Targeted cancer treatment Cancer treatment Cellular imaging, biosensing Cancer therapy Osteoarthritis treatment

References [19] [138] [41] [20] [122] [130] [76] [145] [146] [147]

heat in the tissue leading to eventual tissue death). Some of the recent works on thermosensitive NPs have been summarized in Table 3. The most widely studied thermoresponsive polymer is poly (N-isopropylacrylamide) (referred interchangeably to as PNIPAM/PNIPA/PNIPAAm) with an LCST of about 32–33  C [18]. This polymer has been used for a wide range of applications ranging from thermosensitive nano-/microcarrier to “smart” surface for cell sheet engineering. Our lab has previously synthesized multilayered NPs consisting of iron oxide-embedded polylactic-co-glycolic acid (PLGA) polymer core and PNIPAM-based shell for dual-drug release to treat melanoma. DOX was encapsulated in the shell made of PNIPAM which was modified using acrylamide (AAm) and allylamine (AH) to increase the LCST to 41  C [19]. An alternating magnetic field could be used to produce heat in the iron oxide particles at the site of interest so that LCST can be achieved. Our cytocompatible NPs showed temperature-dependent release of doxorubicin with more of drug release at 41  C than other temperatures

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

(25  C). Polyoxazolines are the other class of biocompatible thermoresponsive polymers having an LCST close to 37  C. Park et al. [20] have developed novel poly(2-isopropyl-2-oxazoline)-based micelles which showed phase separation at 32  C and can potentially be used as a temperature-sensitive carrier for therapeutic agents. Other thermoresponsive polymers include poly(N,N-diethylacrylamide) (PDEAM) [21], poly(methyl vinyl ether) [22], polymethacrylamide (PMAAm) [23], and poloxamer [24].

Light-Sensitive Polymers Light-sensitive polymers are important because they can be used to achieve immediate and highly localized drug release upon exposure to light. These polymers may be responsive to visible light or ultraviolet (UV) light. Azobenzene is a chromatophore that is widely used in the synthesis of lightresponsive polymers due to its unique ability to undergo cis-trans photoisomerization or vice versa depending on the wavelength of incident light [25]. Chen et al. [26] have reported the development of photo-responsive micelles using b-cyclodextrin and a hyperbranched polymer containing amphiphilic azobenzene (HPHEEP-Azo). These micelles self-assembled in the presence of UV light and disassembled on exposure to visible light. The disassembly occurred due to the photoisomerization of azobenzenes from cis to trans form, and this property would be beneficial for light-responsive controlled drug release. Fomina et al. [27] have recently synthesized NPs using a light-sensitive polymer consisting of quinone methide moieties in its backbone. These moieties self-immolate in the presence of UV or near-infrared (NIR) light, resulting in polymer degradation and subsequent drug release. Since NIR can penetrate deep into tissues, these particles could potentially be used for in vivo applications involving drug delivery to deep tissues. Some other reported photosensitive polymers for nanomedical applications include polyurethane with photocleavable 2-nitrophenylethyleneglycol backbone [28], hydroxyethylacrylate and photodegradable methoxy-nitrobenzyl ether derivative-based copolymer [29], and polymers or particles with o-nitrobenzyl ester-based linkages [30, 31].

Electric and Magnetic Field-Responsive Polymers The use of electric field-responsive polymers is highly advantageous for easily controlled and accurate drug delivery following stimulation using an external electric field. Polypyrrole (PPy) is a commonly used conducting polymer due to its good stability, ease of synthesis, and greater conductivity compared to other conductive polymers [32]. It is used for a wide range of biological applications due to its ability to support growth of electrically responsive cells such as neuronal cells [33], bone cells, and smooth muscle cells [34]. Li et al. [32] had synthesized stable, conductive NPs using a copolymer of PPy and 4-sulfonic diphenylamine (SD). The NPs having 50/50 monomer ratio showed the smallest size (20 nm) and highest conductivity (0.217 S cm1) when using FeCl3 as an oxidant during synthesis. Recently, Ge et al. [35] synthesized PPy NPs embedded in a temperature-sensitive poly (lactic-co-glycolic acid) (PLGA)–polyethylene glycol (PEG)–PLGA hydrogel. Drug release from these biocompatible NPs occurred when a weak external DC electric field was applied. Subcutaneous injection of the hydrogel containing fluorescein dye-loaded PPy NPs into FVB (Friend virus B-type) adult mice showed that the application of a 1.5 V cm1 electric field triggered the fluorescein release. The electric field-dependent fluorescein release was also observed via the increasing fluorescence at the injection site, which was detected by fluorescent imaging. Polyaniline is another environmentally stable conducting polymer that has gained attention due to its low cost and ease of manufacture, as well as its desirable optical and electrical properties [36]. Kim et al. [37] have developed nanosized silver–polyaniline–silica complexes using ɤ-irradiation for biosensing applications. These particles (10–30 nm) showed a high semiconductivity of 200 S cm1. Page 8 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

Further, Alves et al. [36] synthesized stable polyaniline NPs using different surfactants, which showed a size range of 25–59 nm and underwent reversible color change from green to blue to violet at pH values of 1.3, 8.1, and 12.4, respectively. This dual property of polyaniline would be highly useful for the development of biosensors, light-emitting devices, and fluorescent pigments. Other polymers that can respond to electrical stimuli and have great potential in biomedical applications include polythiophene, poly(3,4-ethylenedioxythiophene), and poly(phenylenevinylene) [38, 39]. Besides an electric field, stimulus-sensitive drug release can also occur in the presence of a magnetic field. Magnetically responsive systems are essentially polymeric NPs containing g-Fe2O3 or Fe3O4 components. Superparamagnetic iron oxide NPs are of interest as they can flip their direction of magnetization in response to changes in magnetic field and temperature [40]. These systems can be guided to the region of interest in the body using an external magnetic field thus resulting in controlled and accurate drug release at the disease site. As previously described, we have synthesized temperature- and magnetic field-responsive NPs containing PNIPAAm-based shell (LCST ~40  C) and Fe3O4 core for prostate cancer treatment [41]. These particles could be recruited to the disease site using a magnetic field and used to induce hyperthermia by providing an alternating magnetic field, which would result in temperature-dependent release of the encapsulated therapeutic agents. Kong et al. [42] have developed stable lipid–PLGA hybrid NPs (80 nm size) containing Fe3O4 and loaded with camptothecin, which showed stimulus-dependent drug release on application of a remote radio frequency (RF) magnetic field. These particles showed significantly higher MT2 mouse breast cancer cell death in the presence of RF than in the absence of RF, indicating localized heating of the Fe3O4 and subsequent high stimulusresponsive drug release. In addition to iron oxide nanoparticles, manganese oxide-based NPs also possess ferromagnetic properties and can be used for drug delivery applications [43].

Biological and Chemical Stimulus-Responsive Polymers Several polymers and NPs that respond to biological and chemical stimuli have also been developed. This research is attractive as no artificial source of stimulus would need to be provided to encourage drug release. For instance, Zenkl et al. [44] have developed sugar-responsive polymer-based NPs using PNIPAM and phenylboronic acid. The interaction between sugar and phenylboronic acid due to counterion osmotic effects will lead to stimulus-responsive swelling of the particles. In addition, Wanakule et al. [45] developed enzyme-responsive microgels using PEG acrylate and a trypsin-sensitive di-sulfhydryl peptide that can rapidly release encapsulated polystyrene NPs, DNA, and dye within 30 minutes of addition of trypsin digestion buffer. This system can be modified to respond to other disease-specific enzymes as well. Enzyme-responsive hyaluronic acid-based NPs were also developed to treat bacterial infection [46]. The NPs loaded with antimicrobial agent polyhexanide can be cleaved by hyaluronidase produced by several Gram-positive bacteria. The subsequent drug release would aid in killing bacteria effectively [46]. An example of chemical stimulus-responsive NPs is the DNA-functionalized gold NP aggregates linked using an adenosine aptamer. The aptamer switches its structure in response to the presence of adenosine, resulting in dissociation of the NP aggregates and a subsequent change in the color of the NP solution [47].

Copolymerization of Stimulus-Responsive Polymers In order to overcome limitations of some polymers, they can be copolymerized with other polymers in order to improve their properties. One of the major limitations of PNIPAM is that it is not biodegradable and hence cannot be easily cleared from the body. As a result, efforts are being taken toward the development of thermoresponsive and biodegradable PNIPAM-based polymers by copolymerizing it Page 9 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

with other degradable polymers [48]. For example, biocompatible and biodegradable dextran has been copolymerized with PNIPAM using UV cross-linking to form nanosized hydrogel beads. The noticeable decrease in volume at 37  C indicated that the particle attained LCST at this temperature [49]. PNIPAAm can also be copolymerized with hydrophilic monomers to increase their LCST or hydrophobic monomers to decrease their LCST, depending on their application. For instance, the PNIPAAm–AAm–AH synthesized by us had an LCST of 41  C due to the hydrophilic nature of acrylamide [50]. pH-responsive copolymers have also been formed using pH-responsive polymer poly[2-(N,N-dimethylamino)ethyl methacrylate] (PDEA) and the biocompatible PEG. NPs prepared using this polymer combination dissolved rapidly at pH less than six prevalent in cellular lysosomes, resulting in burst release of cisplatin for cancer treatment [51]. Also, thermoresponsive and biocompatible interpenetrating network (IPN) NPs were prepared using poly(oligo(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) ethyl ether methacrylate)–poly(acrylic acid). The particles showed temperature- and pH-dependent properties by gelling at 37  C only at pH 7 while remaining in liquid form in pH 4 at body temperature [52].

Surfactants Used in MP/NP Preparation In order to maintain appropriate particle size and stability, surfactants have to be used in the MP/NP formation in order to maintain surface tension between particles, thus preventing aggregation. Some commonly used surfactants in smart MP/NP formulations are described below.

Anionic Surfactants Sodium dodecyl sulfate, or SDS, remains one of the more popular anionic surfactants currently used in synthesis of NPs, due to its stability enhancement toward developing particles [8]. Studies have shown that SDS in aqueous solution helps stabilize particle surface, providing a size control parameter in synthesis [53, 54]. Shalviri et al. [53] had shown that as the amount of SDS surfactant increases, both average NP diameter and polydispersity values decrease, which provides an ideal requirement for successful synthesis of pH-sensitive poly(methacrylic acid)–polysorbate 80-grafted starch NPs. Despite its usefulness in NP preparation, SDS carries a major drawback by exhibiting toxicity to experimenting cells [54]. Thus, it is essential to remove unreactive SDS after the formation of NPs in order to achieve minimal cytotoxicity effect. Other anionic surfactants used in synthesis of stimulus-responsive NPs include sodium dodecylbenzene sulfonate [55] and dodecylbenzene sulfonic acid [56].

Cationic Surfactants Cetyltrimethylammonium bromide (CTAB) is a type of cationic surfactant used in synthesis of stimulusresponsive NPs. Its qualifications as a surfactant are comparable to other nonionic surfactants such as Tween 80 (polysorbate 80), Pluronic P-123, and Pluronic F-127. Possessing anticancer and chemosensitizing effects, CTAB shows high potential to overcome multidrug resistance (MDR) in cancer [57]. CTAB has been utilized as the surfactant in the synthesis of Fe3O4 NP-capped mesoporous silica with reversible pH responsiveness [58]. Elsewhere, He et al. [57] incorporated CTAB as the surfactant for the synthesis of drug-loaded mesoporous silica NPs (MSNs) because of its chemosensitizing and enhancement of drug efficacy. As demonstrated, the mechanism of overcoming multidrug resistance and showing cell apoptosis effect was mainly supported by chemosensitization of the CTAB surfactant. Overall, CTAB is one of the few cationic surfactants that provide many advantageous properties. Meanwhile, a study integrated NP formulations using three different cationic surfactants – didodecyldimethylammonium bromide (DMAB), dodecyltrimethylammonium bromide Page 10 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

(DTAB), and dodecylamine hydrochloride (DAH) – to encapsulate BSA-Cy5 fluorescent protein [59]. However, only DMAB could generate NPs via stabilizing effect. The two surfactants DTAB and DAH required PVA as the stabilizer first before functionalizing PLGA NPs. While DMAB imparted a positive surface charge on the NPs, DTAB and DAH provided neutralization to the strong negative charge of the particles, suggesting all three surfactants play an important role in binding elastin to the PLGA NPs [59]. Overall, the cationic surfactants discussed here have showcased some additional benefits to NP preparation besides behaving as a good stabilizer.

Nonionic Surfactants Nonionic surfactants offer a variety of choices as the stabilizer in NP preparation, ranging from polyvinyl alcohol (PVA), Span, and polysorbate (also referred to as Tween) to the Pluronic family. PVA, one of the most commonly used emulsifiers in the pharmaceutical industry, is also used in many stimulus-responsive NP syntheses [59, 60, 61]. Arizaga et al. [61] investigated effects of PVA concentrations on NP properties and saw a decrease in sphere size as well as polydispersity when the PVA concentration increased. The research also observed an increase in viscosity with increasing PVA concentration, in which they concluded in the resultant of a stable, smaller, and more uniform NP system with lower polydispersity when using PVA as the surfactant. Alternatively, Span 80 and Tween 80 (also known as polysorbate 80) are other commonly used nonionic surfactants [53, 62, 63]. Tween 80 stabilizes dispersed NPs via steric stabilization. Aside from being a common solubilizing agent, it also could aid coated NPs to be transported across the blood–brain barrier after systemic administration [53]. Besides Span and Tween surfactants, poloxamers or Pluronics are also being used in NP preparations. These are a set of nonionic triblock copolymer surfactants that are relevant to biomedical research due to their easily customized features and, more importantly, the ability to target MDR cancer cells leading to sensitization of chemotherapeutic agents [64]. Yan et al. [64] demonstrated the functions of poloxamer 188 (FDA trade name Pluronic F68) on managing NP morphology, size, cancer cell uptake, and cytotoxicity. Results showed that size distribution and average size of NPs were smaller with the incorporation of poloxamer 188. Moreover, an increased level of uptake and higher cytotoxicity were observed, which suggests advantages of the surfactant in aspects of efficacy in chemotherapy. On the other hand, a study presented the relationship of Pluronic F-127 to the loading efficiency of encapsulated drug [65]. Due to its stabilizing effect on magnetic particles, Pluronic F-127 was able to dissociate the magnetite NPs (MNPs) via steric hindrance. More importantly, as NPs were coated with higher amount of Pluronic F-127, a higher loading efficiency of doxorubicin drug was observed due to its influence on the hydrophobic interaction between doxorubicin and MNPs [65]. Overall, the Pluronic surfactants broadly attribute their features to not only stabilize NPs but also to influence drug loading, cytotoxicity, and cell uptake.

Micro-/Nanoparticle Preparation Techniques Several different techniques such as emulsion, ionic gelation, polymerization, and polyelectrolyte complex formation can be implemented for NP synthesis. These techniques have been briefly summarized below.

Emulsion The emulsion technique is used when different components of the nanoparticle system have varying solubilities. The hydrophobic component dispersed in an organic solvent forms the oil phase, while the hydrophilic component dispersed in water forms the water phase. For example, Wu et al.[66] synthesized Page 11 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

insulin-loaded pH-sensitive PLGA–hydroxypropyl methylcellulose phthalate (PLGA/HP55) NPs using a multiple emulsion solvent evaporation method, for oral drug delivery. Briefly, the insulin solution was added to the polymer solution prepared in methylene chloride and acetone to form the first water-in-oil primary emulsion. This was then poured into the PVA solution to form the final NPs. Sonication was employed to break down the emulsion into appropriate nanosized carriers.

Ionic Gelation and Polyelectrolyte Complex Formation Ionic gelation can be used to facilitate ionic interactions between the polymer and another compound to eventually form nanocarriers. For example, the positive primary amine groups on chitosan can interact with the negative groups on a nontoxic polyanionic cross-linker such as sodium tripolyphosphate to easily form chitosan NPs [67]. This technique is preferred for its simplicity as well as for large-scale production of uniformly dispersed NPs [68]. Polyelectrolyte complex formation is a similar method involving electrostatic interaction between oppositely charged substances such as polymers, drugs, and surfactants for NP formation [69].

Polymerization Techniques NPs can be formed directly from polymers or by polymerization of individual units called monomers. Rahimi et al. [50] used silanized iron oxide particles as a template for free radical polymerization of PNIPAAm–AAm–AH NPs. Ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) were used to initiate and accelerate the reaction. Sun et al. [70] utilized ring opening polymerization along with reversible addition–fragmentation chain transfer (RAFT) polymerization to synthesize poly(e-caprolactone)-block-poly(ethylene oxide)-block-PNIPAAm (PCL-b-PEO-b-PNIPAAm) triblock copolymers for thermosensitive NP preparation. Suspension and dispersion polymerization have also been employed to synthesize stimulus-responsive NPs.

Surface Modification of MPs/NPs In order to facilitate greater circulation time and targeted therapy, NPs can be surface modified using other polymers or biomolecules such as peptides, aptamers, and antibodies. Several commonly used surface modification techniques are briefly discussed in this section.

PEGylation PEG is a common stabilizing polymer possessing advantages such as hydrophilicity, nontoxicity, nonantigenicity, and non-immunogenicity [71]. PEG mainly functions to sterically stabilize NPs and increase their circulation time in the bloodstream due to its inert ability to protect particles from undesired attacks in biological systems [71–73]. As a result, PEG often acts as a hydrophilic stabilizer that prevents NPs from undergoing macrophage recognition, protein adsorption, and enzyme digestion [72]. In current research, PEG has been incorporated in many stimulus-responsive NP systems. Specifically, Yoo et al. [73] investigated the effect of PEG onto folated, superparamagnetic iron oxide NPs for applications in lung cancer imaging, since PEG exhibits excellent biocompatibility and allows their particles to display low cytotoxicity and stability. Unlike the van der Waals force and hydrogen bonds, covalent bonds such as PEG diacid could prevent particle aggregation, improve particle dispersion, and not influence magnetic properties. Another useful application of PEG in encapsulated drug interaction is seen in a study by Deng et al. [74]. When coating PEG–PLA onto hollow magnetic Fe3O4 microspheres with encapsulated cisplatin, the researchers found that the amphiphilic materials interacted with the drugs to provide a more sustained drug release, thus reducing harmful side effects. Page 12 of 31

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PEG has also been exploited in pH- and thermoresponsive NPs for drug delivery applications. For instance, PEG had been incorporated in a pH-responsive, folated NP system as a hydrophilic domain, to serve as a protecting agent from unwanted digestion in the biological media [72] as well as to stabilize the micelles and prolong NP circulation. Pawar et al. [75] promoted PEG as the stabilizer to their polymethacrylic acid, chitosan-based NPs. Due to the established intermolecular hydrogen bonds PEG’s oxygen groups and polymethacrylic acid’s carboxylic groups, PEG helped stabilize the polymer while simultaneously encouraging mucoadhesion and improving chain mobility and flexibility. In the work of Kailasan et al. [76], thermoresponsive polyamidoamine (PAMAM) dendrimers copolymerized with poly(D,L-lactide) (PDLLA) is conjugated with PEG in order to enhance biocompatibility of the material, reduce immunogenicity of dendrimers, and better encapsulate hydrophobic compounds to delay enzymatic hydrolysis. Moreover, PEG has shown to provide camouflage effect that permits macrophage bypass for NPs while also preventing protein adsorption onto NP surface [77].

Conjugation of Biomolecules NPs can be surface conjugated with cell-specific biomolecules for targeted therapy. One of the common targeting moieties being used in current research is folate or vitamin M. Folate and folic acid possess a high receptor affinity toward folate receptor, a powerful biomarker that is often overexpressed on brain, kidney, lung, and breast cancer cells [78]. A number of researches have incorporated folate onto their magnetic field-responsive NPs for the purpose of contrast imaging as well as drug delivery [73, 78, 79]. The results from these studies showed high cellular uptake by folate receptor-overexpressing cells, thus significantly increasing NP cytotoxicity against cancer cells. Such effect could also provide useful means for imaging of cancer cells. Another ligand with a similar targeting mechanism is HA due to the elevated presence of hyaluronic acid receptors on cancer cells. Thus, HA has also been studied on a pH-responsive chitosan NP design, and similar enhanced cell uptake results were shown [80]. In addition to ligands, peptides/aptamers are another class of biomolecules that have been widely studied in the targeting of cancer cells. Domains and integrins are important biomarkers frequently overexpressed in malignant vasculature and tumor tissues. Thus, peptides that specifically bind to these cancer cell biomarkers are exploited as effective targeting ligands for NPs. The peptide responds only to a specific domain on cellular membrane, so researchers often concentrate on an appropriate peptide that binds well with the type of cancer cells being studied. A recent study combined the use of magnetic and peptide ligand for the development of a dual-drug delivery system, in which conjugating tumor-targeting ligand RGD peptides were used to target avb3-integrin-expressing tumor vasculature and consequently administer drugs to tumors [81]. Meanwhile, a research by Park et al. [82] reported the development of novel high-affinity peptides that target a variety of protein targets. The peptides were integrated in superparamagnetic iron oxide NPs for the targeting of fibronectin extra domain B (EDB). The NPs were used for detecting targeted tumors by magnetic resonance imaging (MRI). NP can also be targeted to cells by surface conjugating with antibodies. Maya et al. [83] took advantage of monoclonal antibody cetuximab (Cet) and developed a pH-responsive chitosan nanoparticulate system for targeting epidermal growth factor receptor (EGFR)-overexpressing cells. Due to Cet antibody’s ability to block EGFR activation stimulating tumor growth, NPs were internalized effectively by EGFRoverexpressing cells and consequently reinforced the targeting ability of antibody-conjugated NPs. For the purpose of imaging tumors, biomolecular dyes offer great advantages to NPs. Dye-doped NPs have appeared in a number of researches that aim to serve in MRI applications, due to good photostability, biocompatibility, and easy modifications compared to other luminescent probing techniques such as quantum dots and fluorescent beads [79, 84]. The rhodamine dye family is one of the most common luminescent probes used for the detection of cancer cells. Different types of rhodamine dyes including rhodamine B, rhodamine 123, and rhodamine 6G have been extensively conjugated to stimulusPage 13 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

Table 4 Summary of NP characterization techniques Property characterized Particle size Particle visualization

Instrument used DLS TEM SEM AFM

Particle composition

FTIR EDX

XPS NMR MALDI-TOF Stimulus sensitivity

pH Temperature

Magnetic field

Stability Drug release characteristics

DLS, spectrometer Spectrophotometer, ELISA, assays

Degradation

Weight loss, GPC

Characteristics Laser scattering by NP Brownian motion Detection of transmitted electrons following electron beam interaction with sample Detection of backscattered electrons and radiations following interaction of electron beam with sample Detection of reflection of laser beam at the end of a flexible cantilever on interaction with the sample Variation in transmittance or absorption intensity of IR light Backscattered electromagnetic radiations emitted in the form of characteristic X-rays following electron beam bombardment of sample Measurement of backscattered photoelectrons following X-ray bombardment of sample Detection of electromagnetic radiation emitted from sample in a magnetic field NP components analyzed following ionization with assistance from a proton donor/acceptor matrix Size change in different pH using DLS Visual observation, DLS DSC – assessment of thermal stability based on amount of heat flow through sample UV–Vis spectrometry – detection of sharp changes in optical transmittance due to phase transition VSM/SQUID – detection of magnetic moment of NPs in a uniform magnetic field MRI Particle size change or turbidity measurement over time Detection of drug release at body temperature based on drug absorption/fluorescence wavelengths, binding to antibody or using other assays NP weight measurement at predetermined time points GPC – separation of components based on size and molecular weight

References [85] [92, 93] [90, 91] [95, 96] [97] [98]

[99] [100] [101] [11] [102–104]

[106]

[114] [9]

[121, 122]

responsive NPs in research to illustrate the effectiveness of their NPs in targeting tumor sites [79, 81, 82, 83]. Such incorporation of fluorescent dyes also serves to provide an MRI contrasting agent for the sole purpose of imaging. A study by Sahu et al. [79] aimed to establish this by conjugating a luminescent organic dye, rhodamine B, into their magnetic, silica-shelled NPs. The reported studies demonstrate the wide application of fluorescent dyes in the biomedical research.

Surface Characterization of MPs/NPs Several different characterization techniques are implemented to ensure that the nano-/microparticles synthesized are within the acceptable size range and have all the desired surface properties such as appropriate morphology, surface charge, and functional groups that can aid in successful drug delivery. These techniques have been briefly summarized in Table 4. Page 14 of 31

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Dynamic Light Scattering and Zeta Potential Particle size and surface charge are two very important parameters that can determine the targeting efficacy, deposition, rate of clearance, and cellular uptake of the particles. Dynamic light scattering (DLS) is the most commonly used method of determining the hydrodynamic diameter of the particles suspended in solution. It is also known as photon correlation spectroscopy (PCS) and quasi-elastic light scattering (QELS). The DLS instrument is equipped with a monochromatic laser source and a photon detector. During particle size measurements, the NP suspension is illuminated by the laser, and the subsequently scattered light is recorded by the detector [85]. The scattering of laser light occurs by the Brownian motion of the particles, and this scattered light intensity is converted to mean translational diffusion coefficient (D) by the photon detector. The Stokes–Einstein equation given below is then used to convert the diffusion coefficient into hydrodynamic diameter values: D¼

kT 3pd

where k represents the Boltzmann coefficient, T is the absolute temperature,  is the absolutely zero-shear viscosity of the medium used for NP dispersion, and d stands for the hydrodynamic diameter of the particle [86]. Tauer et al. [87] utilized DLS to observe a decrease in diameter of PNIPAAm-based microgels by about 200 nm with changes in temperature. Further, the DLS can be used to determine the polydispersity of the particles. A polydispersity index (PI) close to 1 indicates large variations in particle size, while values close to 0 indicate that the particles are monodispersed. For example, pH- and ionic strength-responsive poly(4-vinylpyridine) hydrogel NPs formulated by Arizaga et al. [61] showed a polydispersity of 0.139 at the time of preparation and 0.121 after 4 months, indicating that the particles remained uniformly dispersed over time. They also observed that surfactant concentration is one of the factors affecting polydispersity; the more the surfactant used, the smaller the polydispersity value of the NPs. In addition to particle size and dispersity, the zeta potential of the particles can also be determined using a Zetasizer. Zeta potential refers to the electrical double layer around particles, which contains ions of an opposite charge than that of the surface charge of the particles. Particles with zeta potential from 10 mV to +10 mV are considered neutral and prone to aggregation, while charges above +30 mV and below 30 mV show strong cationic and anionic characteristics, respectively, indicating that they can repel each other and result in minimal particle aggregation [88]. Chitosan-based NPs tend to have a positive zeta potential due to the free amino groups of chitosan on their surface, which is beneficial for penetrating the negatively charged cell membranes of most cells [89]. Cross-linking time with glutaraldehyde as a crosslinker can affect the chitosan particle surface charge as demonstrated by Li et al. [89]. Their drug-loaded magnetic and fluorescent chitosan NPs showed a decrease in their zeta potential from +35 to +5 mV when the cross-linking time was increased from 0 to 12 h. The prostate cancer-specific temperature-sensitive PNIPAAM–AAm–AH NPs containing magnetic NPs (MNPs) synthesized by us showed a zeta potential of 27 mV indicating greater stability than MNPs alone, which had a surface charge of 5.1 mV indicating the chance of particle aggregation [41].

Techniques for NP Visualization It is very important to image the formulated NPs in order to gather information about their morphology, porosity, and other surface characteristics. Further, the scales of the NP images obtained can be used to validate the results obtained using DLS. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) are the three most commonly used microscopy techniques for visualizing NPs. In the case of SEM, an “electron gun,” usually prepared using tungsten, Page 15 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

emits an electron beam under vacuum conditions past a series of lenses and toward the specimen. Following interaction with the specimen, some electrons and secondary electrons are reflected by elastic scattering, inelastic scattering, and electromagnetic radiation. Detectors within the SEM collect these backscattered electrons and radiations and convert them into signals that can be used to produce the final NP image [90, 91]. The sample may be coated with conducting materials such as gold, silver, and platinum to make the specimen nonconducting when the electron beam strikes it. The TEM also uses a similar concept as SEM to observe morphology of NPs; however, the TEM produces images of a much higher resolution. In TEM, the electron beam emitted by the electron gun passes through a series of lenses and strikes the specimen. In contrast to SEM, the TEM images are obtained using electrons that are transmitted through the thinly sliced sample. The transmitted electrons pass through an objective, intermediate, and projection lens before striking a fluorescent screen. Upon collision with the fluorescent screen, the kinetic energy of the electrons is converted to visible light energy which can be used to create the final image by direct exposure of a photographic film. Alternatively, digital images can be obtained by coupling the fluorescent screen with a CCD camera [92, 93]. The darkened or shadowed areas on the final image represent areas where electrons were deflected from the sample to various degrees [94]. Another microscopy technique used in visualizing nanomaterials is the AFM, which employs a flexible cantilever consisting of a sharp mechanical tip or probe that “feels” the sample surface to produce images. A laser diode is also used in this system to focus a laser beam at the end of the cantilever. Due to the proximity of the probe to the sample surface, any surface interaction will cause an attractive or repulsive force on the probe which causes the cantilever to undergo bending or oscillation. This deflection of the cantilever causes changes in the reflected laser beam, which is detected by a quadrant photodiode which is sensitive to the position of the laser beam on the cantilever [95, 96]. The signals from the photodiode are used to form the image.

Spectra to Determine NP Composition Different techniques are employed to determine the components, purity, chemical composition, and molecular weights of the NPs formed. Some of the most commonly used techniques are summarized in this section. The Fourier transform infrared spectroscopy (FTIR) involves exposing the specimen to infrared radiation which can get absorbed or transmitted through the sample. The FTIR spectrum is obtained based on variations in the transmittance or absorption intensity [97]. Energy-dispersive X-ray spectroscopy (EDX) is another method of analyzing the elements present in the NP samples. In this method, the specimen placed inside an SEM is bombarded with an electron beam resulting in backscattering of electrons and electromagnetic radiation as mentioned before. These electromagnetic radiations are emitted in the form of characteristic X-rays which have a unique amount of energies for different elements. These X-rays are then used to identify the elemental composition of the sample [98]. X-ray photoelectron spectroscopy (XPS) is another technique quite similar to EDX that can provide information on polymer and elemental composition. However, EDX has a greater sample penetration depth (in micrometers) than XPS which can penetrate only to nanometer depth. Therefore XPS is usually used for determining surface composition [99]. The size and composition of an NP sample can also be detected using nuclear magnetic resonance (NMR) spectroscopy. This method provides information on the size, chemical composition, and mobility of molecules within individual components of the sample. On placing the specimen in a magnetic field, the nuclei of the sample will absorb and emit characteristic electromagnetic radiation at specific frequencies which can be detected by the NMR instrument [100]. 1H NMR is commonly used to obtain spectra in terms of hydrogen-1 nuclei present in the molecules of the sample.

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Another technique used for analyzing the components of a NP system is the matrix-assisted laser dissociation –ionization time-of-flight mass spectrometry (MALDI-TOF MS). In this procedure, the sample and another compound called the matrix are co-crystallized onto a solid phase support (usually prepared using stainless steel) and then exposed to a pulsed nitrogen laser. This causes the activation of the matrix which is vaporized along with the molecules of the sample. The molecules are then ionized with assistance from the matrix, which can either donate or accept protons to aid in the ionization. This method can be used for detecting both polymer composition and biomolecules conjugated to the NPs. The TOF mass spectrometry involves separation of the ionized molecules in an electrostatic field based on their velocities, which depends on their mass-to-charge ratio [101].

Physical and Chemical Characterization of Particles Prior to testing a drug delivery system in terms of its compatibility with cells, it is necessary to ensure that the NPs express their intended physical properties. A range of studies are performed to ensure that the smart nanomaterials respond to external stimuli appropriately and show the required release and degradation characteristics.

Sensitivity to Stimulus The easiest method of determining sensitivity to stimulus is visual observation. For example, magnetic field-responsive systems would be attracted toward an external magnet. In the case of thermoresponsive systems such as our PNIPAAm–AAm–AH NPs, the solution is clear below LCST and cloudy above LCST [41]. Temperature sensitivity can also be detected by differential scanning calorimetry (DSC) and UV–Vis spectrophotometry. In the case of DSC, the thermal stability of the NPs is tested in the instrument by increasing the temperature at a fixed rate. A reference is also used during experimentation and maintained at the same temperature as the sample. On attaining LCST, changes in the molecular structure of the sample take place which in turn changes its thermal stability. As a result, more heat would need to pass through the system to attain the same temperature as the reference. This change in heat flow is used by the DSC to detect the LCST of the sample [102, 103]. UV–Vis spectrophotometry can also be used to detect changes in LCST as demonstrated by our lab previously [104]. At 650 nm wavelength, sharp changes in optical transmittance of the NP solution with increasing temperature indicate that the NPs have undergone phase transition in response to LCST. Another method of detecting stimulus responsiveness is by measuring particle size using DLS as mentioned earlier [105]. Aydin et al. [11] demonstrated that their chitosan NPs showed a sharp increase in particle size by about 300 nm when the pH changed from 3 to 5. Similarly, a significant decrease in size was observed when the particles were placed in pH 7.4 solution than that in pH 5 solution. In the case of magnetic field-responsive systems, the magnetic property can be detected using a superconducting quantum interference device (SQUID) magnetometer or vibrating sample magnetometer (VSM). The VSM and SQUID detect the magnetic moment of the NP sample in a uniform magnetic field, as it vibrates perpendicular to the field. This magnetization of the sample in response to changing magnetic field can be represented in the form of a hysteresis loop [106].

Stability One of the most important properties that NPs are expected to maintain following administration is stability. Unstable NPs tend to form aggregates on administration resulting in blood clot formation in the body which may prove to be fatal to the patient [107]. Instability of NPs can also affect the time spent in circulation and the region of deposition [108]. One of the techniques employed to maintain NP stability Page 17 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_19-1 # Springer International Publishing Switzerland 2015

and size is the use of a higher concentration of surfactants during NP preparation, which can induce steric hindrance and reduce surface tension between the particles [109]. Below its critical micelle concentration (CMC), SDS can significantly improve colloidal stability of NPs [110]. However, above CMC, surfactants tend to self-aggregate and will thus not coat the NPs. Also, high concentrations of surfactants could result in toxic effects and hence should be avoided. PEGylation can also impart steric stability to the particles [111]. However, PEGylation can inhibit mechanisms involved in cellular uptake and endosomal escape, especially during gene delivery to the cells. This is known as the “PEG dilemma” [112]. In order to ensure NP stability before being administered in vivo for treatment, DLS measurements of NP solutions can be taken over a fixed period of time. The NP solutions can be prepared in deionized (DI) water, serum, or electrolytes to study NP stability in experimental solutions, physiological conditions, and the solution used for NP dispersion prior to in vivo administration, respectively [113]. The NP solution will be exposed to different conditions such as temperatures, pH, and heat changes, and then the particle size will be measured at predetermined time intervals. Colloidal stability can also be observed by taking turbidity measurements of the NP solution using a spectrometer. After homogenizing the NP, turbidity was observed at 500 nm wavelength using a spectrometer, as demonstrated by Petri-Fink et al. [114].

Surface Hydration and Wettability Surface hydration and wettability are terms used to describe the interaction between the solid NP surface and the fluid around it, i.e., hydrophobicity/hydrophilicity of the NPs. This property of the NPs can influence their interaction with solutes and components of the blood such as proteins, platelets, and cells. Stimulus-responsive polymers in particular tend to show significant changes in wettability as a result of their phase transition behavior, which can result in a change in hydrophilicity [115]. A fully wettable hydrophilic surface is expected to show a contact angle of 0 . Studies have shown that contact angle of water tends to increase by 20 when heating PNIPAM from 23  C to 50  C indicating a transition from hydrophilicity to hydrophobicity, resulting in lower wettability [116]. Interaction between biomaterials and different solutions can be determined by visualizing changes in surface texture of the materials by AFM. Interaction between the material and solutions containing protein can also be detected by this method [115, 117]. Wettability of surfaces can also be determined by measuring the contact angle using instruments such as a contact angle goniometer or even a long working distance microscope [117, 118].

Drug Release Characteristics As explained earlier, stimulus-responsive NPs tend to show significantly higher drug release in response to changes in external stimuli than in the absence of it. In order to study drug release characteristics, the NP solution can be incubated for drug release in normal conditions (37  C, pH 7.4) as control and then compared with drug release on being exposed to appropriate stimulus. For example, our lab synthesized PNIPAAm–AAm–AH NPs loaded with doxorubicin, and release studies were carried out at 4, 37, and 41  C to compare amount of doxorubicin released in storage, at body temperature, and on providing external heat. It was observed that 78 % of encapsulated DOX was released at 41  C, which was much higher than the ~26 % and ~43 % release observed at 4 and 37  C, respectively [50]. Similarly, to detect insulin release from pH-sensitive hyaluronic NPs in gastric conditions, particles were immersed in simulated gastric fluid (SGF, pH 1.2) for 120 min and then in simulated intestinal fluid (SIF, pH 6.8) for 180 min at 37  C. At different time points, the solution was collected and replaced with the same volume. It was observed that less than 10 % release occurred at SGF, while more than 80 % of encapsulated insulin was released in SIF, indicating that insulin will be protected by the particles from damage in the highly acidic stomach environment [9].

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Degradation Studies Degradation rate and drug release profile of NPs are strongly interconnected. Rapid degradation and subsequent destabilization of the NPs can result in faster drug release from the core. The rate of degradation can be dependent on several parameters such as type of polymer chosen, degree of acetylation in the polymer, and molecular mass [119, 120]. The degradation process can occur via hydrolysis or enzymatic degradation. For example, Hou et al. [121] incubated their chitosan/tripolyphosphate/chondroitin sulfate (Chi/TPP/CS) NPs in the 0.1 mg/ml lysozyme solution, which plays a major role in enzymatic degradation of chitosan, at 37  C by shaking gently. At fixed time points, the particles were collected and weighed to determine weight loss over time due to degradation. It was found that an increase in concentration of the cross-linkers (TPP and CS) resulted in decreased degradation rate of the particles. Peng et al. [122] synthesized thermosensitive and degradable PLGA and monomethyl ether PEG (mPEG) hydrogel NPs, and degradation was carried out in PBS at 37  C. The particles were lyophilized and weighed over time, which showed a decrease in copolymer weight by about 70 % within 31 days. Additionally, gel permeation chromatography (GPC) showed a decrease in molecular weight over time indicating that hydrolysis of ester bonds resulted in degradation of the copolymer.

Types of Stimulus-Responsive Particles Developed for Medical Applications Based on the application, desired degradation and drug release rates, and the region of the body being targeted, different types of polymeric nanovehicles can be used (Fig. 3). Each nanocarrier has unique properties that can aid in accurate drug delivery, as described below.

Micelles, Liposomes, and Dendrimers

Polymeric micelles were first developed in the 1980s and possess the unique property of having a hydrophilic shell and a hydrophobic core for carrying drugs showing varying solubility in water. However, in order to overcome issues with premature drug release during clinical trials, stimulusresponsive micelles were developed recently for more accurate drug release [123]. Dual-responsive micelles were prepared recently by Chen et al. [124] to encapsulate rapamycin (rapa-micelles) for cancer therapy. At acidic pH, the micelles underwent structural dissociation and subsequent drug release indicating pH responsiveness of the carrier. Additionally, 57.6 % of the encapsulated rapamycin could be released at a pH of 5.4 at 37  C within 5 h compared to about 12.5 % drug release observed at 25  C and pH of 7.4. Stimulus-responsive liposomes could also be prepared as lipid-based bilayered nanovehicles that can encapsulate multiple drugs – a hydrophilic compound on the surface and core and a hydrophobic compound in between. For instance, light-responsive liposomes were synthesized by Yavlovich et al. [125] using dipalmitoylphosphatidylcholine (DPPC) and photopolymerizable diacetylene phospholipid (DC8,9PC) for cancer treatment. These liposomes underwent destabilization and released the encapsulated with doxorubicin when the particles were exposed to UV (254 nm wavelength) and visible light (514 nm laser). Polymer vesicles or polymersomes are nanostructures similar to liposomes but with an aqueous core surrounded by the bilayered membrane. For example, biodegradable and pH-responsive polymersomes were prepared by Kim et al. [126] using PEG- and poly(D,L-lactide)-grafted poly(b-amino ester) that showed complete release of encapsulated calcein dye at pH 4.5 and 5.5 within 15 min compared to negligible release at pH 7.4. Lyso-lipid thermosensitive liposomes (LTSLs) prepared using DPPC, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphatidylcholine (MSPC), and 1,2-distearoyl-sn-glycero-3phosphatiylethanol-amine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG(2000)) are currently

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Fig. 3 Representation of different types of stimulus-sensitive nanocarriers in medical applications today

in Phase II and Phase III clinical trials for liver cancer and recurrent breast cancer treatment, respectively. The LTSLs could achieve complete release of encapsulated DOX at a temperature of 42  C [127]. Another set of nanocarriers that have been studied for stimulus-dependent drug release is dendrimers. Dendrimers are hyperbranched treelike nanostructures that are expected to self-assemble or destabilize in response to external stimuli. Poly(benzyl ether) and poly(2-isopropyl-2-oxazoline) (PiPrOx)-based pHand thermoresponsive dendrimers prepared by Kim et al. [128] showed varying LCSTs with changes in pH. While one dendrimer demonstrated a change in LCST from 35  C to 65  C with pH change from 5.5 to 6.9, the other dendrimer, having more carboxylic acid moieties, displayed a greater LCST difference (35–83  C) on changing pH from 5.5 to 6.5. Liu et al. [129] recently synthesized pH-sensitive dendrimers by complexing zwitterionic chitosan (ZWC) with PAMAM. The ZWC protects healthy cells from the effects of PAMAM at neutral pH; however, in acid tumor environment (pH 6.4), ZWC and its protective effect were removed from PAMAM. Thus these dendrimers can be used for cancer treatment by exploiting the cytotoxicity of PAMAM as well as by delivering cancer drugs to the tumor.

Stimulus-Responsive Polymeric Particles As discussed in detail earlier, polymeric NPs can also be engineered to respond to changes in environmental stimulus by undergoing sudden phase transition for burst drug release for various applications. PNIPAM hollow nanospheres containing Fe3O4 and zinc sulfide (ZnS) showed magnetic and luminescent (due to optical properties of ZnS) properties in addition to demonstrating thermosensitive behavior. The drug release was observed to be higher at 42  C than at 37  C and 25  C [130]. These particles also provide sufficient void space for drug loading. pH-sensitive chitosan NPs encapsulated with 5-FU anticancer drug could show a significantly higher release at pH 5 compared to pH 3, 4, 6, and 7.4, indicating their potential for tumor drug delivery [11].

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Dual-Responsive Particles There has been a recent surge in the development of multi-responsive NPs for better controlled delivery of therapeutic reagents in the presence of multiple stimuli. For example, Samah et al. [131] used temperature- and pH-sensitive nanogels prepared using PNIPAAm-co-acrylic acid encapsulated with caffeine for transdermal drug delivery. It was observed that these particles tend to collapse at an LCST of 32  C thereby releasing the core compound. The weak acidic environment (pH 4–7) provided by the skin was also believed to have contributed to the collapsing of the particles. PNIPAM–poly(acrylic acid) (PAA) interpenetrating network has also been utilized to form hollow nanogels with pH- and temperatureresponsive properties [132]. Nearly 80 % of the encapsulated isoniazid (INH) – an antitubercular – was released at pH 1.2 (simulated gastric fluid) and at 37  C compared to 50 % release in pH 7.4 (PBS).

Theranostic Particles

The recently established area of “theranostic nanomedicine” has slowly paved the way for the development of personalized medicine where multiple functions such as disease targeting, diagnosis, and therapy can be integrated into a single NP. This area of research is very promising since the nanotherapeutic system can be used for simultaneous diagnosis and treatment of the disease while reducing cost of treatment and patient discomfort. A schematic of the components generally found in theranostic NP system has been represented in Fig. 4. Cha et al. [133] have developed a nanotherapeutic system consisting of PEGylated gold NP-encapsulated DOX and containing calcium phosphate layers for pH-sensitive theranostic drug delivery. Significantly higher DOX release was observed at pH 4.5 (pH of intracellular lysosomal fluid) compared to 7.4 (extracellular fluid pH). The gold NPs could be used for computed tomography (CT) imaging. Another type of theranostic core–shell NPs was prepared for cancer treatment using iron oxide core, a mesoporous silica shell, and crown ether-based nanovalves at the periphery. Na+ was used as capping agent for the nanovalves to prevent drug leakage. At pH 4 and on application of ultrasound, a significantly higher amount of doxorubicin was released from these biocompatible NPs. This occurs because ultrasound application at low pH triggers breaking down of electrostatic interactions between crown ether’s ethylene glycol chains and the Na+ ions, followed by dissociation of the ions and subsequent leakage of the drug molecules [134].

Scope and Future Direction Since their discovery, stimulus-responsive polymer-based MPs/NPs have received immense attention due to their attractive property of releasing the encapsulated compounds rapidly in response to changing environmental stimuli. This discovery was an important step toward the development of personalized medicine where nanocarriers can be customized based on the condition of the patient. However, several hurdles have to be overcome in order for these particles to transition from the laboratory bench to bedside. Stimulus-sensitive NPs are clearly an important medical tool for providing accurate and targeted therapy. However, the long-term effects of these polymers in the body need to be studied in more detail. As mentioned earlier, one of the obvious limitations of PNIPAm is that it is a nonbiodegradable polymer [48]. Therefore, alternatives need to be devised to maintain the rapid phase transition characteristic of PNIPAm while also undergoing degradation and easy removal from the body. Nanomaterials also need to be optimized in terms of their size and stability. Small sizes (~6 nm) of NPs lead to rapid removal from the body by the kidneys. Large sizes of greater than 200 nm, however, will result in accumulation in the spleen and liver [135]. During the formation process to include desirable properties such as stimulus sensitivity, specificity, biocompatibility, and biodegradability, the size of the particle may increase due to the incorporation of several high molecular weight polymers and large Page 21 of 31

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Fig. 4 Representation of a theranostic NP incorporating both therapeutic and imaging/contrast agents for simultaneous diagnosis and therapy

biomolecules. Incorporation of multiple payloads can also affect particle size. Therefore the researchers should bear in mind that the particle size should be controlled for maximum therapeutic effect following administration. The surface charge of the NPs also plays a crucial role in ensuring optimal cellular uptake and subsequent therapy. A positively charged NP is preferred as they can interact with the negatively charged cell membranes via electrostatic interactions. This positive charge can be achieved by copolymerizing with polymers having NH2 functional groups or by providing appropriate surface coatings that can impart a positive charge to the nano-system. For example, PNIPAM nanocarriers copolymerized with chitosan as shown by Rejinold et al. [136] demonstrated a zeta potential of +28 mV due to the presence of amino groups on chitosan. Besides size and surface charge, long-term stability is another parameter that needs to be optimized before the NPs are administered. The optimum conditions for storage and administration need to be closely studied. Particles should also be characterized extensively to ensure that the stimulus-sensitive polymer of its components is retained during particle formation. Most importantly, the particles should be thoroughly researched in terms of their biocompatibility and biodegradability so that that the particle as a whole as well as its individual components will pose no threat to the patient during degradation following administration. There is no doubt that stimulus-sensitive NPs have immense potential in the field of nanomedicine and drug delivery. A Phase I trial was carried out recently by administering low-temperature-sensitive liposomes containing doxorubicin in combination with doxorubicin to treat canine tumors. The treatment was well tolerated by the animals and showed favorable response indicating the potential of these liposomes in cancer treatment [137]. The results from studies reported in this book chapter and others indicate that well-characterized and optimized “smart” NPs can, therefore, be designed and employed in various medical applications ranging from cancer drug delivery to oral and transdermal delivery for treatments of various diseases.

Conclusion This chapter summarizes the preparation and characterization of nanomaterials responsive to different stimuli, for various medical applications. These NPs have immense potential in terms of delivering Page 22 of 31

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therapeutic agents to the body in a controlled and precise manner. However in order to fully exploit this area of nanomedicine, a better understanding of the physiological conditions of the body is required. For example, good knowledge of temperature and pH variations in different parts of the body in response to diseases and otherwise will enable us to optimize the NP preparation for precise drug delivery only in response to the stimuli of interest. Thus a drug delivery system that releases its encapsulated payload in complete synchronization with changes in its surrounding environment will aid in more effective treatment of diseases than by using conventional treatment methods.

Acknowledgments Authors would like to thank the funding support from DOD (Department of Defense) and CPRIT (Cancer Prevention and Research Institute of Texas). We would also like to acknowledge Miss Alicia J. Sisemore for her help in editing this book chapter.

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50. M. Rahimi, A. Wadajkar, K. Subramanian, M. Yousef, W. Cui, J.T. Hsieh, K.T. Nguyen, In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery. Nanomedicine 6(5), 672–680 (2010) 51. P. Xu, E.A. Van Kirk, W.J. Murdoch, Y. Zhan, D.D. Isaak, M. Radosz, Y. Shen, Anticancer efficacies of cisplatin-releasing pH-responsive nanoparticles. Biomacromolecules 7(3), 829–835 (2006) 52. T. Cai, P.D. Hu, M. Sun, J. Zhou, Y.-T. Tsai, D. Baker, L. Tang, Novel thermogelling dispersions of polymer nanoparticles for controlled protein release. Nanomedicine 8(8), 1301–1308 (2012) 53. A. Shalviri, H.K. Chan, G. Raval, M.J. Abdekhodaie, Q. Liu, H. Heerklotz, X.Y. Wu, Design of pH-responsive nanoparticles of terpolymer of poly(methacrylic acid), polysorbate 80 and starch for delivery of doxorubicin. Colloids Surf. B Biointerfaces 101, 405–413 (2012) 54. S. Shah, A. Pal, R. Gude, S. Devi, Synthesis and characterization of thermo-responsive copolymeric nanoparticles of poly(methyl methacrylate-co-N-vinylcaprolactam). Eur. Polym. J. 46(5), 958–967 (2010) 55. M. Bradley, B. Vincent, Poly(vinylpyridine) core/poly(N-isopropylacrylamide) shell microgel particles: Their characterization and the uptake and release of an anionic surfactant. Langmuir 24(6), 2421–2425 (2008) 56. M.G. Han, S.K. Cho, S.G. Oh, S.S. Im, Preparation and characterization of polyaniline nanoparticles synthesized from DBSA micellar solution. Synth. Met. 126(1), 53–60 (2002) 57. Q. He, Y. Gao, L. Zhang, Z. Zhang, F. Gao, X. Ji, Y. Li, J. Shi, A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance. Biomaterials 32(30), 7711–7720 (2011) 58. Q. Gan, X. Lu, Y. Yuan, J. Qian, H. Zhou, J. Shi, C. Liu, A magnetic, reversible pH-responsive nanogated ensemble based on Fe3O4 nanoparticles-capped mesoporous silica. Biomaterials 32(7), 1932–1942 (2011) 59. B. Sivaraman, A. Ramamurthi, Multifunctional nanoparticles for doxycycline delivery towards localized elastic matrix stabilization and regenerative repair. Acta Biomater. 9(5), 6511–6525 (2013) 60. M. Furlan, J. Kluge, M. Mazzotti, M. Lattuada, Preparation of biocompatible magnetite-PLGA composite nanoparticles using supercritical fluid extraction of emulsions. J. Supercrit. Fluids 54(3), 348–356 (2010) 61. A. Arizaga, G. Ibarz, R. Pinol, Stimuli-responsive poly(4-vinyl pyridine) hydrogel nanoparticles: synthesis by nanoprecipitation and swelling behavior. J. Colloid Interface Sci. 348(2), 668–672 (2010) 62. Y. Bai, Z. Zhang, A. Zhang, L. Chen, C. He, X. Zhuang, X. Chen, Novel thermo- and pH-responsive hydroxypropyl cellulose- and poly (l-glutamic acid)-based microgels for oral insulin controlled release. Carbohydr. Polym. 89(4), 1207–1214 (2012) 63. A. Shalviri, G. Raval, P. Prasad, C. Chan, Q. Liu, H. Heerklotz, A.M. Rauth, X.Y. Wu, pH-Dependent doxorubicin release from terpolymer of starch, polymethacrylic acid and polysorbate 80 nanoparticles for overcoming multi-drug resistance in human breast cancer cells. Eur. J. Pharm. Biopharm. 82(3), 587–597 (2012) 64. F. Yan, C. Zhang, Y. Zheng, L. Mei, L. Tang, C. Song, H. Sun, L. Huang, The effect of poloxamer 188 on nanoparticle morphology, size, cancer cell uptake, and cytotoxicity. Nanomedicine 6(1), 170–178 (2010) 65. S. Park, H.S. Kim, W.J. Kim, H.S. Yoo, Pluronic@Fe3O4 nanoparticles with robust incorporation of doxorubicin by thermo-responsiveness. Int. J. Pharm. 424(1–2), 107–114 (2012) 66. Z. Wu, L. Ling, L. Zhou, X. Guo, W. Jiang, Y. Qian, K. Luo, L. Zhang, Novel preparation of PLGA/ HP55 nanoparticles for oral insulin delivery. Nanoscale Res. Lett. 7(1), 299 (2012) Page 26 of 31

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67. W. Fan, W. Yan, Z. Xu, H. Ni, Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids Surf. B Biointerfaces 90, 21–27 (2012) 68. Y. Dong, W.K. Ng, S. Shen, S. Kim, R.B.H. Tan, Scalable ionic gelation synthesis of chitosan nanoparticles for drug delivery in static mixers. Carbohydr. Polym. 94(2), 940–945 (2013) 69. S. Lankalapalli, V. Kolapalli, Polyelectrolyte complexes: a review of their applicability in drug delivery technology. Indian J. Pharm. Sci. 71(5), 481–487 (2009) 70. P. Sun, Y. Zhang, L. Shi, Z. Gan, Thermosensitive nanoparticles self-assembled from PCL-b-PEOb-PNIPAAm triblock copolymers and their potential for controlled drug release. Macromol. Biosci. 10(6), 621–631 (2010) 71. B. Feng, R.Y. Hong, L.S. Wang, L. Guo, H.Z. Li, J. Ding, Y. Zheng, D.G. Wei, Synthesis of Fe3O4/ APTES/PEG diacid functionalized magnetic nanoparticles for MR imaging. Colloids Surf. A Physicochem. Eng. Asp. 328(1–3), 52–59 (2008) 72. S. Khoee, R. Rahmatolahzadeh, Synthesis and characterization of pH-responsive and folated nanoparticles based on self-assembled brush-like PLGA/PEG/AEMA copolymer with targeted cancer therapy properties: a comprehensive kinetic study. Eur. J. Med. Chem. 50, 416–427 (2012) 73. M.K. Yoo, I.K. Park, H.T. Lim, S.J. Lee, H.L. Jiang, Y.K. Kim, Y.J. Choi, M.H. Cho, C.S. Cho, Folate-PEG-superparamagnetic iron oxide nanoparticles for lung cancer imaging. Acta Biomater. 8(8), 3005–3013 (2012) 74. H. Deng, Z. Lei, Preparation and characterization of hollow Fe3O4/SiO2@PEG-PLA nanoparticles for drug delivery. Composites Part B: Eng. 54, 194–199 (2013) 75. H. Pawar, D. Douroumis, J.S. Boateng, Preparation and optimization of PMAA-chitosan-PEG nanoparticles for oral drug delivery. Colloids Surf. B Biointerfaces 90, 102–108 (2012) 76. A. Kailasan, Q. Yuan, H. Yang, Synthesis and characterization of thermoresponsive polyamidoamine-polyethylene glycol-poly(D, L-lactide) core-shell nanoparticles. Acta Biomater. 6(3), 1131–1139 (2010) 77. N. Gulati, R. Rastogi, A.K. Dinda, R. Saxena, V. Koul, Characterization and cell material interactions of PEGylated PNIPAAM nanoparticles. Colloids Surf. B Biointerfaces 79(1), 164–173 (2010) 78. M. Guo, C. Que, C. Wang, X. Liu, H. Yan, K. Liu, Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery. Biomaterials 32(1), 185–194 (2011) 79. S.K. Sahu, S. Maiti, A. Pramanik, S.K. Ghosh, P. Pramanik, Controlling the thickness of polymeric shell on magnetic nanoparticles loaded with doxorubicin for targeted delivery and MRI contrast agent. Carbohydr. Polym. 87(4), 2593–2604 (2012) 80. A. Jain, S.K. Jain, N. Ganesh, J. Barve, A.M. Beg, Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine 6(1), 179–190 (2010) 81. J.M. Shen, F.Y. Gao, T. Yin, H.X. Zhang, M. Ma, Y.J. Yang, F. Yue, cRGD-functionalized polymeric magnetic nanoparticles as a dual-drug delivery system for safe targeted cancer therapy. Pharmacol. Res. 70(1), 102–115 (2013) 82. J. Park, S. Kim, P.E. Saw, I.H. Lee, M.K. Yu, M. Kim, K. Lee, Y.C. Kim, Y.Y. Jeong, S. Jon, Fibronectin extra domain B-specific aptide conjugated nanoparticles for targeted cancer imaging. J. Control. Release 163(2), 111–118 (2012) 83. S. Maya, L.G. Kumar, B. Sarmento, N. Sanoj Rejinold, D. Menon, S.V. Nair, R. Jayakumar, Cetuximab conjugated O-carboxymethyl chitosan nanoparticles for targeting EGFR overexpressing cancer cells. Carbohydr. Polym. 93(2), 661–669 (2013) 84. Q. Chang, L. Zhu, C. Yu, H. Tang, Synthesis and properties of magnetic and luminescent Fe3O4/ SiO2/Dye/SiO2 nanoparticles. J. Lumin 128(12), 1890–1895 (2008) Page 27 of 31

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85. V.A. Hackley, J.D. Clogston, Measuring the hydrodynamic size of nanoparticles in aqueous media using batch-mode dynamic light scattering. Methods Mol. Biol. 697, 35–52 (2011) 86. H.G. Merkus, Dynamic light scattering, in Particle Size Measurements (Springer, Dordrecht, 2009), pp. 299–317 87. K. Tauer, D. Gau, S. Schulze, A. Volkel, R. Dimova, Thermal property changes of poly (N-isopropylacrylamide) microgel particles and block copolymers. Colloid Polym. Sci. 287(3), 299–312 (2009) 88. Clogston JD, Patri AK (2011) Zeta potential measurement. In: Characterization of Nanoparticles Intended for Drug Delivery. Methods in Molecular Biology, vol 697, 2010 edn., pp 63–70 89. L. Li, D. Chen, Y. Zhang, Z. Deng, X. Ren, X. Meng, F. Tang, J. Ren, L. Zhang, Magnetic and fluorescent multifunctional chitosan nanoparticles as a smart drug delivery system. Nanotechnology 18(40), 405102 (2007) 90. S.J.B. Reed, Electron Microprobe Analysis and Scanning Electron Microscopy in Geology (Cambridge University Press, New York, 2005) 91. K.C.A. Smith, C.W. Oatley, The scanning electron microscope and its fields of application. Brit. J. Appl. Phys. 6(11), 391 (1955) 92. K. Nagashima, J. Zheng, D. Parmiter, A.K. Patri, Biological tissue and cell culture specimen preparation for TEM nanoparticle characterization. Methods Mol. Biol. 697, 83–91 (2011) 93. L. Reimer, H. Kohl, Transmission Electron Microscopy: Physics of Image Formation, vol. 36 (Springer, New York, 2008) 94. J.J. Bozzola, L.D. Russell, Electron Microscopy: Principles and Techniques for Biologists (Jones & Bartlett Learning, Sudbury, Mass, 1999) 95. W. Sun, Atomic force microscopy for cell and tissue niches, in Imaging in Cellular and Tissue Engineering (CRC Press, Boca Raton, 2013), pp. 59–87 96. G. Binnig, C.F. Quate, C. Gerber, Atomic force microscope. Phys. Rev. Lett. 56(9), 930–933 (1986) 97. C.-P.S. Hsu, Infrared spectroscopy, in Handbook of Instrumental Techniques for Analytical Chemistry, ed. by F. Settle (Prentice Hall, Upper Saddle River, 1997), pp. 247–283 98. P. Ngo, Energy dispersive spectroscopy, in Failure Analysis of Integrated Circuits, ed. by L. Wagner. The Springer International Series in Engineering and Computer Science, vol. 494 (Springer US, Norwell, 1999), pp. 205–215 99. J.M. Pringle, O. Winther-Jensen, C. Lynam, G.G. Wallace, M. Forsyth, D.R. MacFarlane, One-step synthesis of conducting polymer–noble metal nanoparticle composites using an ionic liquid. Adv. Funct. Mater. 18(14), 2031–2040 (2008) 100. C. Mayer, G.A. Webb, NMR studies of nanoparticles, in Annual Reports on NMR Spectroscopy, vol. 55 (Academic, London, 2005), pp. 205–258 101. A.P. Kafka, T. Kleffmann, T. Rades, A. McDowell, The application of MALDI TOF MS in biopharmaceutical research. Int. J. Pharm. 417(1–2), 70–82 (2011) 102. P.S. Gill, S.R. Sauerbrunn, M. Reading, Modulated differential scanning calorimetry. J. Therm. Anal. 40(3), 931–939 (1993) 103. N. Ormategui, S. Zhang, I. Loinaz, R. Brydson, A. Nelson, A. Vakurov, Interaction of poly (N-isopropylacrylamide) (pNIPAM) based nanoparticles and their linear polymer precursor with phospholipid membrane models. Bioelectrochemistry 87, 211–219 (2012) 104. M. Rahimi, S. Kilaru, G.E. Sleiman, A. Saleh, D. Rudkevich, K. Nguyen, Synthesis and characterization of thermo-sensitive nanoparticles for drug delivery applications. J. Biomed. Nanotechnol. 4(4), 482–490 (2008)

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105. J. Brijitta, B.V. Tata, T. Kaliyappan, Phase behavior of poly(N-isopropylacrylamide) nanogel dispersions: temperature dependent particle size and interactions. J. Nanosci. Nanotechnol. 9(9), 5323–5328 (2009) 106. S. Foner, Versatile and sensitive vibrating sample magnetometer. Rev. Sci. Instrum. 30(7), 548–557 (1959) 107. S. Lazzari, D. Moscatelli, F. Codari, M. Salmona, M. Morbidelli, L. Diomede, Colloidal stability of polymeric nanoparticles in biological fluids. J. Nanopart Res. 14(6), 1–10 (2012) 108. F. Alexis, E. Pridgen, L.K. Molnar, O.C. Farokhzad, Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5(4), 505–515 (2008) 109. H.-J. Lee, B. Doo Chin, S.-M. Yang, O.O. Park, Surfactant effect on the stability and electrorheological properties of polyaniline particle suspension. J. Colloid Interface Sci. 206(2), 424–438 (1998) 110. J. Chen, H. Xue, Y. Yao, H. Yang, A. Li, M. Xu, Q. Chen, R. Cheng, Effect of surfactant concentration on the complex structure of poly(N-isopropylacrylamide)/sodium n-dodecyl sulfate in aqueous solutions. Macromolecules 45(13), 5524–5529 (2012) 111. D.E. Owens III, N.A. Peppas, Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307(1), 93–102 (2006) 112. H. Hatakeyama, H. Akita, H. Harashima, A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. Adv. Drug Deliv. Rev. 63(3), 152–160 (2011) 113. M. Pavlin, V.B. Bregar, Stability of nanoparticle suspensions in different biologically relevant media. Dig. J. Nanomater. Biostruct. 7(4), 1389–1400 (2012) 114. A. Petri-Fink, B. Steitz, A. Finka, J. Salaklang, H. Hofmann, Effect of cell media on polymer coated superparamagnetic iron oxide nanoparticles (SPIONs): colloidal stability, cytotoxicity, and cellular uptake studies. Eur. J. Pharm. Biopharm. 68(1), 129–137 (2008) 115. K.-S. Liao, H. Fu, A. Wan, J.D. Batteas, D.E. Bergbreiter, Designing surfaces with wettability that varies in response to solute identity and concentration. Langmuir 25(1), 26–28 (2008) 116. M. Seeber, B. Zdyrko, R. Burtovvy, T. Andrukh, C.-C. Tsai, J.R. Owens, K.G. Kornev, I. Luzinov, Surface grafting of thermoresponsive microgel nanoparticles. Soft Matter 7(21), 9962–9971 (2011) 117. L.-C. Xu, C.A. Siedlecki, Effects of surface wettability and contact time on protein adhesion to biomaterial surfaces. Biomaterials 28(22), 3273–3283 (2007) 118. H.S. Wi, S. Cingarapu, K.J. Klabunde, B.M. Law, Nanoparticle adsorption at liquid-vapor surfaces: Influence of nanoparticle thermodynamics, wettability, and line tension. Langmuir 27(16), 9979–9984 (2011) 119. T. Kean, M. Thanou, Biodegradation, biodistribution and toxicity of chitosan. Adv. Drug Deliv. Rev. 62(1), 3–11 (2010) 120. D.T. O'Hagan, H. Jeffery, S.S. Davis, The preparation and characterization of poly(lactide-coglycolide) microparticles: III. Microparticle/polymer degradation rates and the in vitro release of a model protein. Int. J. Pharm. 103(1), 37–45 (1994) 121. Y. Hou, J. Hu, H. Park, M. Lee, Chitosan-based nanoparticles as a sustained protein release carrier for tissue engineering applications. J. Biomed. Mater. Res. A 100A(4), 939–947 (2012) 122. K.-T. Peng, C.-F. Chen, I.M. Chu, Y.-M. Li, W.-H. Hsu, R.W.-W. Hsu, P.-J. Chang, Treatment of osteomyelitis with teicoplanin-encapsulated biodegradable thermosensitive hydrogel nanoparticles. Biomaterials 31(19), 5227–5236 (2010) 123. N. Rapoport, Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Prog. Polym. Sci. 32(8–9), 962–990 (2007)

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124. Y.-C. Chen, C.-L. Lo, Y.-F. Lin, G.-H. Hsiue, Rapamycin encapsulated in dual-responsive micelles for cancer therapy. Biomaterials 34(4), 1115–1127 (2013) 125. A. Yavlovich, A. Singh, R. Blumenthal, A. Puri, A novel class of photo-triggerable liposomes containing DPPC:DC8,9PC as vehicles for delivery of doxorubcin to cells. Biochimica et Biophysica Acta (BBA) – Biomembranes 1808(1), 117–126 (2011) 126. M.S. Kim, D.S. Lee, Biodegradable and pH-sensitive polymersome with tuning permeable membrane for drug delivery carrier. Chem. Comm. 46(25), 4481–4483 (2010) 127. T. Tagami, M.J. Ernsting, S.-D. Li, Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin. J. Control. Release 152(2), 303–309 (2011) 128. J.-H. Kim, E. Lee, J.-S. Park, K. Kataoka, W.-D. Jang, Dual stimuli-responsive dendritic-linear block copolymers. Chem. Comm. 48(30), 3662–3664 (2012) 129. K.C. Liu, Y. Yeo, Zwitterionic chitosan-polyamidoamine dendrimer complex nanoparticles as a pH-sensitive drug carrier. Mol. Pharm. 10(5), 1695–1704 (2013) 130. G. Liu, D. Hu, M. Chen, C. Wang, L. Wu, Multifunctional PNIPAM/Fe3O4-ZnS hybrid hollow spheres: synthesis, characterization, and properties. J. Colloid Interface Sci. 397, 73–79 (2013) 131. N.H.A. Samah, C.M. Heard, Enhanced in vitro transdermal delivery of caffeine using a temperatureand pH-sensitive nanogel, poly(NIPAM-co-AAc). Int. J. Pharm. 453, 630–640 (2013) 132. Z. Xing, C. Wang, J. Yan, L. Zhang, L. Li, L. Zha, Dual stimuli responsive hollow nanogels with IPN structure for temperature controlling drug loading and pH triggering drug release. Soft Matter 7(18), 7992–7997 (2011) 133. E.-J. Cha, I.-C. Sun, S. Lee, K. Kim, I. Kwon, C.-H. Ahn, Development of a pH sensitive nanocarrier using calcium phosphate coated gold nanoparticles as a platform for a potential theranostic material. Macromol. Res. 20(3), 319–326 (2012) 134. S.-F. Lee, X.-M. Zhu, Y.-X.J. Wang, S.-H. Xuan, Q. You, W.-H. Chan, C.-H. Wong, F. Wang, J.C. Yu, C.H.K. Cheng, K.C.-F. Leung, Ultrasound, pH, and magnetically responsive crown-ethercoated core/shell nanoparticles as drug encapsulation and release systems. ACS Appl. Mater. Interfaces 5(5), 1566–1574 (2013) 135. A. Albanese, P.S. Tang, W.C. Chan, The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012) 136. N. Rejinold, P.R. Sreerekha, K.P. Chennazhi, S.V. Nair, R. Jayakumar, Biocompatible, biodegradable and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drug delivery. Int. J. Biol. Macromol. 49(2), 161–172 (2011) 137. M.L. Hauck, S.M. LaRue, W.P. Petros, J.M. Poulson, D. Yu, I. Spasojevic, A.F. Pruitt, A. Klein, B. Case, D.E. Thrall, D. Needham, M.W. Dewhirst, Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors. Clin. Cancer Res. 12(13), 4004–4010 (2006) 138. T. Ta, A.J. Convertine, C.R. Reyes, P.S. Stayton, T.M. Porter, Thermosensitive liposomes modified with poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for triggered release of doxorubicin. Biomacromolecules 11(8), 1915–1920 (2010) 139. P. He, Z. Tang, L. Lin, M. Deng, X. Pang, X. Zhuang, X. Chen, Novel biodegradable and pH-Sensitive Poly(ester amide) microspheres for oral insulin delivery. Macromol. Biosci. 12(4), 547–556 (2012) 140. Y. Meissner, N. Ubrich, F.E. Ghazouani, P. Maincent, A. Lamprecht, Low molecular weight heparin loaded pH-sensitive microparticles. Int. J. Pharm. 335(1–2), 147–153 (2007) 141. M.M. Rahman, A. Elaissari, Temperature and magnetic dual responsive microparticles for DNA separation. Sep. Purif. Technol. 81(3), 286–294 (2011) Page 30 of 31

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142. A.S. Wadajkar, S. Santimano, L. Tang, K.T. Nguyen, Magnetic-based multi-layer microparticles for endothelial progenitor cell isolation, enrichment, and detachment. Biomaterials 35(2), 654–663 (2014) 143. R. Yin, J. Han, J. Zhang, J. Nie, Glucose-responsive composite microparticles based on chitosan, concanavalin A and dextran for insulin delivery. Colloids Surf. B Biointerfaces 76(2), 483–488 (2010) 144. R.V. Joshi, C.E. Nelson, K.M. Poole, M.C. Skala, C.L. Duvall, Dual pH- and temperatureresponsive microparticles for protein delivery to ischemic tissues. Acta Biomater. 9(5), 6526–6534 (2013) 145. F. Tang, N. Ma, X. Wang, F. He, L. Li, Hybrid conjugated polymer-Ag@ PNIPAM fluorescent nanoparticles with metal-enhanced fluorescence. J. Mater. Chem. 21(42), 16943–16948 (2011) 146. D. Bielska, A. Karewicz, K. Kaminski, I. Kielkowicz, T. Lachowicz, K. Szczubialka, M. Nowakowska, Self-organized thermo-responsive hydroxypropyl cellulose nanoparticles for curcumin delivery. Eur. Polym. J. 49, 2485–2494 (2013) 147. R.L. Bartlett II, S. Sharma, A. Panitch, Cell-penetrating peptides released from thermosensitive nanoparticles suppress pro-inflammatory cytokine response by specifically targeting inflamed cartilage explants. Nanomedicine 9(3), 419–427 (2013)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

Wet Media Milling: An Effective Way to Solve Drug Solubility Issue Ranjita Shegokar* Freie Universit€at BerlinInstitute of PharmacyDepartment Pharmaceutics, Biopharmaceutics & NutriCosmeticsKelchstraße 31, Berlin, Germany

Abstract Drug synthesis, high-throughput screening generates billions of poorly soluble drugs which are neglected in further developments due to solubility issues. In the last 20 years, nanonization by milling is being effectively used commercially to save these drugs by overcoming solubility problems in commercial way. Various labs at industry and academic level successfully investigated milling technique alone and in combination with other techniques to reduce particle size, thereby increasing the dissolution velocity of drug. Milling offers ease of production, efficient control of production parameters, freedom of small to industrial batch size, liberty to produce highly concentrated suspensions, and improved stability of final product. Nanonized slurries exhibited promising results in vitro and in vivo and many fold increase in bioavailability. Nanosuspensions are investigated for organ or cellular delivery in various diseases like HIV/AIDS, malaria, and other infectious disease conditions. The issue of metal abrasion and contamination is now nullified by effective engineering solutions. In this chapter, recent updates on milling techniques and their applications in pharmaceutical field are discussed.

Keywords Milling techniques; Nanonization; Nanosuspensions Solubility enhancement; Nanosuspensions; Organ targeting

Introduction Background on Use of Milling Milling is used in the pharmaceutical industry to reduce particle size of raw materials and to achieve more consistency in size without changing the characteristics of the original powder. Optimized particle-size distribution can reduce problems in blending, compression, and coating besides improving the drug performance. However, extensive grinding results in an increased particle surface energy and can also deform crystal lattice. Milling is commonly used in food, chemicals, and cosmetics industry. Simple milling operations are performed routinely in pharmaceutical industry like in dry granulation which allows product uniformity, optimizing product solubility, and improving bioavailability. In attrition mill, to get micron-sized particles, powder blend is subjected to heavy turbulence by using two air inlets at different pressure. The powder processed in this way is very cohesive. Other size reduction techniques in pharma are hammer milling and cone milling. Various types of dry mills are available and can be selected depending upon the nature of the staring material and requirements of the finished product. The hammer mills and pin mills are examples of mechanical impact mills, while spiral jet mills, loop jet mills, and fluidized bed jet mills are based on the micronization or fluid energy mill principle. *Email: [email protected] Page 1 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

Milling and homogenization can be effectively used to increase surface area and thereby dissolution rate. Subsequently, solubility problems can be overcome by milling poorly water-soluble drugs (micron sized) to nanometer-sized drug particles. The size reduction can be done by several mechanical reduction methods (top-down approaches), supercritical fluid processes, cryogenic spraying, and solvent evaporation methods. Among them, mechanical size reduction using milling is a very common and well-accepted technique in pharmaceutical industry because of: • • • • • • • • • • • •

Simplicity of process Cost-effectiveness of both equipment and process Robust particle-size control in both micron and submicron range Equipment scalability from lab-scale to industrial-scale production (10 g to >500 kg batch) Minimal batch-to-batch variation Limited or no contamination of the active ingredient Process repeatability High yield, more than 95 % No use of solvents Processing of concentrated suspension/slurries FDA-approved milling equipments Ease of production

Figure. 1 shows biopharmaceutical classification of drugs based on solubility and permeability. The type of milling media (nature of milling balls), amount of milling media, rotation speed, powder mass, and milling time are determining factors for the effectiveness of milling. Smaller rotation speed causes cascading of balls results in grinding action, while at higher speed, they impact with each other, resulting in reduction of particle size. The smaller ball reduces the size to fine range if the time duration is increased. Generally, high speed, large the ratio of milling ball:drug, and long milling time give a high degree of comminution. Milling beads of plastic, glass, ceramics such as aluminum oxide and zirconium oxide, steel, and tungsten carbide can be used depending upon the application. For soft materials, dry grinding at low temperatures is preferred. However, for further size reduction of soft materials to nanoparticles, a solid additive must be used in media mill as the next step, e.g., for grinding of zinc oxide to particle sizes 30 kg, 5–8  C, one batch at a time): the coarse slurry is recirculated through the milling chamber till the desired particle size is reached. The milling mechanism involves attrition and impact, thereby decreasing particle size from micrometer to nanometer range. The impact could be between milling wall to beads, beads to bead, bead to drug, drug to drug crystals, etc. (A 2) is production set up for lab scale (batch size > 1 mg, 3–5  C, 24 batches at a time for first setup and for vial setup it could be any number, batch size more than 5 g, 3–25  C). Initial optimization of surfactant, production parameters, rotating speed, and drug: milling media ratio can be optimized economically at small scale. This setup is very useful for drug available in low quantity (e.g., NCEs) and for expensive drugs

Sometimes, nanonizing helps to reduce the amount of active ingredient used in one particular application because of enhanced color or dissolution property, thereby reducing total cost, e.g., organic pigments offer intense color strength upon nanonization than micron-sized particles. Recently, NetzschCondux has developed patented s-Jet® system, which is a fluidized bed jet milling operated by steam and is capable of producing a dry powder with mean size less than 200 nanometers in one go. In comparison to wet milling, steam jet milling eliminates the step of drying and de-agglomeration yet still produces nanoparticles. Heat-sensitive products can be processed by media milling, while water-sensitive material by steam jet grinding. In some cases, steam jet milling is more energy-intensive than media milling and its use would add additional costs to the product. In general, milling time varies from 15 min to 7 days depending upon the rotation speed (80–4,800 rpm). The bead size employed to produce nanosuspension is between 0.5 and 1.0 and drug concentration between 2 % and 30 % w/w. The use of high mechanical forces above critical pressure

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

values increases the changes in crystal lattice vibrations, thereby changing the physical structure and causes formation of amorphous mass. This amorphous mass reunions with other particles and often causes stability problems and this can be avoided by controlled process parameters and by understanding the drug and excipient properties and intereactions. Peltonen et al. discussed critical process parameters for stabilization of nanocrystals [5].

Combination of Milling Techniques Industries are always looking for the cost-effective and time-efficient production methods. A set of combinative technologies (CT) is generated to produce nanocrystals in nanometer and in ultrafine range quickly. CT combines bottom-up and top-down processes to improve either physical stability or particle-size reduction effectiveness. As mentioned earlier, the degree of particle-size reduction mainly depends on compound properties like hardness, crystallinity, and morphology [6]. It is difficult to manipulate the particle size (ultrafine particles) beyond a certain processing point. Therefore, spraydrying and freeze-drying techniques can be used to modify API properties into brittle, fragile starting material, thereby making particle-size reduction easier in the next step by either milling or homogenization. Generally, for wet media milling and homogenization micron-sized active ingredient is used as starting material. Sometimes, larger-sized active material causes clogging or formation of large aggregates, in this case reseting the process is time-consuming on top of long processing times. This issue can be solved by adjusting batch volume, capacity of milling chamber or by installation of series of homogenizers. The first CT process is called Nanoedge™ which is based on a combination of micro-precipitation and homogenization by Baxter. The following CT processes are developed by Mueller and coworkers: H96 – freeze-drying + HPH H69 – precipitation + HPH H42 – spray-drying + HPH CT – milling + HPH at low pressure (Smart Crystals) H69 process involves precipitation directly in the dissipation chamber of the homogenizer. The nonaqueous solvent can act as a cosolvent thereby increasing the solubility of the drug. However, crystallization of small crystals might cause stability problems. The solvent is removed by different techniques to ensure complete physical and chemical stability. Other CT processes like H42 and H69 involve spray-drying of organic drug solutions to produce brittle starting material. Glibenclamide nanosuspensions were processed by applying the design of experiment using H96 process [7]. Results indicate that lyophilization parameters played a critical role in determining the final particle size of nanosuspension. Spray-drying combination approach can reduce the risk of aggregation compared to the precipitation approach. Freeze-drying can be employed for temperature-sensitive and/or expensive materials to produce extremely brittle starting material. Amphotericin B nanocrystals (100 nm) were produced by applying freeze-drying and HPH (H96 technology) [8]. However, only the production of Smart Crystals involves milling. To our knowledge, no other report is available on combination techniques using milling.

Effect of Milling on Size and Solubility The dissolution rate can be calculated using Nernst–Brunner/Noyes–Whitney which is based on the surface area available for dissolution (Eq. 1): Page 5 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

  dX A  D Xd ¼ Cs
dt h V

(1)

where dX/dt = dissolution rate Xd = amount dissolved A = particle surface area D = diffusion coefficient V = volume of fluid available for dissolution Cs = saturation solubility h = effective boundary layer thickness In addition to the dissolution rate enhancement, an increase in the saturation solubility is expected upon nanonization [9] and can be described by the Freundlich–Ostwald equation (Eq. 2):   2gM S ¼ S 1 exp (2) rrRT where S = saturation solubility of the nanosized API S1 = saturation solubility of coarse API crystal g = interfacial surface tension p = density of solid T = absolute temperature R = gas constant r = radius of particle M = molecular weight of drug The attractive forces or van der Waals forces cause irreversible aggregation in liquid dispersion. To overcome this attractive interaction, steric stabilization and electrostatic stabilization are required, thereby forming repulsive forces. Steric stabilization is mostly achieved by adsorbing polymers onto the particle surface, while electrostatic stabilization is obtained by adsorbing charged molecules, e.g., ionic surfactants or charged polymers, onto the particle surface. The most commonly used stabilizers/polymers include polysorbates, poloxamers, cellulose derivatives, lecithins, bile salts, etc. Bead milling in the presence of an effective stabilizing agent can disrupt micron-sized drug particles by impact and shearing force to submicron range, and the shaft present within milling chamber provides kinetic energy to media for milling. Zeta potential values in the
15 to
30 mV are common for well-stabilized nanosuspensions.

Applications of Milling This section involves the use of nanosuspensions in oral, dermal, pulmonary, and intravenous applications. Available reports which use milling technique are incorporated; however, some high pressure

Page 6 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015 Media milling

Solubility in water (mg/ml)

800 HPH

700 600 500 400 300 200

Coarse drug

100 0

10 min

2h

Production Techniques

Fig. 3 Saturation solubility enhancement of nevirapine based on the production techniques. Milling effectively reduces size, thereby causing high increase in saturation solubility compared to homogenization. Also milling time needs to be optimized to get desired particle-size distribution

homogenization (HPH) experiments are discussed here since the increase in bioavailability and saturation solubility will be the same or superior if milling is used.

Bioavailability Increase and Targeting In vivo performance of silybin nanosuspensions with different particle sizes was evaluated in mice upon intravenous administration and hepatoprotective effects were evaluated in beagle dogs. Nanosuspension with large particle size helped to target the liver and spleen. Nanosuspensions having both lower particle size and larger particle size showed excellent hepatoprotective action [10, 11]. In another study, to target tumor cells, a polyethylene glycol (PEG), PEG–surface-modified docetaxel–lipid-based nanosuspensions (204 nm, PDI 0.192, ~34 mV) and a folic acid–PEG–surfacemodified–docetaxel–lipid-based NS (220 nm, PDI 0.173,
28 mV) were prepared. The in vitro cytotoxicity studies of spherical nanosuspension by MTT assay in a murine malignant melanoma cell line (B16) and a human hepatoblastoma cell line (HepG2) exhibited dose-dependent cytotoxicity. On the other hand, blank PEG-coated and folic acid-coated nanosuspensions showed no sign of toxicity as control. Similarly, in vivo antitumor efficacy, tissue distribution, and pharmacokinetics in Kunming mice bearing B16 cells showed strong tumor inhibition when treated with PEGylated lipid-based nanosuspensions (87.93 %  2.55 %) and folic acid-decorated–PEG–lipid-based NS (92.09 %  2.72 %) compared to marketed formulation (78.44 %  5.16 %). Significant differences in tumor volume and weights were noted for developed nanosuspensions and marketed formulation-treated group. Nanosuspension showed extended-release profile after 12 h than that of Duopafei ® (8 h) resulting in prolonged residence time of about ~2.40 h for both formulations. The AUC upon i.v. administration of both nanosuspensions increased to about 1.59 and 1.66 times, respectively [12]. In another study, coated paclitaxel nanosuspensions prepared by HPH technique was evaluated for their cellular uptake and for targeting potential in tumor-bearing mouse models. All the nanosuspensions prolonged the mouse survival time at reduced dose in two different xenograft orthotopic murine cancer models when administered by two different routes [13]. Shegokar et al. produced nevirapine nanosuspensions (NVP-NS, 460 nm) for HIV targeting by HPH and milling having excellent plasma stability. A fourfold increase in saturation solubility was observed (Fig. 3). NVP-NS selectively accumulated in the macrophages and showed dose-dependent toxicity.

Page 7 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

Technetium-labeled bare and surface modified nanosuspensions when administered in rat via intravenous injection showed significant accumulation in the spleen, liver, lungs, and heart. Toxicity studies (acute and repeated dose) exhibited that formulation is safe even at doubled therapeutic dose without any severe toxicity signs. In scale-up studies, similar particle size distribution was obtained. Milling resulted in superior size reduction yet keeping crystalline nature intact (Shegokar et al. 2011). Loviride nanosuspension (264 nm) by milling was produced and freeze-dried in the presence of sucrose (560–590 nm). In Caco-2 cells, freeze-dried nanopowder showed superior drug amount in cells (1.59  0.02 mg) as compared to the physical mixture (sucrose and untreated drug) (0.93  0.01 mg) and the coarse drug (0.74  0.03 mg) at the end of 120 min [14]. Downscaling of loviride and other compounds was also performed [15]. Lipoid E80-stabilized indinavir nanosuspension was produced by HPH when tested in monocyte-derived macrophages pre-infected by HIV-1ADA. Nanosuspensions showed 99 % suppression profile as that water-soluble counterpart indinavir sulfate of 97 %. Bone marrow-derived macrophage (BMM) cells loaded with nanosuspension and upon intravenous administration in mice exhibited higher drug levels in tissues like the lungs, liver, spleen, and kidneys. In another work, rilpivirine depot nanosuspension (200 nm) was studied via intramuscular or subcutaneous route in rats and dogs. A dose-dependent sustained release of drug was observed over 2 months in rat and 6 months in dogs. Levels were 100-fold high at the end of 30 days in the lymph nodes compared to the plasma levels obtained after intramuscular administration in rats [16]. To improve the bioavailability of BMS-488043, media milling was used and compared its effect in vivo against coarse drug and amorphous drug followed oral administration in beagle dogs. The nanosuspensions showed 4.7-fold increase in Cmax and 4.6-fold in AUC0–24 over amorphous coprecipitates [17]. Gahoi et al. prepared hydroxypropylmethylcellulose (HPMC) E3 and Tween 80-stabilized lumefantrine nanocrystals (251 nm) by milling for 6 h [18]. The IC50 was 175 times less coarse at concentration of 17.5 mg/ml when tested in Plasmodium falciparum. Lumefantrine nanosuspension has a dose 42 times lower than that of positive control, i.e., chloroquine at 4.2 ng/ml concentrations. In Plasmodium yoelii nigeriensis-infected Swiss mice, it took 18 days for lumefantrine spray-dried powder to clear parasitemia at a dose of 60 mg/kg and 28 days for coarse drug to reduce it to only 60 %. The nanopowder showed a mean survival time of more than 28 days at all doses, while it was more than 24 days for coarse drug at lower dose of 15 mg/kg. Polymer- and surfactant-stabilized dihydroartemisinin nanosuspensions were prepared using vibrating rod mill. Binary mixtures (drug/polyvinylpyrrolidone K30 and also drug/sodium cholate) and ternary mixtures (drug/PVP K30/sodium cholate) were ground and mixed with water. Nanosuspension obtained from ternary mixtures showed excellent stability as that of binary mixtures. The nanosuspensions exhibited higher in vitro antimalarial activity against Plasmodium falciparum than microsuspensions [19]. Clofazimine nanosuspensions prepared by HPH (385 nm) injected to mice infected with M. avium showed significant reduction in bacterial loads in the liver at 72.5 mg/kg tissue, in the spleen at 81.4 mg/kg tissue, and in the lungs at 35.0 mg/kg tissue [20]. Nanocrystals were as effective as marketed liposomes. The itraconazole nanosuspension in dogs showed improved efficacy and prevented the negative inotropic effect of Sporanox(R) (marketed itraconazole) injection. Milled poloxamer 407-stabilized itraconazole nanosuspensions (294 nm) increased dissolution of drug by ninefold and 5.3-fold over marketed formulation. Aphidicolin nanosuspension improved performance against extracellular promastigotes and intracellular amastigotes of Leishmania donovani in murine macrophages [21, 22]. In another study, oral amphotericin B nanosuspensions (528 nm) showed reduction in parasite load by 28.6 % in mouse model compared to control. Atovaquone nanosuspensions (279 nm) were produced using HPH tested in macrophages infected with the BK strain of Toxoplasma gondii, and mice infected with ME49 strain of Toxoplasma gondii showed improved cellular uptake [23]. Several other studies showed successful use of Page 8 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

nanosuspension as drug delivery system, for example, oleanolic acid nanosuspensions (285 nm) significantly enhanced hepatoprotective effect in rodent [24]. Metronidazole-magnetite nanosuspension showed reduction in dose of drug with enhanced anthelmintic activity when studied on Indian earthworms (Pheretima poi) [25]. Puerarin nanosuspension (82 nm) showed targeting efficiency to the brain as that of nanoemulsion but to the liver and kidney following oral administration in mice. Oridonin nanosuspensions showed inhibitory effects in human prostate cancer cell line (PC-3), thereby resulting in cell proliferation and suppression [26]. Oridonin [27] and mycoepoxydiene in prostate cancer were also studied. Camptothecin nanocrystals of 200–700 nm having zeta potential of
40 mV was prepared by sonication–precipitation method showed significant inhibition at rate of 65 % of tumor growth in MCF-7 xenografted BALB/c mice compared with water-soluble salt at inhibition rate of 52 %. The tumor accumulation of nanonized drug was fivefold higher compared with that of salt solution [28]. All studies confirmed successful use of nanonization by either milling or homogenization. These nanosized particles facilitates fast dissolution thereby increasing the bioavailability. Their nanometer size aid in faster engulfing by cellular components, thereby targeting specific organ or tissue. Accumulation of nanosuspensions in particular organ maintains drug level by slowly releasing active ingredient.

Penetration Enhancement Dermal delivery (skin area 2 m2) is an appealing application route used in medicine and cosmetics, offering certain advantages over oral and parenteral route. Various drug delivery systems like nanoemulsions, solid lipid nanoparticles, and liposomes are successfully used to deliver active ingredients into various layers of the skin. However, the penetration in the skin layers is limited by the barrier property of the stratum corneum resulting in longer lag times counted in hours. To increase therapeutic effect, faster penetration or diffusion is very important which mainly depends on the properties of drug, particle size, and solubility. Skin temperature, age, health condition of the skin, and the contact time with drug delivery system are other important factors. Three different routes are identified by which drug permeates through stratum corneum via intercellular, trans-cellular, and follicular pathways. Slow dissolution of nanocrystals helps to maintain sustained drug levels. Fast growth of $32 B by 2015 in dermal delivery market is forecasted, which might give push to nanocrystal platform in dermal drug application. To setup PK/PD relations by subcutaneous route, crystalline nanosuspensions of 1,3-dicyclohexyl urea (DCU, 800 nm) were prepared on Glen Mills using lead-free glass beads (0.5–0.75 mm) by stirring at 1,200 rpm for 24 h in Tween 80 and phosphate buffer (pH 7.4) mixture. DCU nanosuspension was administered through subcutaneous and oral routes at 30 mg/kg dose to male Sprague–Dawley rats. Oral route has a short half-life and high plasma/tissue ratio, while subcutaneous route has been found to be extremely well tested; this could be due to 20-fold increase in dissolution rate. A threefold enhancement, i.e., 10.2 h, in apparent T1/2 and lower plasma P/T ratio of 4 with slow release was noted, while oral administration showed T1/2 of only 2.6 h. Coarse suspension (mean size 20.2 mm) exhibited reduced absorption rate resulting in fivefold less exposure. Nanosuspension increased the exposure which was caused by the quick and steady dissolution (dissolution rate-limited absorption) and can be helpful to establish pharmacokinetic/pharmacodynamic relation [29]. Nanosuspension-based glycoside antioxidant cosmetic product with rutin was launched by Juvena in 2007 and with hesperidin by La Prairie in 2008 which exhibited excellent antioxidant effect. This effect is due to increase in the penetration of poorly soluble drug or active ingredient into the skin due to increased saturation solubility promoting passive penetration when nanonized. The sun protection factor was 500 times higher for nanonized formulation compared to the water-soluble rutin counterpart. Rutin nanocrystals also reduced red spot in healthy human volunteers in a separate study.

Page 9 of 17

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_20-1 # Springer International Publishing Switzerland 2015

A lutein nanosuspension for dermal delivery was for the first time explored by Mitri et al., using nanosuspensions prepared by HPH that resulted in a 26-fold increase in saturation solubility. Penetration of nanocrystals from a synthetic cellulose nitrate membrane showed 35 % lutein release at 6 h and 60 % at 24 h, while it was > 1, tN is very high and the magnetic moments of nanoparticles are “frozen” on the uniaxial anisotropy axes. In this case, and in normal conditions, the magnetization is stable. A variation similar to that of Fig. 20, continuous curve, was found in the case of soft Ni-Zn ferrite nanoparticles (the anisotropy constant is 1.5  103 Jm3) [5], where the area of stability of magnetization (Hc ~ constant) is virtually absent at room temperature (Fig. 21). In this case, besides the low anisotropy and high temperature (room temperature) at which the measurement of the coercive field was made, the variation is also influenced by the existence of a distribution of diameters of the nanoparticles from the sample (in small nanoparticles the spontaneous magnetization fluctuates along the easy magnetization axis).

Page 30 of 38

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015 50

Hc [Oe]

40 30 20 10 0 10

20

30 (311) [nm]

40

50

Fig. 21 Coercivity as a function of the average diameter of nanocrystallites [5] (# IOP Publishing. Reproduced by permission of IOP Publishing. All rights reserved)

It should be noted that some discrepancies between the calculated (Eq. 79 or 80) and experimental values [133–137] are due to the effects presented in sections “Saturation Magnetization of Nanoparticles” and “Magnetic Anisotropy of Nanoparticles,” regarding decreases of the saturation magnetization and increases of magnetic anisotropy for nanoparticles, which can dramatically change the magnetic behavior.

Superparamagnetic Behavior of the Nanoparticles

In the area of small diameters, where Dm < Dmt (generally less than 10 nm for nanoparticles with moderate anisotropy), and at room temperature (~300 K), when the condition s > 1 is met and s slightly greater than 1 (Eq. 81), the relaxation time of the magnetic moments of the nanoparticles, oriented or not, is very small, of the order of 109 s. Under these conditions, the magnetization of single-domain nanoparticles fluctuates rapidly along the easy magnetization axis [122], being always in thermodynamic equilibrium, and when applying an external magnetic field, it follows, almost instantly, the field variations. This system, from a magnetic point of view, behaves like a system of paramagnetic atoms (Langevin) [138], in the absence of interactions, where the atomic magnetic moment exists instead of the nanoparticle magnetic moment. Having in view this basic feature between this two paramagnetic systems, atoms or nanoparticles (which contains >105 atoms) with their magnetic moments ! ! (atomic magnetic moment for paramagnetic atom ( m a ) and nanoparticle magnetic moment ( m m, N P ) for nanoparticle (see section “Magnetic Behavior of Nanoparticles in an External Field”), in this case the system of nanoparticles was called superparamagnetic (SPM) [129], and the behavior in the external field, superparamagnetic behavior. Under these conditions for the magnetization of the nanoparticle system, the atomic paramagnetism theory of Langevin applies [138]. Thus, the magnetization of a SPM nanoparticle system is given by the formula [139]   m0 mp H kBT M SPM ðH, T Þ ¼ nmm, NP cth  ; (82) m0 mp H kBT where n is the concentration of nanoparticles in the system, mm,NP is the magnetic moment of the nanoparticle, and the parenthesis contains the Langevin function LðH, T Þ ¼ cth

m0 mm, N P H kBT  : m0 mm, NP H kBT

(83)

Page 31 of 38

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

The magnetization as a function of magnetic field, M SPM ðH, T Þ ¼ f ðH ÞT , is without hysteresis loop (Hc = 0), and the curve of first magnetization (for H > 0) not having an inflection point, being defferent from that of the other nanoparticles, ferro- or ferrimagnetic, single-domain, stable or less stable, or with a magnetic domain structure, where there is always a hysteresis loop (small ar large) and with an inflection point in their first magnetization curve in a static external magnetic field (see sections “Hysteresis Magnetic Behavior of Multi-domain Nanoparticles” and “Single-Domain Nanoparticles with Stable Magnetization”). For a system of nanoparticles to have a superparamagnetic behavior in the external field, in the absence of interactions, two conditions must be met: (i) the magnetization curves M ¼ f ðH Þ recorded at different temperatures must be without hysteresis and follow the Langevin function, and (ii) the same magnetization curves in the representation M =M sat ¼ f ðH=T Þ should overlap. In reality, there is a size distribution of nanoparticles in a system; therefore, for a rigorous approach, their distribution function should also be considered. In most cases, it was found that the nanoparticle distribution is lognormal [140–143], ( ) 1 ½lnðDÞ  lnðD0 Þ 2 ; (84) f ðDÞ ¼ pffiffiffiffiffiffi exp  2l2 2plD where D0 and l are distribution parameters. In these conditions, the magnetization of the nanoparticle system will be 1 ð

M SPM ¼ M sat L½xðH, T , Dm Þ f ðDm Þd ðDm Þ;

(85)

0

where the argument of the Langevin function is xðH, T , Dm Þ ¼

p m0 D3m M s H ; 6 kB T

(86)

in the approximation of spherical nanoparticles. In formula (85) it was taken into account Eq. 5 for the 1.0

0.8

MM∞

0.6

0.4 experimental points 0.2

0.0

theoretical curve

0

50

100 150 H (kA/m)

200

250

Fig. 22 Reduced magnetization curve of the nanocomposite (Zn0.15Ni0.85Fe2O4)0.15/(SiO2)0.85 registered at room temperature and 50 Hz frequency of the magnetization field (H) (Reprinted from [18], Copyright (2007), with permission from Elsevier) Page 32 of 38

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

12 8

experiment fit

M [kA/m]

4 0 –4 –8 –12 –120

–80

–40

0 H [kA/m]

40

80

120

Fig. 23 Magnetization curve at room temperature [71] (# IOP Publishing. Reproduced by permission of IOP Publishing. All rights reserved)

saturation magnetization of the system of nanoparticles and Eq. 23 for the diameter of the magnetic nanoparticles (given that Dm < D (8), as shown in the section “Surface Spin Disorder in Nanoparticles and Saturation Magnetization”). In Fig. 22 the first magnetization (reduced) curve for Ni-Zn nanoparticles isolated in a SiO2 amorphous matrix (nanocomposite), having a concentration of 15 % and the mean magnetic diameter < Dm > = 8.9 nm [18], is shown, and in Fig. 23 the magnetization–remagnetization curve of the Fe3O4 nanoparticles covered with oleic acid and dispersed in kerosene (nanofluid), with mean magnetic diameter of 10.9 nm and the narrow lognormal distribution of their sizes, is shown [71]. The continuous line represents the fitting to the Langevin function. The analysis of the curves obtained experimentally, in the area of low fields ( x > 1 ) [71, 144], enables the determination of the distribution parameters (D0 and l) and then of the mean magnetic diameter of the nanoparticles in the system,   hDm i ¼ D0 exp l2 =2 :

(87)

This is a very important issue for the magnetic nanoparticles because it allows the evaluation of the thickness of the surface layer of the nanoparticles (for SPM behavior), knowing that Dm < D (see section “Saturation Magnetization of Nanoparticles”) in various cases (small nanoparticles, surfacted nanoparticles, nanoparticles embedded in various matrices, etc.), using electron microscopy (TEM or HR-TEM) [20, 145] or other techniques, such as Small Angle Neutron Scattering (SANS), etc., to determine the physical diameter (D). Given that the thickness of the nanoparticles’ surface layer is of the order of 1 nm [18, 19, 32], the two diameters (magnetic and physical) must be determined with high accuracy. Therefore, in a more accurate analysis, especially in the case of broad distribution of nanoparticle diameters, for the determination of the mean magnetic diameter, it must be taken into account that the magnetic moment of the nanoparticle also depends on the magnetic diameter, mm, NP ðDm Þ ¼ pM s D3m =6:

(88)

In this case, for the magnetization of the nanoparticle system, function will be used [71, 146]:

Page 33 of 38

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015 1 ð

M SPM ¼ n mp ðDm ÞL½xðH, T , Dm Þ f ðDm Þd ðDm Þ;

(89)

0

instead of the one given by Eq. 85.

Conclusion The finite size of nanoparticles is a critical parameter that, according to its value, leads to a certain magnetic structure: multi-domain, with nonuniform magnetization, or single domain, with uniform and stable magnetization or with fluctuant magnetization. Consequently, the nanoparticles will have a certain magnetic behavior in the external magnetic field, from ferro- or ferrimagnetic with large hysteresis loop, for big-sized nanoparticles (tens to hundreds of nm), similar to the bulk, to a behavior with no hysteresis, for smaller sizes, and, respectively, to a superparamagnetic behavior for very small-sized nanoparticles (a few nm). The size of nanoparticles is also reflected in the structure of the spins (magnetic atomic moments) from the surface of the nanoparticles, which are no longer aligned under the action of the exchange or superexchange interaction (being placed in a disorder structure), with the spins from the core of the nanoparticles, which are ferro- or ferrimagnetically aligned, a structure that becomes dominant in the case of small-sized nanoparticles, causing a considerable decrease of the saturation magnetization of nanoparticles. Consequently, they must take into consideration a model for the core–shell nanoparticles: core, where the magnetic moments are aligned, and shell, where the magnetic moments are in a disorder structure. The noncollinearity of the spins from the surface of the nanoparticles is reflected in the decrease of the saturation magnetization of the nanoparticles, as compared to that of the corresponding bulk material, the effect being more intense when the nanoparticles are smaller (a few nm). Furthermore, the decrease of the saturation magnetization is higher in the case of ferrimagnetic nanoparticles, where the exchange interaction, which aligns the atomic magnetic moments, takes place through the ions of oxygen (superexchange interaction). The effect of the size decrease of nanoparticles also reflects upon the variation of the saturation magnetization of nanoparticles as a function of temperature, which is different from that of the corresponding bulk material, in the case of many nanostructures. Also, the Curie temperature of nanoparticles decreases along with the decrease of their size, the decrease being more pronounced when the nanoparticles are smaller, in the range of nanometers. The magnetic anisotropy also modifies in the case of nanoparticles, in some cases becoming unusually high, as compared to the magnetocrystalline anisotropy of the corresponding bulk material, especially in the case of small nanoparticles (a few nm). An important contribution to the magnetic anisotropy is due to the surface anisotropy component, which may even become dominant in the case of small nanoparticles, as compared to the magnetocrystalline anisotropy or to the shape anisotropy. Besides the nature of the material, the value of this contribution also depends on the nanoparticles being surfactant or not or embedded in different crystalline or amorphous matrices. When the nanoparticles are embedded in matrices, very high magnetic anisotropies may occur, one or two orders of magnitude higher than the magnetocrystalline anisotropy, due to the contribution of anisotropy determined by tensions (stress anisotropy). All these aspects must be taken into consideration for the accurate fundamental study of the magnetic properties of nanoparticles and their practical future applications in nanotechnology.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

38. C. Vázquez-Vázquez, M.A. López-Quintela, M.C. Buján-Núňez, J. Rivas, J. Nanopart. Res. 13, 1663 (2011) 39. K. Mandal, S. Mitra, P.A. Kumar, Europhys. Lett. 75, 618 (2006) 40. C. Caizer, Appl. Phys. A 80, 1745 (2005) 41. S. Mørup, B.R. Hansen, Phys. Rev. B 72, 024418 (2005) 42. M.D. Kuz’min, A.M. Tishin, Phys. Lett. A 341, 240 (2005) 43. G.F. Goya, T.S. Berquó, F.C. Fonseca, J. Appl. Phys. 94, 3520 (2003) 44. J. Wang, W. Wu, F. Zhao, G. Zhao, Appl. Phys. Lett. 98, 083107 (2011) 45. H.M. Lu, Z.H. Cao, C.L. Zhao, P.Y. Li, X.K. Meng, J. Appl. Phys. 103, 123526 (2008) 46. W. Wu, X. Lin, H. Duan, J. Wang, Int. J. Mod. Phys. B 26, 1250073 (2012) 47. Xe. He, H. Shi, Particuology, 10, 497 (2012) 48. H. Mayama, T. Naito, Physica E 41, 1878 (2009) 49. N.S. Gajbhiye, G. Balaji, M. Ghafari, Phys. Status Solidi A 189, 357 (2002) 50. M.E. Fisher, A.E. Ferdinand, Phys. Rev. Lett. 19, 169 (1967) 51. F. Huang, G.J. Mankey, M.T. Kief, R.F. Willis, J. Appl. Phys. 73, 6760 (1993) 52. K. Chen, A.M. Ferrenberg, D.P. Landau, Phys. Rev. B 48, 3249 (1993) 53. J. Mazo-Zuluaga, J. Restrepo, J. Mejia-Lopez, J. Phys. Condens. Matter 20, 195213 (2008) 54. F. Bloch, Z Phys 61, 206 (1930) 55. A.H. Eschenfelder, in: Landolt-Börnstein, Magnetic properties I (Springer, Berlin, 1962) 56. A.T. Aldred, P.H. Frohle, Int. J. Magnet. 2, 195 (1972) 57. A.T. Aldred, Phys. Rev. B 11, 2597 (1975) 58. J.F. Dillon, in Landolt-Börnstein, Magnetic properties I (Springer, Berlin, 1962) 59. P.V. Hendriksen, S. Linderoth, P.A. Lindgard, J. Magn. Magn. Mater. 104–107, 1577 (1992) 60. S. Linderoth, L. Balcells, A. Labarta, J. Tejada, P.V. Hendriksen, S.A. Sethi, J. Magn. Magn. Mater. 124, 269 (1993) 61. P.V. Hendriksen, S. Linderoth, P.A. Lindgard, Phys. Rev. B 48, 7259 (1993) 62. C. Caizer, Habil. Thesis (2013) 63. C. Caizer, Solid State Commun. 124, 53 (2002) 64. A.H. Eschenfelder, J. Appl. Phys. 29, 378 (1958) 65. B. Berkovsky, V. Bashtovoy, Magnetic Fluids and Applications Handbook (Begell House, New York, 1996) 66. M. Xu, P.J. Ridler, J. Appl. Phys. 82, 326 (1997) 67. Yu.I. Raikher, M.I. Shliomis, Adv. Chem. Phys., 87, 3 (1994) 68. R.V. Upadhyay, D. Srinivas, R.V. Mehta, J. Magn. Magn. Mater. 214, 105 (2000) 69. M.D. Sastry, Y. Babu, P.S. Goyal, R.V. Mehta, R.V. Upadhyay, D. Srinivas, J. Magn. Magn. Mater. 149, 64 (1995) 70. E. Tronc, A. Ezzir, R. Cherkaoui, C. Chanéac, M. Noguès, H. Kachkachi, D. Fiorani, A.M. Testa, J.M. Grenèche, J.P. Jolivet, J. Magn. Magn. Mater. 221, 63 (2000) 71. C. Caizer, J. Phys. Condens. Matter 15, 765 (2003) 72. K. Honda, S. Kaya, Sci. Rep. Tohoku Univ. 15, 721 (1926) 73. S. Kaya, Sci. Rep. Tohoku Univ. 17, 639 (1928) 74. S. Kaya, Sci. Rep. Tohoku Univ. 17, 1157 (1928) 75. E. Kneller, Ferromagnetismus (Springer, Berlin, 1962) 76. H.C. Akulov, Zs. Phys. 52, 389 (1928) 77. G. Aubert, J. Appl. Phys. 39, 504 (1968) 78. W.J. Carr, Handbook of Phys., XVIII, 274 (1960) 79. C. Kittel, J.H. van Vleck, Phys. Rev. 118, 1231 (1960) Page 36 of 38

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

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L. Neel, Compt. Rend. 237, 1613 (1953) L. Neel, J. Phys. Radium 15, 225 (1954) F. Bødker, S. Mørup, S. Linderoth, Phys. Rev. Lett. 72, 282 (1994) C. Papusoi, J. Magn. Magn. Mater. 195, 708 (1999) C. Caizer, Magnetic Nanofluids (in Romanian) (Eurobit Publishing House, Timisoara, 2004) F. Gazeau, J.C. Bacri, F. Gendron, R. Perzynski, L. Raikher Yu, V.I. Stepanov, E. Dubois, J. Magn. Magn. Mater. 186, 175 (1998) A. van Broese Groenou, J.A. Schulkes, D.A. Annis, J. Appl. Phys 38, 1133 (1967) J.K. Vassiliou, V. Mehrotra, M.W. Russell, E.P. Giannelis, J. Appl. Phys. 73, 5109 (1993) J.M.D. Coey, D. Khalafalla, Phys. Status Solidi A 11, 229 (1972) A.H. Morrish, E.P. Valstyn, J. Phys. Soc. Jpn. 17, 392 (1962) S. Mørup, J. Magn. Magn. Mater. 37, 39 (1983) V. Skumryev, S. Stoyanov, Y. Zhang, G. Hadjipanayis, D. Givord, J. Nogués, Nature 423, 850 (2003) R.H. Kodama, A.E. Berkowitz, Phys. Rev. B 50, 0321 (1999) H. Kachkachi, M. Dimian, Phys. Rev. B 66, 174419 (2002) H. Kachkachi, E. Bonet, Phys. Rev. B 73, 224402 (2006) M. Jamet, W. Wernsdorfer, C. Thirion, V. Dupuis, P. Mélinon, A. Pérez, D. Mailly, Phys. Rev. B 69, 024401 (2004) E. De Biasi, R.D. Zysler, C.A. Ramos, H. Romero, D. Fiorani, Phys. Rev. B 71, 104408 (2005) J. Mazo-Zuluaga, J. Restrepo, J. Mejía-López, J. Appl. Phys. 103, 113906 (2008) A. Hubert, R. Sch€afer, Magnetic Domains (Springer, Berlin, 1998) E. Becker, H. Polley, Ann. Phys. 37, 534 (1940) R. Grossinger, Phys. Status Solidi A 66, 665 (1981) C. Caizer, V. Tura, J. Magn. Magn. Mater. 301, 513 (2006) H. Kojima, in Ferromagnetic Materials ed. by E.P. Wohlfarth (North-Holland, Amsterdam, 1982) C. Kittel, Phys. Rev. 70, 965 (1946) L. Neel, Compt. Rend. Acad. Sci. Paris, 224, 1488 and 1550 (1947) C. Kittel, Rev. Mod. Phys. 21, 541 (1949) C. Caizer, M. Stefanescu, Physica B 327, 129 (2003) L. Landau, E. Lifshitz, Phys. Z. S. 8, 153 (1935) E.C. Stoner, E.P. Wohlfarth, Philos. Trans. R. Soc. Lond. A, 240, 599 (1948) J.C. Slonkzewski, Research Memo., IBM Research Center, N.Y. (1956, unpublished) D.O. Smith, J. Appl. Phys. 29, 264 (1958) W. Wernsdorfer, C. Thirion, N. Demoncy, H. Pascard, D. Mailly, J. Magn. Magn. Mater. 242–245, 132 (2002) A. Stancu, L. Spinu, IEEE Trans. Magn. 34, 3867 (1998) A. Stancu, I. Chiorescu, IEEE Trans. Magn. 33, 2573 (1997) B.D. Cullity, Introduction to Magnetic Materials (Addison-Wesley, Reading, 1972) W. Wernsdorfer et al., Phys. Rev. Lett. 79, 4014 (1997) E.M. Chudnovsky, L. Gunther, Phys. Rev. Lett. 60, 661 (1988) E.M. Chudnovsky, J. Tejada, Macroscopic Quantum Tunneling of the Magnetic Moment (Cambridge University Press, Cambridge, 1998) L. Neel, C. R. Acad. Sci. Paris, 224, 1488 and 1550 (1947) C.P. Bean, J. Appl. Phys. 26, 1381 (1955) R.B. Campbell, J. Appl. Phys. 28, 381 (1957)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_24-1 # Springer International Publishing Switzerland 2015

121. B. Barbara, Magnetization Reversal of Nano-particles (Springer, Berlin-Heidelberg, 2001) (in: E. Beaurepaire, F. Scheurer, G. Krill and J.P. Kappler (Eds.): LNP 565, 157 (2001)) 122. L. Néel, Ann. Geophys. 5, 99 (1949) 123. L. Néel, Adv. Phys. 4, 191 (1955) 124. W.F. Brown, J. Appl. Phys. 30, 130S (1959) 125. A. Aharoni, Phys. Rev. A 135, 447 (1964) 126. C.H. Back, D. Weller, J. Heidmann, D. Mauri, D. Guarisco, E.L. Garwin, H.C. Siegmann, Phys. Rev. Lett. 81, 3251 (1998) 127. J.L. Dormann, F. D’Orazio, F. Lucari, E. Tronc, P. Prené, J.P. Jolivet, D. Fiorani, R. Cherkaoui, M. Nogués, Phys. Rev. B 53, 14291 (1996) 128. J.L. Dormann, L. Spinu, E. Tronc, J.P. Jolivet, F. Lucari, F. D’Orazio, D. Fiorani, J. Magn. Magn. Mater. 183, L255 (1998) 129. C.P. Bean, L.D. Livingston, J. Appl. Phys. 30, 120S (1959) 130. C. Caizer, J. Phys. Condens. Matter 17, 2019 (2005) 131. C.L. Dennis, R.P. Borges, L.D. Buda, U. Ebels, J.F. Gregg, M. Hehn, E. Jouguelet, K. Qunadjela, I. Petej, I.L. Prejbeanu, M.J. Thornton, J. Phys. Condens. Matter 14, R1175 (2002) 132. F. Kneller, F.E. Luborsky, J. Appl. Phys. 34, 656 (1963) 133. H. Pleifer, Phys. Status Solidi A 118, 295 (1990) 134. G.I. Frolov, O.I. Bachina, M.M. Zav’yalova, S.I. Ravochkin, Tech. Phys. 53, 1059 (2008) 135. F.C. Fonseca, G.F. Goya, R.F. Jardim, R. Muccillo, N.L.V. Carreño, E. Longo, E.R. Leite, Phys. Rev. B 66, 104406 (2002) 136. J.M. Vargas, W.C. Nunes, L.M. Socolovsky, M. Knobel, D. Zanchet, Phys. Rev. B 72, 184428 (2005) 137. S.V. Vonsovskii, Magnetism (Wiley, New York, 1974) 138. P. Langevin, Ann. Chem. Phys. 5, 70 (1905) 139. I.S. Jacobs, C.P. Bean, in: Magnetism III, ed by G.T. Rado, H. Suhl (Academic Press, New York, 1963) 140. K. O’Grady, A. Bradbury, J. Magn. Magn. Mater. 39, 91 (1994) 141. I.I. Yaacob, A.C. Nunes, A. Bose, J. Colloid Interface Sci. 171, 73 (1995) 142. N. Moumen, M.P. Pileni, Chem. Mater. 8, 11128 (1996) 143. J.C. Bacri, R. Perzinski, D. Salin, V. Cabuil, R. Massart, J. Magn. Magn. Mater. 62, 36 (1986) 144. R.W. Chantrell, J. Popplewel, S.W. Charles, IEEE Trans. Magn. MAG-14, 975 (1978) 145. M. Stefanescu, C. Caizer, M. Stoia, O. Stefanescu, Acta Mater. 54, 1249 (2006) 146. A.F. Pshenichnikov, W.V. Mekhonoshin, A.V. Lebedev, J. Magn. Magn. Mater. 161, 94 (1996)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Emission Properties of Metal Nanoparticles S. A. Nepijko*, H. J. Elmers and G. Schönhense Institute of Physics, University of Mainz, Mainz, Germany

Abstract Nanoparticles emit electrons and photons when they are excited by electron injection via electric current; electromagnetic radiation via microwave fields; laser radiation in infrared, visible and synchrotron (X-ray) ranges; and electron and ion bombardment. In each case, the emission mechanism depends on characteristic length scales of the nanoparticle. If the particle size is commensurate with it or is smaller, a size dependence of emission is observed [1–3]. Also, it is interesting that nanoparticles may demonstrate properties absent in bulk material.

Electron Emission from Metal Nanoparticles Excitation by Electron Injection

Excitation by electron injection into nanoparticles via electron tunneling (electric current flow through an ensemble of tunnel-coupled metal nanoparticles on a dielectric substrate) is accompanied by electron emission [1–4]. Electron emission is observed as soon as the conductivity deviates from an ohmic behavior. Corresponding experiments are realized “in situ”, e. g., when an ensemble of gold nanoparticles is deposited onto an insulating substrate directly in the column of a transmission electron microscope [5]. The main discussion in the literature concerning the mechanism of electron emission is connected with field emission [6] and electron gas heating [7]. In the first case, it is supposed that an electric field is strongly enhanced near nanoparticles and thus sufficient for field emission because of the small radius of curvature of nanoparticles. In the second case, the electron gas heating results from an attenuation of the electron–phonon interaction in nanoparticles. If the size is much smaller than the electron mean free path, the electrons execute a periodic motion within the particle without volume scattering and are reflected specularly from the boundaries. This oscillation has the frequency o ¼ av : If the electron velocity v is of the order of the Fermi electron velocity vF  108 m/s and the particle dimension is a = 10 nm, then o  1016 s1, i.e., o is an order of magnitude higher than the Debye frequency (maximum frequency) of the phonon spectrum (oDðAu1Þ = 1015 s1). The larger the frequency difference for electron and phonon subsystems, the less they exchange energy with one another. Experimental studies show that the electron–phonon interaction constant observed in ten nanometer-sized gold particles is several orders of magnitude lower than in the case of bulk material [8]. The energy fed into a nanoparticle under current excitation is absorbed by its electron subsystem. If the electron–phonon interaction is sufficiently attenuated, the electron subsystem temperature increases and electrons become heated, whereas the lattice remains relatively cold. The electron emission takes place under such conditions. Electron emission provoked by electron transport has been visualized using emission electron microscopy (EEM) [9–11]. Figure 1a–d shows a series of EEM images of a silver nanoparticle film (caesium was used to reduce the work function). The images have been acquired at different voltages applied between the contacts Uf = 0 (a), 8 (b), 10 (c), and 11 V (d). The gap with a silver nanoparticle film between the silver contacts is 5 mm. Nanoparticle emissivity considerably differs because of the spread of the particle *Email: [email protected] Page 1 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 1 EEM image series of a silver nanoparticle film in the 5 mm gap with cesium adsorbate in an emission electron microscope taken at voltages Uf = 0 (a), 8 (b), 10 (c), and 11 V (d). Arrows indicate the electron emission centers

size. Two emission centers (the spots corresponding to them are marked by arrows) are visualized at Uf = 8 V (Fig. 1b). The upper spot intensity is larger than the lower one. When the voltage rises up to Uf = 10 V (Fig. 1c), the intensity of both spots increases, but now the lower spot is more intensive than the upper one. The reason is a degradation of the upper spot at high electron current. At Uf = 11 V (Fig. 1d), the upper spot is completely burned out (irreversibly disappears), but a new spot arises. The area marked by a small square in Fig. 1b is shown in Fig. 2a in more detail. The line AB is drawn parallel to the electrodes of the silver nanoparticle film through the electron emission center. In this case, the influence of the microfields is minimal. Because of further increase of Uf, the emission center image is stretched in the perpendicular direction. The intensity profile taken along the line AB is shown in Fig. 2b. Its full width at half maximum is equal to D = 0.84 mm. Since the images in Fig. 1a–d are taken with the help of the emission electron microscope with the extractor (anode) voltage Uext = 1.5 kVand the distance between it and the object (cathode) l = 2 mm, the energy distribution of electrons emitted from the emission center has a width of e ¼ U ext eD=l = 0.6 eV [11]. EEM measurements show that the microfield near the center of emission is some orders of magnitude smaller than the field at which the field emission is expected [10, 11]. The energy distribution of the emitted electrons can be measured using an electrostatic cylindrical electron lens (Möllenstedt analyzer) installed in the photoemission electron microscope [12]. Another method is a retarding field analyzer in combination with the immersion objective incorporated in a scanning electron microscope [13]. These investigations show that electrons are not emitted from the Fermi level, as in the case of field emission, but from the vicinity of the vacuum level, as expected for emission of hot electrons. The observed width of the energy distribution is determined by the type of energy analyzer and by electric microfields at the surface of the nanoparticles. The energy width will appear large if electrons are emitted by several different emission centers. By increasing the applied voltage, one may burn all emission centers except the last one. Then, the electron temperature is determined by the high-energy branch of the distribution which is described well by the MaxwellBoltzmann distribution function. It may reach several thousand Kelvin in gold nanoparticles [13] (see also [14]). In the case of field emission, a linear dependence of log UI e2 as a function of U1f is expected. Assuming f

that the field in the vicinity of the emission center is proportional to the applied voltage E ¼ bU f , where b is a constant geometric factor, the Fowler-Nordheim equation takes the form I e  E 2 exp f

#E ðE Þ E

3=2

 U 2f exp f

# U ðU f Þ Uf

3=2

 U 2f exp f Uf

3=2

, where #E(E) and #U(Uf) are Nordheim Page 2 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 2 EEM image of the area marked by a square in Fig. 1b (a) and intensity profile measured along the line AB (b)

ffi , where W is electric functions weakly depending on E and Uf. In the case when plotted log Ie versus p1ffiffiffi W power, gives a linear dependence, the electron emission is driven q byffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi electron gas heating. pffiffiffiffiffiffiffi It is described 2 pf ffiffiffiffiffi  W exp , where T ¼ T þ aW  aW for electron gas by Richardson’s law I e ¼ AT 2e exp f e ph Te aW temperature much higher than the lattice temperature T e >> T ph and A and a are constants [1]. On the other hand, the functional dependence described above is not an unequivocal proof in favor of other mechanisms. Use of logarithmic coordinates would require measurements of emission current in the range of several orders of magnitude. In reality, this range is about one order of magnitude because the metal nanoparticle film does not withstand high input power. The emission spot (emission center) obtains a fine structure in the form of arcs (Fig. 3), when introducing a high power into the nanoparticle [8, 15]. It was suggested that capillary waves appear on a liquid (molten) particle. At the same time, at change of the sign of high voltage on the collector from positive to negative, a current of positive ion emission was registered as well [15].

Excitation by Fast Electrons They demonstrate peculiarities of true secondary electron emission with the help of an electron energy analyzer installed in a scanning electron microscope [16] taking as an example gold nanoparticles. The structure of films with particle sizes smaller than the resolution of the scanning electron microscope has been investigated in a transmission electron microscope. The sample has been prepared in such a way that nanoparticle films of varying mass thickness are located in the vicinity of a solid film. Total currents of secondary emission from nanoparticles I and from continuous films I0, as well as currents I* and I*0 for electrons with energies higher than 50 eV were measured to account for the contribution of high-energy secondary electrons. The real secondary emission level of nanoparticle films was characterized by the value s ¼ ðI  I  Þ= I 0  I 0 ¼ i=i0 . Differentiation of retardation curves of emission current at the modulation of the retarding potential with amplitude of 0.2 V was used to obtain the energy distribution of secondary electrons. The investigations did not reveal significant differences between the energy distribution of true secondary electrons from gold nanoparticle films on a carbon substrate with mass thicknesses 0.25–25 nm (correspondence between the mass thickness and average particle size is shown in Table 1) and the corresponding distribution of a continuous film. Figure 4a shows energy distributions of true secondary electrons obtained at an incident electron energy of 25 keV emitted by the continuous film (curve 1) and by the nanoparticle film with mass thickness d = 8 nm (curves 2, 3). Curve 3 is curve 2 after scaling to the maximum amplitude of curve 1. Distinctions of amplitudes of curves 1 and 2 are explained by the difference of true secondary emission coefficients. The shift of the low-energy branch in the secondary electron energy distribution is associated with a size dependence of the work function (see Fig. 4b).

Page 3 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 3 Image of the cross-section of the electron beam emitted by an emission center (an individual gold nanoparticle). “Fine structure” (a) disappears with the decrease of introduced power (b)

Table 1 Correspondence between mass thickness d and average particle size a in a gold nanoparticle film d (nm) a (nm)

0.25 4

0.5 6

1 10

2 14

4 26

8 60

15 120

25 180

Fig. 4 Energy distribution of true secondary electrons of continuous Au film (curve 1) and Au nanoparticle film with mass thickness 8 nm (curves 2, 3) (a). Shift of the low-energy part of the energy distribution versus mass thickness (b). Ur is the retarding potential

The measurements show that the ratio of emission currents i/i0 of nanoparticles and continuous gold films on the carbon substrate depends on the energy of the primary electrons E as well as on the mass thickness of the nanoparticle film d (Fig. 5). The values i given in Fig. 5 correspond to the total emission current from the nanoparticle film and from the substrate (the contribution of the latter is significant at small mass thicknesses d). The value i/i0 corresponds to the ratio of emission currents of the substrate and the continuous film at d = 0. The true secondary electron emission current for films with mass thickness Page 4 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 5 Ratio between true secondary electron emission currents from nanoparticle and continuous gold films on a carbon substrate i/i0 versus mass thickness d at different primary electron energies E = 25 (1), 10 (2) and 2 keV (3) Table 2 Calculated values of maximum penetration depth L and maximum energy dissipation depth l for electrons with initial energy E in gold [16] E (keV) L (nm) l (nm)

2 21 3

10 170 25

25 566 80

3 to 25 nm is larger than for the continuous film at the primary energy of E = 25 keV, as shown in Fig. 5. In addition, there is a maximum of the current ratio i/i0 for films with mass thickness about 8 nm. The ratio of currents i/i0 for films with mass thicknesses d> 8 nm decreases when the energy E decreases, and the maximum position is shifted to smaller mass thicknesses. The ratio of currents i/i0 increases with decreasing E for small mass thicknesses as well as for the substrate. The dependence i=i0 ¼ f ðd ÞjE¼const is nonmonotonic because of the mass thickness-dependent variation of the ratio of the nanoparticle size and the penetration depth L and depth of energy dissipation maximum l of primary electrons (see [17]). It is seen from comparison of Tables 1 and 2 that at the energy E = 25 keV, maximum penetration depth L for films of all mass thicknesses exceeds the average size (diameter) of nanoparticles a that is the whole volume of nanoparticles and i/i0> 1 gets excited. The surface emission current density is higher for nanoparticles with sizes a close to the depth of energy dissipation maximum l of primary electrons. It follows from Tables 1 and 2 that at d = 8 nm, the size of nanoparticles a = 60 nm is close to l = 80 nm at E = 25 keV, and the dependence of current ratio i/i0 on mass thickness passes through the maximum. As energy E decreases, the maximum penetration depth L decreases too (Table 2), therefore the whole volume of large nanoparticles does not get excited, and the current ratio i/i0 decreases for films with large mass thicknesses. Also with a decrease of energy E, the maximum energy dissipation depth l decreases too, whence the maximum of i/i0 must shift to smaller mass thicknesses, which was observed in the experiment. The shift of the low-energy branch of the secondary electron distribution for gold nanoparticle films with mass thicknesses 4 nm 20 nm and d< 4 nm, the shift of the low-energy branch of the secondary electron distribution happens already in the direction of smaller energies. This occurs because the particles for d> 20 nm are so large that the contribution of the surface energy to their free energy is not determinative any more, and therefore less closely packed planes with smaller work function contribute to the faceting as well. Although the faceting of the particles for d< 4 nm is formed by the most closely packed planes, the size dependence of the work function f has the main influence. The work function of nanoparticles and its size dependence play a very important role in the description of practically all electron emission properties. It is determined by the energy necessary for the electron transfer from the Fermi level to the “local” vacuum level and the energy spent on the electron transfer from the vacuum level to infinity, f ¼ fI þ fII . Here, the first component fI is the difference between the “local” vacuum level Ev and the Fermi level EF, determined by the electron structure of the material. For the second component, one considers the electron interaction with its positive image charge. It appears effectively at a certain distance under the surface due to redistribution of free charge carriers. For a plane, perfectly conducting surface classical electrodynamics yields the surface charge distribution to arrange such that the field in the half space is equivalent to that generated by a positive unit charge being placed at the symmetric position inside the conductor. The image force is determined by the curvature of the surface. For nonplanar surfaces, if a metal particle decreases in size, firstly the size dependence of fII appears for diameters about 10–20 nm and smaller when the number of atoms on the geometric surface of the particle becomes of the same order of magnitude as the total number of atoms in it. For sizes below 1–2 nm, the diameter is on the order of magnitude of the de Broglie wavelength of the electrons (for metals 0.2–0.3 nm). In this case, a significant quantization of the electron structure occurs resulting in a size dependence of fI. Size dependences fI and fII behave oppositely, that is, a number of competing mechanisms take part in formation of size dependence of f, leading to its growth as well as to its decrease with the particle size decrease [2, 19–21].

Photon Excitation The emission of photoelectrons results from incident electromagnetic radiation on metal nanoparticles.. It is characterized by a nonmonotonic size dependence [22–24]. Figure 6 shows the electron emission current from a silver film with a wedge-shaped thickness profile excited by a high-pressure mercury lamp (photon energy cutoff hn = 5.2 eV corresponding to wavelength l = 250 nm) [22]. In this case, they observe the normal one-photon photoemission or threshold emission process because the photon energy exceeds the work function of silver. In the case of decreasing mass thickness in areas of continuous A and discontinuous B films, the intensity of emission drops. For even smaller mass thickness, in the area of nanoparticle film C, the intensity increases again and finally decreases in the range of very small coverage. For the excitation of photoelectrons from a solid film, the photon energy has to be larger than the work function and the electron momentum must have a directional component toward the surface. The latter requirement is always the case for a small particle. As a consequence, the photoelectron emission intensity increases with the transition from a solid film to a nanoparticle film. The final decrease of electron yield with the further decrease of the mass thickness d results from the decreasing coverage of the surface. For the investigation of photoemission from nanoparticles, the use of short-pulse lasers with a pulse duration smaller than the characteristic timescale of electron excitation processes is very interesting. The experimentally observed dependences of the electron emission current on the mass thickness from the same sample as in Fig. 6 but excited by laser pulses with wavelength l = 800 nm (quantum energy hn = 1.55 eV), power P = 500 mW, repetition rate f = 80 MHz, pulse duration t = 18 fs (a) and l = 400 nm (hn = 3.1 eV), P = 100 mW, f = 80 MHz, t = 27 fs (second harmonic) (b) are shown in Fig. 7 Page 6 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 6 Electron emission current from a silver film with wedge-shaped thickness profile under high-pressure mercury lamp excitation (hn 5.2 eV). The distance from the edge of the film and corresponding mass thickness are plotted on the bottom and top abscissa, respectively. Areas A, B and C correspond to continuous, discontinuous and nanoparticle films

Fig. 7 Electron emission current from the same film as Fig. 6 but under femtosecond laser excitation at 800 nm (a) and 400 nm (b). Other designations are given in the text

[22]. The curves in Figs. 6 and 7 in the areas (A-B) behave oppositely. The maximum in Fig. 7 appears distinctly in area D on the decreasing branch in contrast to the behavior shown in Fig. 6. To shed further light on the mechanism of electron emission, the dependence of its intensity on the power of the laser beam is informative. Figure 8 shows the dependence of the photoemission intensity of the silver film with d = 1.2 nm (the maximum of the particle size distribution histogram corresponds to about a = 5 nm) on the average power upon excitation with 800 nm (squares) and 400 nm (crosses) wavelength. These curves were scaled to superimpose each other. In the case of n photon photoemission, the double-logarithmic plot reveals a power law with the integer exponent of n [25]. Under 400 nm excitation, the dependence of the photocurrent on the beam power accurately enough exhibits the value of n = 2 (Fig. 9). Obviously, this is a clear fingerprint of true two-photon photoemission throughout the accessible power range from 15 to 100 mW. In the case of 800 nm excitation, the accuracy of the measurements does not allow to approximate the experimental curves with a power function. They show saturation at laser power densities above 150 mW that corresponds to field strength of E  3107 V/cm. The saturation most likely results from space charge effects. Figure 10 [23] visualizes the size dependence of the total photoemission yield. The figure shows an EEM image of a stepped wedge of a silver nanoparticle film of different mass obtained by exciting

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 8 Electron emission current versus average laser power for a silver nanoparticle film with mass thickness of 1.2 nm at 800 nm (squares) and 400 nm excitation (crosses)

Fig. 9 The same result is shown in Fig. 8 (crosses) on a log-log scale with linear fit of the measurement at 400 nm

photoelectrons by femtosecond laser radiation with 400 nm wavelength. The mass thickness is 0 (1), 2 (2), 5 (3), 20 (4), and 100 nm (5). The latter case corresponds to a continuous film. The stepped wedge deposited on a Si(111) substrate was used. Energy distributions of photoelectrons are measured by emission electron microscopy using the time-of-flight (TOF) technique (Fig. 11) [23]. The spectra shown in Fig. 11 are numbered in correspondence to the regions defined in Fig. 10. Integration of the spectra results in the total electron yield of photoemission. The yield is the largest for curve 3 in Fig. 11 (step 3 in Fig. 10 is the brightest as well). The spectral dependence is determined by parameters of the nanoparticle film and of the excitation [22–24]. Depending on the excitation mechanism, the intensity of photoemission may be several orders of magnitude larger (see Figs. 6 and 7) for nanoparticles in comparison to continuous films. They also see the work function effect mentioned above when they compare the low-energy cutoff (left-hand end of spectra) of the continuous films with the nanoparticle films (1–4).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 10 EEM image of a stepped wedge of a silver nanoparticle film with mass thicknesses d = 0 (1), 2 (2), 5 (3), 20 (4) and 100 nm (5) under femtosecond laser illumination at 400 nm. The step boundaries are indicated by arrows

Fig. 11 Spectra (intensity of the electron emission current plotted as a function of the electron final state energy above EF) for the square areas 1–5 marked in Fig. 10 taken under femtosecond laser illumination at 400 nm. Since the intensity from the continuous silver film (region 5) is very small, the corresponding spectrum was scaled by a factor of 36. The inset shows spectra of regions 5 (continuous film), 2 and 3 plotted with their original intensities. The Fermi edge is marked by an arrow

For metal particles of a few nanometers in size, the work function decreases in consequence of its size dependence [2, 19–21]. The appearance of a complementary peak at d = 0.6 nm (a = 3.5 nm) is most likely related to this phenomenon. EEM investigations of electron photoemission were carried out not only on metal nanoparticle films (integral effect) but also for individual particles, e.g., probing areas with strongly differing curvatures. Homogeneous photoelectron emission from silver particles with crescent-like shapes is observed upon excitation with frequencies above the silver plasmon frequency. At lower photon energies, the emission is localized at tips of the structure (areas of maximal curvature) (Fig. 12a, b) [26]. This enhancement effect is also obtained for cylindrical and spherical particles close to each other and spherical particles on a metal plane with monomolecular organic layers for separation [27, 28]. As a result of the laser pulse (sequential or simultaneous direct multiphoton excitation [29]), localized surface plasmons are excited in a nanoparticle, acting as an optical antenna. One channel of plasmon de-excitation is the formation of a photoelectron. When the frequency of the exciting field (laser radiation) is close to the plasmon eigenfrequency, the maximum of localized surface plasmon resonance is observed with a high efficiency of light absorption. Simultaneously, the strong amplification of optical near fields by plasmon excitation reduces the surface

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 12 EEM images of the crescent-like silver particle (dashed line) under high pressure mercury lamp (hn 5.2 eV) (a) and femtosecond laser (hn = 3.1 eV) irradiation (b)

barrier and amplifies significantly the electron emission yield. Thus, metal nanoparticles behave like antennas for the optical range of wavelengths [30]. The mechanism of multiphoton photoemission is observed for silver films with wedge-shaped thickness profile for the areas A, B, and the majority of area C (Fig. 7). This, however, is not true for silver particle films with mass thickness d 0.6 nm (a 3.5 nm). In the latter case, investigations with infrared laser excitation turned out to be important for the understanding of the photoelectron emission mechanism. A pulsed CO2 TEA laser with l = 10.6 mm (hn = 0.12 eV), f = 30 Hz, t = 0.2 to 1.0 ms was used to irradiate gold, copper, and carbon films on a silicon wafer substrate [31–35]. Since the silicon substrate is transparent for l = 10.6 mm, it does not absorb energy of the laser irradiation. Within the range of 104105 W/cm2, the emission current from the nanoparticle films is stable and the shape of the emission pulses reproduces quite closely that of the laser pulses. The delay time of the emission is estimated less than 2108 s. The work functions f of the materials under study (from 4.5 to 5.5 eV) are by a factor of about 40 higher than the photon energy hn = 0.12 eV. Thus, the multiphoton photoemission can be excluded as a possible emission mechanism. The field emission mechanism seems also improbable due to low electric fields (104 V/cm) produced by the laser. A thermionic mechanism cannot explain the observed stable current densities of 102 A/cm2 as well. Figure 13 shows the emission current Ie from a carbon nanoparticle film as a function of the power ffi, this dependence is seen to be W density in the CO2 laser beam [36]. When plotted as log Ie versus p1ffiffiffi W linear in agreement with the theory connecting electron emission with heating of the electron gas in a nanoparticle. In this case, the emission current was measured in quite a wide range – almost four orders of magnitude. It turned out to be possible because the carbon nanoparticle film withstands much higher introduced power, in contrast to metal nanoparticle films. Finally, they shall pay attention to the fact that electron emission from a metal nanoparticle film is observed during excitation by an electromagnetic wave in the infrared, visible, and even microwave ranges. Fig. 14 shows the dependence of the electron emission current from a gold nanoparticle film (a = 10 nm) on the microwave power [37]. It was placed into a segment of a waveguide of 10-centimeter range in the plane parallel to the electric component of the microwave field E. The length of the microwave impulses was t = 1.7 ms, their repetition frequency did not exceed f = 2 kHz, and the field strength of the pulsed microwave field was 3103 V/cm. A Faraday cylinder was used for emission current registration. Measures were taken for suppression of secondary-electron resonance of the film discharge and charge due to the emission current. The dependence in Fig. 14 is characterized by saturation and reproducibility. An electron-microscopic study of the gold nanoparticle film revealed no change in its structure after the experiment. The efficiency of electron emission upon microwave excitation is 20–25 %; the emission current reached 0.25 mA per 1 W.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 13 Dependence of the electron emission current from a carbon nanoparticle film on silicon substrate excited by a CO2 ffi laser as a function of the power density, exhibiting a straight line in coordinates log Ie and p1ffiffiffi W

Fig. 14 Dependence of electron emission current from a gold nanoparticle film on the power of an applied microwave. The explanations are given in the text

Photon Emission from Metal Nanoparticles Excitation by Electron Injection

The electric current through a metal nanoparticle film is not only accompanied by the emission of electrons but also of photons [1–4]. Centers of photon emission (light emission) may be observed with the naked eye in low-illuminated conditions. With increasing input power, one observes a shift of emission color from red to blue. The blue shift is reversible [38]. Spectral investigations were carried out on one emission center in order to simplify the interpretation of the results. With this purpose, all emission centers but one were burnt by a fast increase of voltage (input power) applied to the metal nanoparticle film. Upon slow increase of input power, the emission center melts at certain power, which is controlled by the appearance of emission of positive ions. The particle material evaporates and the particle size reduces. The distance between this evaporating particle and adjacent ones along the current line then increases, leading to a decrease in the tunnel current and, consequently, to a decrease in power fed into the evaporating particle. This process lasts until the molten particle becomes solid and ceases evaporation, i.e., the emission center under study does not disappear of its own accord (If the applied voltage increases rapidly, it is possible to feed sufficient power to evaporate this particle completely). Figure 15a–c illustrates the evolution of the light emission spectrum from a single emission center in a palladium nanoparticle film, the size of which decreases from (a) to (c). With decreasing size of the emission center,

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 15 Light emission spectra measured for individual emission centers upon varying palladium particle size. It is 8 nm (a), 8 nm> a> 1.5 nm (b) and 1.5 nm (c). The decompositions of spectra into Gaussian peak function are shown as thin dashed lines. The energy positions of the peaks are shown with vertical dashed lines

the high-energy part of the spectrum increases in intensity. Spectra in Fig. 15a–c were decomposed into bell-shaped peak functions using self-congruent calculations in such a way that the sum of the constituting functions fit the measured spectra. To describe the bell-shaped peak functions, either Gaussian, Lorentzian, or mixed Gaussian and Lorentzian peak functions are used, but the best results are obtained for Gaussian peak functions. As seen from Fig. 15a–c, the energy position of the peaks coincides for all spectra very well. Only the relative intensities of the light emission spectra peaks change for the different sizes of particles. The energy position of peaks is well defined in the low-energy spectral range (they are equal to 1.37, 1.65, 1.97, and 2.26 eV). The energy positions of peaks in the high-energy range are less defined because in this spectral part the light emission intensity is very low. The series of light emission spectra from the copper nanoparticle film (a = 7 nm) given in Fig. 16 clearly demonstrate the development of a high-energy part of the spectrum upon the increase of applied voltage (input power) from (a) to (j) [39]. Curve (a) shows the spectrum registered certainly above the noise level. The spectrum (b) contains only one peak at 1.65 еV. Then, new peaks appear successively at 1.9, 2.1, 2.6, and 2.9 еV in spectra from (c) to (g). At last, the redistribution of intensity of the peaks in favor of high-energy peaks is observed in spectra from (h) to (f). It is seen as a change in color of the emission center. A similar result is obtained for a silver nanoparticle film (Fig. 17) [40]. In this case, the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 16 Spectra of the light emission during passage of an electric current through a copper nanoparticle film. The following voltages were applied to the film Uf = 5 (a), 8 (b), 15 (c), 19 (d), 24 (e), 27 (f), 32 (g), 35 (h), 37 (i) and 40 V (j). The theoretical curve is shown as dotted line

most interesting observation is the occurrence of photons with a quantum energy of hn = 2 eV at the applied voltage of only Uf = 1 V, that is, hn > U f (see inset in Fig. 17). Unlike most metals, the plasmon frequency of silver is located in the visible spectral region. A shoulder-shape peculiarity connected with the plasmon is denoted by a small arrow in Fig. 17. Its light emission angular distribution is approximately spherically symmetric [41], which is realized in the case of plasma radiation from a spherical particle [42]. The investigations concerning the influence of vacuum conditions on the light emission caused by passing a current through a silver nanoparticle film are interesting. When the pressure of residual gas increases ( p> 106 mbar), narrow lines arise in the light emission spectrum (Fig. 18) [43]. There are reasons to believe that these lines correspond to the light emission from residual gas atoms and molecules adsorbed on the nanoparticles. The spectrum shown in Fig. 18 reveals peaks corresponding to the Balmer Ha (656 nm) and Hb (486 nm) series of hydrogen, as well as lines caused by excitation of neon (588 nm), oxygen (777 and 844 nm), and nitrogen, oxygen, argon (844 nm). The substrate may also contribute to the light emission resulting from the electric current through the metal nanoparticle film. In the light emission spectrum of a gold nanoparticle film prepared on a semiconducting crystal, one observes a peculiarity in the spectral range corresponding to the recombination radiation of the substrate [44]. These peculiarities do not appear when dielectric substrates (glass, quartz, mica, sapphire, and so on) are used. The light emission is accompanied by the electron emission. Both emission processes are closely correlated (Fig. 19). Photons and electrons are emitted from the same emission centers [1, 3], indicating that photon and electron emission happens simultaneously. It can be supposed that (i) by analogy with the photo effect, the electron emission is caused by photon absorption, (ii) by analogy with the inverse photo

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 17 Spectra of light emission from a silver nanoparticle film at applied voltages of Uf = 1 (a), 3 (b), 5 (c), 8 (d), 10 (e), 13 ( f ) and 14 V (g). The inset shows the curve (a) on an expanded scale

Fig. 18 Light emission spectrum caused by passing a current through a silver nanoparticle film with narrow spectral lines due to excitation of residual gases

Fig. 19 Time fluctuation of the integral light emission Iph (1) and of the electron emission Ie (2) during current passage through a gold nanoparticle film

effect, photon emission is caused by absorbed electrons, or (iii) electron and photon emission occurs simultaneously as a result of the excitation process. In order to distinguish between these models, one may estimate the rate of electrons and photons emitted by an individual emission center. It turns out that an individual center can emit up to 1010-1011 electrons and 109 photons per second in the visible spectral

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

region [1]. The quantum yield of photoemission is usually in the range of fractions of percent and decreases upon approach to the threshold frequency. Light absorption of small metal particles is reduced in comparison to bulk material, and the radiation in ultraviolet region is comparatively small. Therefore, model (i) is unlikely. The inverse photoemission process (ii) is unlikely, too, because the radiation yield of visible light from a metal as a result of bombardment by slow electrons with energy below 100 eV is estimated to be 109–1010 photons per electron and fast decreasing with decreasing energy [1] (see also [45]). In conclusion, one can assume that electron and photon emission occurs simultaneously and independently. The photon emission cannot be explained by thermal radiation. This can be concluded from the currentinduced light emission spectra for palladium [38], copper [39], silver [40, 41, 43], and gold [44, 46] nanoparticle films showing a complex structure in contrast to the spectrum of thermal radiation with a pffiffiffi cutoff at the wavelength l ¼ 2pap(emitting and adsorption of light with wavelength exceeding the ffiffiffi diameter a of particle by a factor of 2p is prohibited [47]). The complex structure of the light emission spectra also indicates that the decelerating radiation (Bremsstrahlung) cannot be responsible for the observed radiation, because in this case one would observe a sharp high-energy maximum and gradual decrease toward low energies. Similarly, the photon emission is not related to discharge effects. Finally, they shall discuss the role of the electron gas heating in metal nanoparticles. The light radiation from metal nanoparticles containing nonequilibrium hot electrons may be caused (1) by inelastic tunneling (from one nanoparticle to another) and by inelastic reflection off the potential barrier (inside a nanoparticle), (2) by interband transitions, and (3) by decay of plasmons excited by fast (overbarrier) electrons. (1) Inelastic tunneling and reflection are supported by high densities of the tunnel current and high development of the interfaces in metal nanoparticle films. Since the dimensions of the nanoparticles are much smaller than the length of photon mean free path as well as its wavelength, there is no reason to consider the photon movement in a nanoparticle. Each generated photon can escape the nanoparticle immediately (there is no balance between radiation and substance). The main contribution to the radiation in the visible spectral range is caused by electrons tunneling inelastically or reflecting off the  top of the barrier, and the number of these electrons is proportional to exp  k BfT e , where kB is the

Boltzmann constant and Te is the temperature of the electron system. This model explains the fact that light emission in the visible region appears simultaneously with electron emission and also that timedependent fluctuations of the intensities repeat each other well (Fig. 19). The effect of photon emission caused by inelastic reflection is inverse to the surface photo effect. (2) The photon emission caused by recombination of electron–hole excitation in the particle volume may be regarded as an effect inverse to the photo effect in the bulk. In the simplest model, one assumes that transitions from the Fermi level to excited holes at larger binding energy are the dominant processes and matrix elements are considered to be constant. In this case, the emission spectrum reflects the total density of states below the Fermi level (see, e.g., theoretical curve drawn by dotted line in Fig. 16). The spectrum differs for the case of direct and indirect transitions. The contribution of indirect transitions related to the surface and not requiring conservation of quasimomentum increases with decreasing particle size. Therefore, the size dependence of the spectrum results both from changes of the electronic structure in the ground state and from varying probabilities of direct and indirect transitions. (3) The photon emission related to the decay of plasmons requires the maintenance of a stationary high density of these collective excitations. Unbalanced electrons with energy sufficient for excitation of plasma oscillation appear as a result of electron gas heating (or, as described below, are injected into nanoparticles during their bombarding by electrons). They resume that the frequency of the plasma oscillation is large for most metals and semimetals have a small frequency in comparison with

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

frequencies of the visible spectral region. Of course, the plasma frequency may shift because of size, shape, and influence of adjacent nanoparticles (their concentration), but these changes are not large. The radiation may get into the visible region due to radiation transitions between separated plasmon levels.

Excitation by Electron Bombardment Electron bombardment is usually realized by an electron gun using a thermal cathode. The thermal radiation from the cathode is a disadvantage which impedes measurements of weak luminous flux [48]. This disadvantage is eliminated if a field electron emitter is used. In this case, the emitter may be considered as a tungsten sphere with very small diameter. Figure 20 shows the photon emission spectrum using an electron gun for the electron bombardment of the same copper nanoparticle film as shown in Fig. 16 with electron energy of 405 eV. The experimental spectrum is compared with a theoretical curve. The peaks at 3.9 and 4.5 eV are strongly reduced because of the absorption of ultraviolet light during its passage through the glass substrate or window. Nevertheless, they can be clearly observed, and this is the main distinction between current-induced and electron bombardment-induced light emission spectra. The photon emission intensity induced by low-energy electron bombardment is much weaker than the intensity recorded during current excitation (see experimental curves in Figs. 16 and 20). For this reason, the features at 1.65 and 1.9 eV in the spectrum obtained by current excitation are not visible in the case of electron bombardment. In both cases, peaks are observed at 2.1, 2.6–2.65, and 2.9–3.0 eV. The results suggest that despite differences in spectra the underlying mechanisms of photon emission are similar for both excitation methods. An analogous experiment has been carried out with silver nanoparticle films [49]. In this case, the plasmon energy is in the visible spectral region. For silver nanoparticle films deposited on an amorphous carbon substrate with the maximum of the particle size distribution at a = 30, 8, and 2.5 nm, the plasmon energy is 3.76, 4.13, and 4.28 eV (wavelength 330, 300, and 290 nm), respectively (Fig. 21). Curves (1)–(3) in Fig. 21 are normalized for the convenient comparison. Figure 22a–d [50] shows the light emission spectrum deformation for palladium particles of different sizes excited by electron bombardment. The substrate is a single crystal of NiAl(110) covered with an epitaxial film of 0.5 nm thick g-Al2O3. The electron bombardment results in weak light emission intensity (Fig. 22a). The intensity is one order of magnitude larger if a palladium nanoparticle film with a = 3.5 nm (Fig. 22b) is deposited. Peaks (stripes) are observed at 1.8, 2.3, and 3.0 eV. For very small particles of 1.5 and 1 nm size, light emission increases and high-energy peaks (wide stripes) appear at 3.7 and 4.6 eV (Fig. 22c, d). In order to allow for comparison of light emission spectra in Fig. 22a–c, the electron current was kept constant at 5 mA by adjusting the applied voltage. Investigations concerning the adsorption of CO gas have been carried out in the same experimental run. Upon backfilling the chamber with CO (5108 mbar) and cooling the sample to 100 K, the light emission intensity of the band is reduced at 3.0 eV and becomes stronger at 4.5 eV (Fig. 23). In the general case, during electron bombardment, the excitation is transmitted to a large number of nanoparticles with a broad size distribution. As a result, the measured light emission spectrum has an averaged character. Using a scanning tunneling microscope coupled with a light spectrometer, one has the possibility of measuring the light emission spectrum of an individual particle with known size. A scanning tunneling microscope surrounded by a parabolic mirror has been used benefiting from the large acceptance angle for the photon collection. These measurements have been carried out on a gold nanoparticle film on a native oxide-covered silicon wafer (n-type silicon, r  0.01 Ocm) [51]. Figures 24 and 25a show the light emission spectrum of a gold particle with size a = 5 nm at voltages on the tungsten tip (gap

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 20 Light emission spectrum for a copper nanoparticle film undergoing bombardment by low-energy electrons (energy of electrons in the beam is 405 eV). The theoretical curve is shown as a dotted line

Fig. 21 Intensity normalized spectra of light emission from silver nanoparticles with average sizes of a = 30 (1), 8 (2) and 2.5 nm (3) excited by electron bombardment

voltage) of Utip = 3 and 10 V (current from the point is equal to itip = 1 and 10 nA), respectively. The different gap voltages cause large spectral differences because the spectra are measured in (i) the tunnel (Utip< 5 V) and (ii) in the field emission modes (Utip> 5 V). In case of Utip< 5 V, the tunneling process is accompanied by an excitation of plasmons [52] as a result of strong electromagnetic interaction between tip and nanoparticle causing collective electron oscillations of the coupled electron gases. Decay of the tip-induced plasmon results in a peak at 1.62 eV in Fig. 24 (see also [53–55]). The peak at 1.62 eV is present for both polarities of the gap voltage. This experiment represents an elementary process explaining aspects of the current-induced light emission in metal nanoparticle films as discussed in the previous section. For larger gap voltages Utip> 5 V, the field emission mode is realized, that is, the excitation of the investigated nanoparticle is caused by bombarding of low-energy electrons (Fig. 25a). Here, Fig. 25b is decisive for the interpretation of the results. It was obtained at Utip = 10 V and gives a photon emission spectrum from the pure substrate without gold nanoparticles. The spectra shown in Fig. 25a, b have been deconvoluted using Gaussian peak functions. The comparison of deconvolutions shows that energy positions of the peaks at 1.69 and 1.98 eV are identical for positions on a gold particle and on the bare substrate. They assume that in the field emission mode, the electrons from the tip illuminate the investigated nanoparticle as well as partially the substrate. The simultaneous illumination is possible when the tip radius is much larger than the investigated particle. The peak at 2.22 eV corresponds to excitation and decay of the Mie plasmon, in the mode polarized perpendicular to the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 22 Light emission spectra of a NiAl(110) substrate without (a) and with g-Al2O3 film (b) and also after deposition of palladium nanoparticles with average sizes of a = 3.5 (c), 1.5 (d) and 1 nm (e) undergoing bombardment by low-energy electrons. Other designations are given in the text

substrate [55, 56]. Its position on the energy scale is determined by the material, size and shape of the nanoparticles, their concentration, and the dielectric constant of the environment. The peak at 1.45 eV is clearly observed but not discussed [55, 56]. The excitation process consists of an electron transfer from the tip to unoccupied energy levels of the gold nanoparticles and a subsequent transition to the Fermi level accompanied by photon emission. This makes the present measurements very informative for the investigation of the electron density of states above the Fermi level. Scanning tunneling microscopy investigations of light emission were also carried out for individual silver nanoparticles [57–59].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Fig. 23 Deformation of light emission spectra from palladium nanoparticles prepared on g-Al2O3/NiAl(110) substrate upon CO adsorption (average particle size a = 3 nm, CO pressure p = 5108 mbar). The band at 3.0 eV decreases, while a new arises at 4.5 eV. Arrows show the deformation direction. Other designations are given in the text

Fig. 24 Light emission spectrum of a gold nanoparticle with size about a = 5 nm obtained by means of a scanning tunnelling microscope in tunnelling mode. Other designations are given in the text

Fig. 25 Light emission spectra of the same gold particle as in Fig. 24 deposited on a native oxide covered silicon substrate (a), and of the substrate itself (b) taken at identical experimental conditions by means of a scanning tunnelling microscope in field emission mode. Other designations are given in the text

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

Conclusion Photon and electron emission properties of metal nanoparticles have been discussed in respect to basic science and to technological applications. Nanoparticles can be used as electron emitters in vacuum electronic devices, coatings with defined characteristics of secondary electron emission, image converters in devices for infrared vision, sensors, and many more. In respect to basic science, one can determine the electron structure, plasmon energy, concentration of free charge carriers (electrons), and other aspects of nanoparticles from spectral measurements. The size dependence of the emission properties appears at nanoparticle sizes commensurate or below characteristic length scales. These characteristic length scales are the electron mean free path, the maximum penetration depth and depth of energy dissipation maximum for primary electrons, and other quantities. The surface plays an increasing role with the decrease of the size. The number of atoms on the geometric surface is commensurate with the general number of atoms for particle size a =15–20 nm. At this size, the quasimomentum is no longer conserved. In the case of interband transitions, the ratio of direct and indirect transitions changes in favor of the latter ones. The limitation on the electron momentum direction needed for the emission of electrons into vacuum is lifted, and all electrons are able to escape the particle. In addition, the work function becomes size dependent, thus changing the emission characteristics of metal nanoparticles. A characteristic length scale for electron structure quantization is the de Broglie wavelength (0.2–0.3 nm for metals).

References 1. P.G. Borziak, Yu.A. Kulyupin, Electronic Processes in Island Metal Films (Naukova Dumka, Kiev, 1980) 2. S.A. Nepijko, Physical Properties of Small Metal Particles (Naukova Dumka, Kiev, 1985) 3. R.D. Fedorovich, A.G. Naumovets, P.M. Tomchuk, Electron and light emission from island metal films and generation of hot electrons in nanoparticles. Phys. Rep. 328, 73–179 (2000) 4. P.G. Borziak, O.G. Sarbej, R.D. Fedorowitsh, Neue Bescheinungen in sehr d€ unnen Metallschichten. Phys. Status Solidi 8, 55–58 (1965) 5. P.G. Borziak, Yu.A. Kulyupin, S.A. Nepijko, V.G. Shamonya, Electrical conductivity and electron emission from discontinuous metal films of homogeneous structure. Thin Solid Films 76, 359–378 (1981) 6. G. Dittmer, Electrical conduction and electron emission of discontinuous thin films. Thin Solid Films 9, 317–328 (1972) 7. P.M. Tomchuk, R.D. Fedorovich, Emission of hot electrons from thin metal films. Sov. Phys. Solid State (USA) 8, 226–227 (1966) 8. S.A. Gorban’, S.A. Nepijko, P.M. Tomchuk, Electron-phonon interaction in small metal islands deposited on an insulating substrate. Int. J. Electr. 70, 485–490 (1970) 9. A. Gloskovskii, D.A. Valdaitsev, S.A. Nepijko, G. Schönhense, Electrical and emission properties of current-carrying silver nanocluster films investigated by emission electron microscopy. Microsc. Microanal. 9, 176–177 (2003) 10. A. Gloskovskii, D. Valdaitsev, S.A. Nepijko, N.N. Sedov, G. Schönhense, Electrical and emission properties of current-carrying silver cluster films detected by an emission electron microscope. Appl. Phys. A 79, 707–712 (2004)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

11. A. Gloskovskii, D.A. Valdaitsev, L.V. Viduta, S.A. Nepijko, G. Schönhense, Investigation of the local electron emission from current-carrying silver cluster films by an emission electron microscope. Thin Solid Films 518, 4030–4034 (2010) 12. R. Blessing, H. Pagnia, Electron emission from gold island films. Phys. Status Solidi B 110, 537–542 (1982) 13. Yu.A. Kulyupin, S.A. Nepijko, V.I. Stepkin, Energy distribution of electrons emitted by island-type films. Bull. Acad. Sci. USSR, Phys. Ser. (USA), 46, 78–81 (1982) 14. M. Bischoff, H. Pagnia, J. Trickl, Energy distribution of emitted electrons from electroformed MIM structures: the carbon island model. Int. J. Electr. 73, 1009–1010 (1992) 15. V.V. Vladimirov, S.A. Gorban’, S.A. Nepijko, Observation of ion emission and instability during the flow of current through metal-island films. Sov. J. Commun. Electron. (USA), 36, 135–140 (1991) 16. S.A. Nepijko, V.I. Styopkin, Some features of true secondary electron emission of island-gold type films. Bull. Acad. Sci. USSR, Phys. Ser. (USA), 46, 144–148 (1982) 17. H.-J. Fitting, H. Glaefeke, W. Wild, Electron penetration and energy transfer in solid targets. Phys. Status Solidi A 43, 185–190 (1977) 18. P. Vernier, E. Coquet, E. Boursey, Variations du travail de sortie de l’or avec la face cristallographique. CR Acad. Sci. Paris 264, 986–989 (1967) 19. R. Carron, Sensibilité photoélectrique des couches minces métalliques. Ann. Phys. (N.Y.), 10, 595–622 (1965) 20. D.M. Wood, Classical size dependence of the work function of small metallic spheres. Phys. Rev. Lett. 46, 749 (1981) 21. W.A. de Heer, The physics of simple metal clusters: experimental aspects and simple models. Rev. Mod. Phys. 65, 611–676 (1993) 22. A. Gloskovskii, D.A. Valdaitsev, M. Cinchetti, S.A. Nepijko, J. Lange, M. Aeschlimann, M. Bauer, M. Klimenkov, L.V. Viduta, P.M. Tomchuk, G. Schönhense, Electron emission from films of Ag and Au nanoparticles excited by a femtosecond pump-probe laser. Phys. Rev. B 77, 195427 (2008) [11 pages] 23. M. Cinchetti, D.A. Valdaitsev, A. Gloskovskii, A. Oelsner, S.A. Nepijko, G. Schönhense, Photoemission time-of-flight spectromicroscopy of Ag nanoparticle films on Si(111). J. Electron. Spectrosc. Relat. Phenom. 137–140, 249–257 (2004) 24. A. Gloskovskii, D. Valdaitsev, S.A. Nepijko, G. Schönhense, B. Rethfeld, Coexisting electron emission mechanisms in small metal particles observed in fs-laser excited PEEM. Surf. Sci. 601, 4706–4713 (2007) 25. M. Aeschlimann, C.A. Schmuttenmaer, H.E. Elsayed-Ali, R.J.D. Miller, J. Cao, Y. Gao, D.A. Mantell, Observation of surface enhanced multiphoton photoemission from metal surfaces in the short pulse limit. J. Chem. Phys. 102, 8606–8613 (1995) 26. M. Cinchetti, A. Gloskovskii, S.A. Nepjiko, G. Schönhense, H. Rochholz, M. Kreiter, Photoemission electron microscopy as a tool for the investigation of optical near fields. Phys. Rev. Lett. 95, 047601 (2005) [4 pages] 27. F. Schertz, M. Schmelzeisen, M. Kreiter, H.J. Elmers, G. Schönhense, Field emission of electrons generated by the near field of strongly coupled plasmons. Phys. Rev. Lett. 108, 237602 (2012) [5 pages] 28. F. Schertz, M. Schmelzeisen, R. Mohammadi, M. Kreiter, H.J. Elmers, G. Schönhense, Near field of strongly coupled plasmons: uncovering dark modes. Nano Lett. 12, 1885–1890 (2012) 29. J. Lehmann, M. Merschdorf, W. Pfeiffer, A. Thon, S. Voll, G. Gerber, Surface plasmon dynamics in silver nanoparticles studied by femtosecond time-resolved photoemission. Phys. Rev. Lett. 85, 2921–2924 (2000) Page 21 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

30. P. Bharadwaj, B. Deutsch, L. Novotny, Optical antennas. Adv. Opt. Photon. 1, 438–483 (2009) 31. L.I. Andreeva, A.A. Benditskii, L.V. Viduta, A.B.. Granovskii, Yu.A. Kulyupin, M.A. Makedontsev, G.I. Rukman, B.M. Stepanov, R.D. Fedorovich, M.A. Shoitov, A.I. Yuzhin, Electron emission induced by the action of CO2 laser radiation on island metal films. Sov. Phys. Solid State (USA) 26, 923–924 (1984) 32. A.A. Benditskii, L.V. Viduta, Yu.A. Kulyupin, A.P. Ostranitsa, P.M. Tomchuk, R.D. Fedorovich, V.A. Yakovlev, Interaction between laser radiation and island metallic films. Bull. Acad. Sci. USSR, Phys. Ser. (USA), 50, 170–173 (1986) 33. A.A. Benditskiĭ, L.V. Viduta, V.I. Konov, S.M. Pimenov, A.M. Prokhorov, P.M. Tomchuk, R.D. Fedorovich, N.I. Chapliev, V.A. Yakovlev, Scanning electron microscopic study of the interaction of laser IR radiation with island metallic films. Poverkhnost’ Fiz. Khim. Mekh. 10, 48–55 (1988) 34. R.D. Fedorovich, A.G. Naumovets, A.P. Ostranitsa, P.M. Tomchuk, Electron emission from regular chain-like island structures. Int. J. Electr. 69, 179–183 (1990) 35. A.A. Benditsky, D.B. Dan’ko, R.D. Fedorovich, S.A. Nepijko, L.V. Viduta, Use of the fine dispersed systems as IR detectors. Int. J. Electr. 77, 985–988 (1994) 36. L.V. Viduta, O.E. Kiyayev, A.G. Naumovets, A.P. Ostranitsa, R.D. Fedorovich, Electron emission from gold and graphite films having a special structure in the presence of a current flow and excitation by an IR laser. Sov. J. Commun. Technol. Electron. 37, 98–104 (1992) 37. D.A. Ganichev, V.S. Dokuchaev, S.A. Fridrikhov, P.G. Borziak, Yu.G. Zav’yalov, Yu.A. Kulyupin, Electron emission from discontinuous metallic films in a SHF field. Pis’ma v Zh. Tekh. Fiz. (USSR), 1, 386–389 (1975) 38. S.A. Nepijko, D.N. Ievlev, L.V. Viduta, W. Schulze, G. Ertl, The light emission observed from small palladium particles during passage of electronic current. ChemPhysChem 3, 680–685 (2002) 39. S.A. Nepijko, R.D. Fedorovich, L.V. Viduta, D.N. Ievlev, W. Schulze, Light emission from small copper particles excited by current passage or by low-energy electron bombardment. Phys. B 301, 261–266 (2001) 40. S.A. Nepijko, R.D. Fedorovich, L.V. Viduta, D.N. Ievlev, W. Schulze, Light emission from Ag cluster films excited by conduction current. Ann. Phys. (Leipzig) 9, 125–131 (2000) 41. I.A. Konovalov, K.N. Pilipchak, P.M. Tomchuk, Luminescence of island silver films during passage of an electric current. Opt. Spectr. (USA) 50, 348–349 (1981) 42. J.W. Little, T.L. Ferrell, T.A. Callcott, E.T. Arakawa, Radiative decay of surface plasmons on oblate spheroids. Phys. Rev. B 26, 5953–5956 (1982) 43. S.A. Nepijko, D.N. Ievlev, W. Schulze, Influence of vacuum conditions on the light emission caused by passing a current through a silver cluster film. Phys. B 304, 45–50 (2001) 44. M. Bischoff, H. Pagnia, Electroluminescence spectra from gold island structure thin films. Thin Solid Films 29, 303–312 (1975) 45. A.H. Mahan, A. Gallagher, Transition radiation for the diagnosis of low-energy electron beams. Rev. Sci. Instrum. 47, 81–83 (1976) 46. Yu.A. Kulyupin, K.N. Pilipchak, On the radiation of discontinuous gold films by electric current transmission. Phys. Status Solidi A 11, K15–K19 (1972) 47. W.K. McGregor, On the radiation from small particles. J. Quant. Spectrosc. Radiat. Transfer 19, 659–664 (1978) 48. P. Borziak, I. Konovalov, Yu. Kulyupin, K. Pilipchak, Cathodoluminescence from metal films. Thin Solid Films 35, L9–L12 (1976) 49. S.A. Nepijko, D.N. Ievlev, W. Schulze, Size dependence of the plasmon peak position in electron stimulated photon emission spectra of Ag clusters supported on amorphous carbon film. Eur. Phys. J. D 24, 115–117 (2003) Page 22 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_25-1 # Springer International Publishing Switzerland 2015

50. M. Adelt, S. Nepijko, W. Drachsel, H.-J. Freund, Size-dependent luminescence of small palladium particles. Chem. Phys. Lett. 291, 425–432 (1998) 51. S.A. Nepijko, A. Chernenkaya, K. Medjanik, S.V. Chernov, A.A. Sapozhnik, A.V. Yarmak, L.V. Odnodvorets, W. Schulze, G. Schönhense, Spectral measurement of light emission from individual Au nanoparticles using scanning tunnelling microscopy. (In preparation) 52. B.N.J. Persson, A. Baratoff, Theory of photon emission in electron tunneling to metallic particles. Phys. Rev. Lett. 68, 3224–3227 (1992) 53. Z.C. Dong, X.L. Zhang, H.Y. Gao, Y. Luo, C. Zhang, L.G. Chen, R. Zhang, X. Tao, Y. Zhang, J.L. Yang, J.G. Hou, Generation of molecular hot electroluminescence by resonant nanocavity plasmons. Nat. Photonics 4, 50–54 (2010) 54. T. Wang, E. Boer-Duchemin, Y. Zhang, G. Comtet, G. Dujardin, Excitation of propagating surface plasmons with a scanning tunnelling microscope. Nanotechnology 22, 175201 (2011) [6 pages] 55. N. Nilius, N. Ernst, H.-J. Freund, Tip influence on plasmon excitations in single gold particles in an STM. Phys. Rev. B 65, 115421 (2002) [8 pages] 56. N. Nilius, N. Ernst, H.-J. Freund, Photon emission from individual supported gold clusters: thin film versus bulk oxide. Surf. Sci. 478, L327–L332 (2001) 57. A. Downes, M.E. Welland, Photon emission from Ag and Au clusters in the scanning tunneling microscope. Appl. Phys. Lett. 72, 2671–2673 (1998) 58. N. Nilius, N. Ernst, H.-J. Freund, Photon emission spectroscopy of individual oxide-supported silver clusters in a scanning tunneling microscope. Phys. Rev. Lett. 84, 3994–3997 (2000) 59. N. Nilius, A. Cörper, G. Bozdech, N. Ernst, H.-J. Freund, Experiments on individual aluminasupported adatoms and clusters. Prog. Surf. Sci. 67, 99–121 (2001)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Formation of Nanoparticles and Decoration of Organic Crystals Paul Jara*, Bárbara Herrera and Nicolás Yutronic Departamento de Química, Facultad de Ciencias, Universidad de Chile, Santiago, Chile

Abstract In the last decades, nanoparticles have been of great research interest due to their unique quantum size effect and optical, electronic, magnetic, and supramolecular properties. In recent year, the face-selective adhesion of gold nanoparticles onto the crystal faces of organic crystals, also called “decoration” has been reported for first time. The organic single crystals may have surfaces with different chemical nature, allowing the opportunity to explore a wide variety of composite materials with highlights on anisotropic properties. The metal nanoparticle preparation methods can be classified as chemical and physical methods. Chemical methods consist mainly in the decomposition or precipitation of inorganic salts. For example, it is possible to obtain gold nanoparticles from a gold precursor like HAuCl4. Physical methods involve principally the production of gas phase atoms or clusters by diving of the bulk material. Other remarkable preparation method is the sputtering, where a high-purity metal target is bombarded with argon ions, followed by the subsequent deposition of the sputtered metal atoms on the surface of a substrate support to create a uniform dispersion of nanoparticles. This technique has some advantages over other preparation methods like the no contamination from solvent or precursor molecules on the surface. Also, the process is economical and environmentally friendly, since the metal excess is recoverable from the chamber and without liquid waste.

Keywords Cyclodextrin; Inclusion compounds; Metal nanoparticles; Nanodecoration; Sputter deposition; Functionalized surface

Nanoparticles and Nanodecoration Metal nanoparticles (NPs) raised much interest in science and technology due to specific size-dependent properties which can be utilized in advanced technologies such as sensor applications (Franke et al. [1] and Zhang et al. [2]), medical diagnostics (Wilson [3]), catalysis (Corma and Garcia [4]), and nanoelectronics (Schmid and Simon [5]). They have good chemical stability and can be surface functionalized, according to the nature, with almost every type of coordinating molecule. The metal nanoparticles preparation methods can be classified as chemical and physical methods Veith et al. [6]. Chemical methods consist mainly in the decomposition or precipitation of inorganic salts. For example, it is possible to obtain gold nanoparticles (AuNPs) from a gold precursor like HAuCl4 (Turkevich et al. [7]). These chemical methods are described in several papers and reviews and are the most widely used techniques in basic research because of the availability of reactants and the relatively low costs of production on the laboratory scale. *Email: [email protected] Page 1 of 14

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Table 1 Principal previous work in nanodecoration Year 2005

Title Nanoparticle-coated microcrystals

2006

Anisotropic decoration of gold nanoparticles onto specific crystal faces of organic single crystals Ordered arrangement of gold nanoparticles on a-cyclodextrinsdodecanethiol inclusion compound produced by magnetron sputtering Face-preferred deposition of gold nanoparticles on a-cyclodextrin/octanethiol inclusion compound Selective deposition of metal complex nanocrystals onto the surfaces of organic single crystals bearing pyridine moieties Selective nanodecoration of modified cyclodextrin crystals with gold nanorods

2007

2007 2009 2013

Author and references M. Murugesan et al., Chem. Commun. 21, 2677–2679 (2005) [15] Y. Fujiki et al., Angew. Chem. Int. Ed. 45, 4764–4767 (2006) [16] L. Barrientos et al., New J. Chem. 31, 1400–1402 (2007) [11] S. Rodríguez-Llamazares et al., J. Colloid Interface Sci. 316, 202–205 (2007) [17] Y. Fujiki et al., Cryst. Growth Des. 9, 2751–2755 (2009) [18] B. Herrera et al. J. Colloid Interface Sci. 389, 42–45 (2013) [23]

Physical methods involve principally the production of gas phase atoms or clusters by diving of the bulk material (Chen and Kimura [8] and Watson et al. [9]). Other remarkable preparation method is the sputtering, where a high-purity metal target is bombarded with argon ions, followed by the subsequent deposition of the sputtered metal atoms on the surface of a substrate support to create a uniform dispersion of nanoparticles Asanithi et al. [10]. This technique has some advantages over other preparation methods like the no contamination from solvent or precursor molecules on the surface. Also, the process is economical and environmentally friendly, since the metal excess is recoverable from the chamber and without liquid waste (Barrientos et al. [11]). On the other hand, several protocols have been developed for the manufacture of the particle assembly into one, two, and three dimensions (Homberger and Simon [12]). Different concepts have been developed for the design of novel materials based on the unique size-dependent properties of single nanoparticles and their collective properties in assemblies, owing, e.g., to dipolar, magnetic (Gambardella et al. [13]), or electronic coupling (Schmid et al. [14]). The study of intrinsic properties of the NPs is of current interest. Therefore, it is necessary that these are ordered and possess low size dispersion. The use of an active crystal substrate can be useful for this purpose. Murugesan et al., reported for the first time the potassium sulfate crystal coated with AuNPs (Murugesan et al. [15]). An interesting concept was reported by Fujiki some years ago (Fujiki et al. [16]), achieving the selective adhesion of AuNPs onto the crystal faces of organic crystals (Table 1). In this work, hexagonal single crystals of L-cystine providing different functional groups on the crystal faces were decorated with gold nanoparticles. This research gave new perspectives for the use the organic single crystals that have surfaces with different chemical nature, allowing the opportunity to explore a wide variety of composite materials with highlights on anisotropic properties. Recent reports have shown that AuNPs can be deposited on a selected face {001} of a-cyclodextrin with octanethiol (a-CD/OT) and a-cyclodextrin with dodecanethiol (a-CD/DDT) inclusion compound (IC) crystals (Rodríguez-Llamazares et al. [17]; Barrientos [11]). In this approach two actual chemistry areas converge, the molecular recognition phenomena applied to the a-CD IC and the assembly of metal nanoparticles based on multivalent binding. Another interesting example of decoration was reported by Fujiki et al. where specific crystal faces of organic compounds with pyridine moieties were decorated with palladium complex nanocrystals (Fujiki et al. [18]). Hence, the exploration of a wide variety of inorganicorganic hybrid materials with anisotropic properties may be expected (Fujiki et al. [16]).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Table 2 Schematic representation of cyclodextrins and decoration with nanoparticles A

Representation of b-cyclodextrin

B

Frontal and perpendicular view of channel on the hexagonal structure of 2a-CD/dodecanethiol IC

C

Schematic representation of AuNPs onto crystal plane {001} of a-CD IC

Nanoscience and Cyclodextrins Degradation of starch by the action of the enzyme transferase produces an intramolecular reaction forming cyclic products, the so-called cyclodextrins (CDs) which contain glucose units linked through a-1.4 bonds. The best known a-CD, b-CD, and g-CD are formed by 6, 7 and 8 units of D-(+) glucose, respectively (D’Souza [19]). The spatial structure of CDs corresponds to a truncated cone, and the size of its internal cavity depends of the number of glucose units in the molecule, being 0.57, 0.78, and 0.95 nm3 for a-CD, b-CD, and g-CD, respectively (Loftsson and Duchêne [20]) (Table 2). Guest molecules can be enclosed in these cavities, bound via noncovalent interactions, whereas hydrophobic and van der Waals attraction are the mayor driving forces for the formation of IC. Three possible types of structural packing for a-CDs are reported, the so-called cage type, layer type, and channel type (Rodríguez-Llamazares et al. [21]). For the channel type of the a-CD host, two possible arrangements for the included guest molecules exist, namely, head-totail and head-to-head orientation (D’Souza [19]). Actually, CDs are used in pharmaceutical industry,

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Fig. 1 Schematic representation of basic structure of IC (a) and a-CD IC crystal with specific plane {001} (b)

chemical catalysis, and separation technology, in the field of chemical nanostructure (RodríguezLlamazares et al. [17]), and recently in potential application in mining (Liu et al. [22]). In some cases the CD IC can be crystallized like well-defined single crystals with supramolecular assemblies constructed by noncovalent bonds. The size range of crystals is of a few millimeters with shapes dependent on the number of units of glucose molecules that compose them and the included guest molecule. Interestingly these crystals are anisotropic polyhedrons that provide crystal faces with interfaces of different chemical nature due to anisotropic arrangements of the CD unit and to the shape of organic molecules included (Herrera et al. [23]). The organic crystal surface can be considered like a tool for the formation, growth, and attachment of particles where the functional group on the interface of organic crystal has a fundamental role. Thereby, the CDs IC are a fascinating topic in modern supramolecular chemistry as they serve as models for understanding molecular recognition (Harata [24] and Wenz et al. [25]) and as precursors for designing novel nanomaterials (Daniel and Astruc [26] and Díaz et al. [27]). In the nanoscience field, the CDs have been used for the phase transfer of nanoparticles in liquid of different polarity (Wang et al. [28] and Lala et al. [29]) and to prepare colloidal AuNPs by chemical reduction in the presence of unmodified (Liu et al. [30]) and thiolated a- and b-CDs (Liu et al. [31]) and by femtosecond laser ablation (Kabashin et al. [32]). An alternative and even more versatile concept recently introduced is the use of CD IC for the preparation of nanoparticles. The most recent method utilizes the well-defined surface functionality of IC, where the surface functional groups –SH, –NH2, and –COOH can be adjusted by the guest molecules. Hence, two actually very interesting chemistry areas converge, i.e., supramolecular chemistry, applied to the formation of CD IC, and the assembly of metal nanoparticles (Barrientos et al. [33]). In solid a-CDs/alkyl-guest IC, the alkyl chain is located in the apolar and relatively poor electron density zone of the CD cavities (Rodríguez-Llamazares et al. [21]). The functional group of the guest molecule could be located at the extreme boundary of a CD unit, in the rich electron space density ({001} crystal plane). These functional groups –SH (Jara et al. [34]), –COOH (Rodríguez-Llamazares et al. [35]), and –NH2 (Jara et al. [36]) are available to interact with the particles being able to stabilize it (Fig. 1).

Ordered Arrangement Functionalized surface of CD IC crystal can be used to immobilize different nanostructures such as nanoparticles and nanorods. The method described utilizes the surface functionality of CD IC, where the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Fig. 2 Photographs that reveal the change of microcrystal color after decoration with AuNRs

Fig. 3 Selective nanodecoration with gold nanorods onto crystal surface (a) and zoomed image detailing the nanostructures (b)

functional groups of alkyl-guest interact directly with the metal nanostructures. Recently, it has been reported that gold nanorods (AuNRs) stabilized in cetyltrimethylammonium bromide (CTAB) (Nikoobakht and El-Sayed [37]; Smith and Korgel [38]) can be deposited onto crystals of a-CD IC that contained octanethiol (OT) as guest (Herrera et al. [23]). The selective adhesion (decoration) occurs specifically at the {001} crystal planes through the interaction between the –SH groups of OT molecules in the ICs and the AuNRs. The preparation of a-CD with OT (a-CD/OT) IC decorated with AuNRs was carried out by adding a-CD/OT IC crystals to AuNRs colloidal dispersion. When the colorless a-CD/OT IC microcrystals were immersed into a dispersion of AuNRs, the color of crystal changes to pink immediately, related to the optical properties of the AuNRs (Tong et al. [39] and Pérez-Juste et al. [40]) (Fig. 2). The surfactants CTAB molecules are displaced from the surface of the AuNRs by strong interaction between the –SH groups outside the {001} crystal plane of the a-CD/OT IC and the surface of the AuNRs, which caused disruption of CTAB bilayer, immobilizing the AuNRs onto the plane. In the SEM micrographs (Fig. 3), a laterally aligned pattern of AuNRs is observed on the surface of the IC due to the lateral interaction between the remaining CTAB molecules that tend to self-assemble (Sau and Murphy [41]). Also, AuNRs is adhered like a single-coat deposit on the crystal surface due to the greatest interaction between the IC and AuNRs compared with the van der Walls forces between CTAB molecules surrounding AuNRs. The a-CD/OT IC crystal plane is decorated with AuNRs by the action of dynamic functionalized surface, where the –SH groups of the guest molecule protruded from this particular crystal plane. The Page 5 of 14

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Element

Weight%

Atomic%

C Au S

O Au

0

1

C

55.32

67.90

O

33.08

30.48

S

1.93

0.89

Au

9.67

0.72

Totals

100

Au

Au

2

3

4

5

6

7

8

9

Au

Au

10

11

Sum Spectrum

Au

12

13

14

15

16

Full Scale 1526 cts Cursor: 0.000 keV

17 keV

Fig. 4 EDS spectrum realized onto nanodecorated crystal surface

Fig. 5 Simplified schema of metal nanoparticle deposition by sputtering process on crystal surfaces

guest molecules act as a pivot that displaced the CTAB molecules from AuNRs surface. The single coating of AuNRs onto the crystal surface allows the study of individual optical properties, which are of great utility in nanochemistry and interface phenomenon (Herrera et al. [23]). This work is the first report of the selective adhesion of AuNRs onto organic supramolecular crystals; this phenomenon is denominated as “nanodecoration.” Energy-dispersive X-ray spectroscopy (EDS) analysis is a very useful technique to confirm the presence of metal nanoparticles attached on organic crystals. In this case the analysis performed on samples of decorated crystals indicated the gold presence in a specific crystal face coming from AuNRs and the sulfur presence that corresponds to free –SH groups of the guest molecule that protrude from this crystallographic plane. So the main conclusion is that AuNRs deposition on a-CD/OT IC crystals is governed by interactions with thiol groups (Fig. 4).

Magnetron Sputtering Deposition Sputtering is an alternative vacuum-coating technique to thermal evaporation. Unlike evaporation, sputtering does not rely on directly heating the deposition material but uses momentum transfers to vaporize the deposition material, metals, noble metals and graphite [42]. In a simple sputtering system, the material to be sputtered (target material) has a negative polarity placed on it to become the cathode of gas (argon)-filled diode. A high voltage is applied between cathode

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

and anode and a conductive gas discharge results. The electric current is carried by positively charged gas ions accelerated toward the cathode and electrons toward the anode. When an energetic gas ion strikes the target, it can lose energy to single target atom and dislodge it from the bulk material. This action is called sputtering. The sputtered target atom then diffuses through the gas until it meets a solid surface and condenses. This process is called sputter deposition (Fig. 5). The planar magnetron sputtering source is a development of the simple DC diode sputtering source. It is much more efficient than simple diode system, and it has the added advantage that the magnet system traps the electrons close to the target. The electron current (a potential source of sample heating) flows to the front of the dark space shield rather than to the specimen table. The typical standard target is a gold disk of approximately 60 mm diameter and 0.1 mm thick, for example. It is held in position by threaded clamping ring. Sputtering has a specific advantage for coating SEM samples, for example, in that the sputtered atoms have a random direction when arriving at the sample. This results in better coverage of rough samples and, therefore, results in less charging effects. Also, direct current magnetron sputtering has long been used to prepare thin films, nanostructured coatings, and nanoparticles of different metals (Barrientos et al. [33]), including metal oxide, nitride, and carbide films (Asanithi et al. [10]). Many studies in literature have been reported from properties of gold films sputtered under different conditions. Reznickova et al. have recently studied the deposit of gold films onto borosilicate glass substrate (Reznickova et al. [43]). Mean thickness of sputtered gold film was quantified by gravimetry, film contact angle was determined by goniometry, and surface morphology was examined by atomic force microscopy. The electrical sheet resistance was determined by two-point technique. It was determined so that the thickness of deposited AuNPs is an increasing function of sputtering time and current. Atomic force microscopy images prove the formation of separated gold islands in the initial deposition stage and a continuous gold coverage for longer deposition times. In a recent work, a method to generate metal nanoparticles by sputter deposition of metals in the 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid like capture medium has been reported (Hatakeyama et al. [44]). By specific selection of the ionic liquid used like capture medium and its temperature for the deposition, the size of the synthesized nanoparticles can be controlled. Different sputtering conditions were used, which influences the formation processes and the size distributions of AuNPs. The temperature of the target and applied voltage are conditions that also have influence on the size of AuNPs generated in the capture media. In this case, the working distance between the target and the surface of the capture media, sputtering time, and discharge current have little or no influence. The authors emphasize that lower temperature of the target and higher applied voltage are optimal conditions for generating size-controlled smaller nanoparticles (Hatakeyama et al. [44]). Based on these antecedents, it is possible to conclude that sputtering conditions play an important role in determining the size of the nanoparticles using liquid or solid substrates.

Formation of Nanoparticles by Sputter Deposition on Cyclodextrin Inclusion Compounds Several chemical methods have been used for metal nanoparticle preparation. Organic molecules are commonly used as stabilizers for the nanoparticles in such synthesis. The stabilizer, however, is difficult to remove after synthesis (Zhou et al. [45]). In this sense, magnetron sputtering has some advantages over other preparation methods like the no contamination from solvent or precursor molecules on the surface. Also, the process is economical and environmentally friendly, since the metal excess is recoverable from the chamber and without liquid waste.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Fig. 6 Optical spectra of AuNPs on the 2a-CD/DDT microcrystal surface, recorded in diffuse reflectance (Kubelka-Munk transformation) and spectra of AuNP colloid stabilized by citrate molecules

Fig. 7 SEM image of preferential adhesion of AuNPs on a-CD IC crystal

Typically the process involves the spread of IC microcrystals on the surface of a glass to form a homogeneous layer previously being exposed to the sputtering. Fine high-purity metal target cathode is utilized. Noble metals and metals have been deposited onto the substrate by this technique in inert atmosphere at room temperature with 25 mA of current and 0.05 mbar of vacuum (Barrientos et al. [33]). CD IC crystal with a functionalized surface can be used like substrate inside sputter chamber. The process leads to the formation of nanoparticles that interact with the functional group of guest molecules present in the specific crystallographic plane. The result is the self-assembly of AuNPs produced by sputter deposition onto microcrystal faces of IC (Barrientos et al. [11]). Optical properties of sputtered AuNPs on the surface of a-CD IC can be analyzed by UV-vis diffuse reflections spectroscopy. The characteristic of surface plasmon resonance for AuNPs dispersion presents a maximum absorption around 530 nm. The particles in colloidal dispersion have a maximum extinction around 520 nm (Chen and Kimura [8]); the plasmon band observed here is shifted to longer wavelengths and broadened (Fig. 6). The broadening together with a red shift of the maximum extinction can be

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

Fig. 8 Schematic representation for the AuNPs deposition onto crystal plane {001} of 2a-CD/DDT IC (a), TEM image shows the hexagonal arrangement of the AuNPs onto 2a-CD/DDT (b)

assigned to a dipolar coupling between closely neighbored nanoparticles and to a change of the dielectric environment. Scanning electron microscopy (SEM) is a powerful tool for the study of selective organic crystal decoration with metal nanoparticles. SEM image reveal AuNPs adhered preferentially on selected crystal faces (Fig. 7). The absence of any aggregated particles indicates that the nanoparticles present in the sample must be bound to the microcrystal surface. The transmission electron microscopy (TEM) allows better visualization of metal nanoparticles adhered to a crystal. TEM micrograph shows AuNPs grown onto a-CD/DDT IC crystal by sputter deposition. Several linear arrangements on the microcrystals surface are observed, leading partially to hexagonal ordering in some areas. The 2a-CD/DDT IC has a hexagonal structure where the dodecanethiol molecules are ordered along the c axis. The preferential plane where functional groups of guest molecules are exposed is assumed to be the {001} Miller plane in the crystalline structure (Fig. 8a). The average of interparticle spacing of 50 Å was observed by TEM; this distance corresponds to twice of the CDs unit diameter that indicates that the AuNPs are located in alternated form on the CDs in the supramolecular structure. The average interparticle spacing is in the order of the nanoparticle size. The protection and immobilization of AuNPs are due to Au-S interaction with the free dangling –SH groups of the guest molecule, located at the {001} crystal plane. Therefore the functionalized surfaces of these crystals are an efficient way of storing the nanoparticles in the solid state without aggregation. The preferential adhesion onto {001} plane of the CD IC crystal occurs because –SH groups from the guest molecules found within the CDs lean out toward the outside of this crystal. These –SH groups form a two-dimensional hexagonal pattern that interacts with the metal nanoparticles, arranging them in an ordered way preventing aggregation (Fig. 8b). The varied type of surfactant guest and metal nanoparticles should provide a various composite material decorated by self-assembled nanoparticles. Experiments made in pure CDs lead to the formations of AuNP aggregates and sporadic nanorods of nonselective way on the crystals of planes (Barrientos et al. [11]). For effective particle growth by sputtering deposition, the choice of guest molecule present in the inclusion compound is relevant. Thus, silver nanoparticles (AgNPs) were obtained through the process of sputtering on a-CD IC with carboxylic alkyl-guest molecules (Herrera et al. [46]). The functional group of these guest molecules has a greater affinity for AgNPs based on the Pearson concept of acids and bases hard and soft. According to this principle, “a hard acid binds to a hard base and a soft acid binds to a soft base” (Pearson [47]). The –COOH group is classified as a hard base and the –SH

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

a

b

Amount of AgNPs Gauss of Amount of AgNPs

140 120

8.5 ± 0.7nm

Frecuency

100 80 60 40 20 0 4

5

6

7

8

9 10 11 12 13 14 15

Particle diameter (nm)

Fig. 9 Micrograph TEM of AgNPs obtained on a-CD/stearic acid IC (a) and respective histogram (b)

Fig. 10 Optical spectra of oxidized CuNPs on the a-CD/DDA microcrystal surface, recorded in diffuse reflectance (KubelkaMunk transformation) showing the absorption for different exposure times of sputtering (5 s sequence)

group corresponds to a soft base; on the other hand, Ag is regarded as a hard acid and the Au as a soft acid. The –SH/Au y and –COOH/Ag are prevalent interactions. These interactions enable the stabilization of NPs in either solid-state or colloidal dispersions. The use of IC that possesses guest molecules with functional group mentioned promotes a better adhesion of nanoparticles on the crystal surface, producing a more efficient process with lower dispersion in size and homogeneity (Fig. 9). In summary, with the appropriate support, the sputtering technique is a useful tool for the preparation of metal nanoparticles. This technique is attractive to the industry for its scalability and environmental protection.

Size of the Deposited NPs

As mentioned in this chapter, the use of substrates of a-CD IC with a morphology-specific surface, wherein the functional group of the guest molecule protrudes into the preferential outside from a crystal plane, is an efficient method for the preparation of nanoparticles by sputtering. The population and particle size can be controlled by varying parameters, such as distance between the target and the surface of the substrate, sputtering time, discharge current, and others. Thus, this technique allows accurate control of the size as a function of exposure time, which can be visualized by optical spectroscopic techniques.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

The optical properties of nanoparticles can be characterized by UV-visible in solid state. For example, copper oxide nanoparticles (Cu2ONPs) exhibits an intense peak centered at approximately 270 nm due to inter-band transition of copper electron from deep level of valence band (Swarnkar et al. [48]). Particle growth can be monitored by diffuse reflectance spectroscopy. The increase in the absorption intensity of the particles is indicative of an increase in population and size of the Cu2ONPs formed by sputtering deposition onto the specific {001} crystal plane of a-CD/alkyl-amine IC (Silva et al. [49]) (Fig. 10). The characteristic absorption band can be observed with a maxima at 261 nm for the Cu2ONPs onto a-CD/dodecylamine, similar to the absorption peaks of Cu2ONPs (270 nm) from oxidation of colloidal solution of Cu nanoparticles synthesized by laser ablation of copper in water (Swarnkar et al. [48]). The characteristic surface plasmon resonance with a maximum absorption around 600 nm is not observed due to rapid oxidation of Cu nanoparticles (CuNPs) exposed to air after sputtering. To prepare CuNPs, a-CD/alkyl-amine IC microcrystals were dispersed inside of the magnetron sputtering chamber, and copper deposits were prepared in a short time (5 s) using widely reported conditions (0.5 mbar in vacuum, 30 mA current, and 220 V) (Silva et al. [49]). The CuNP size depends on the time of exposure to sputtering. This is evidence that the particles are not formed in the plasma phase before landing, but that their nucleation and growth occurs onto the IC. When the exposure time is over 50 s, a decreased absorbance or a shifting toward longer wavelengths of surface plasmon resonance of the nanoparticles is produced. Continuous copper coverage and larger size nanoparticles to a longer time are generated (Silva et al. [49]).

Conclusions In the last decade, the formation and adhesion of nanoparticles onto organic crystal denominated decoration, has been development. The principal approach of this studies are the obtaining of ordered nanoparticles and controlling size dispersion. Specifically, cyclodextrin inclusion compounds crystals possess anisotropic surfaces. These functionalized surfaces act as an adequate template for preparing metal nanoparticles by sputter deposition technique using suitable parameters allowing a narrow particle distributions. Furthermore, this specific functionalized surface allows the immobilization of metal nanoparticles prepared by chemical methods, offering a great variability in the possible decoration. In both cases, the nature of guest molecule included can be elected in order to improve the control of the binding mechanism of the nanoparticle to the crystal surface. The nanodecoration has potential applications for storing nanoparticles with conservation of their properties.

References 1. M.E. Franke, T.J. Koplin, U. Simon, Metal and metal oxide nanoparticles in chemiresistors: does the nanoscale matter? Small 2, 36–50 (2006) 2. X. Zhang, Q. Guo, D. Cui, Recent advances in nanotechnology applied to biosensors. Sensors 9(2), 1033–1053 (2009) 3. R. Wilson, The use of gold nanoparticles in diagnostics and detection. Chem. Soc. Rev. 37, 2028–2045 (2008)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_26-1 # Springer International Publishing Switzerland 2015

4. A. Corma, H. Garcia, Supported gold nanoparticles as catalysts for organic reactions. Chem. Soc. Rev. 37(9), 2096–2126 (2008) 5. G. Schmid, U. Simon, Gold nanoparticles: assembly and electrical properties in 1–3 dimensions. Chem. Commun. 6, 697–710 (2005) 6. G.M. Veith, A.R. Lupini, S.J. Pennycook, G.W. Ownby, N.J. Dudney, Nanoparticles of gold on g-Al2O3 produced by dc magnetron sputtering. J. Catal. 231(1), 151–158 (2005) 7. J. Turkevich, P.C. Stevenson, J. Hillier, The formation of colloidal gold. J. Phys. Chem. 57(7), 670–673 (1953) 8. S. Chen, K. Kimura, A new strategy for the synthesis of semiconductor–metal hybrid nanocomposites: electrostatic self-assembly of nanoparticles. Chem. Lett. 3, 233–234 (1999) 9. K.J. Watson, J. Zhu, S.T. Nguyen, C.A. Mirkin, Hybrid nanoparticles with block copolymer shell structures. J. Am. Chem. Soc. 121(2), 462–463 (1999) 10. P. Asanithi, S. Chaiyakun, P. Limsuwan, Growth of silver nanoparticles by DC magnetron sputtering. Dig. J. Nanomater. (2012). doi:10.1155/2012/963609 11. L. Barrientos, N. Yutronic, F. del Monte, M.C. Gutiérrez, P. Jara, Ordered arrangement of gold nanoparticles on a-cyclodextrins-dodecanethiol inclusion compound produced by magnetron sputtering. New J. Chem. 31(8), 1400–1402 (2007) 12. M. Homberger, U. Simon, On the application potential of AuNPs in nanoelectronics and medicine. Phil. Trans. R. Soc. A 368, 1405–1453 (2010) 13. P. Gambardella, S. Rusponi, M. Veronese, S.S. Dhesi, C. Grazioli, A. Dallmeyer, I. Cabria, R. Zeller, P. Dederichs, K. Kern, C. Carbone, H. Brune, Giant magnetic anisotropy of single cobalt atoms and nanoparticles. Science 300, 1130–1133 (2003) 14. G. Schmid, T. Reuter, U. Simon, M. Noyong, K. Blech, V. Santhanam, D. J€ager, H. Slomka, H. L€uth, M.I. Lepsa, Generation and electrical contacting of gold quantum dots. Colloid Polym. Sci. 286, 1029–1037 (2008) 15. M. Murugesan, D. Cunningham, J. L. Martinez-Albertos, R. M. Vrcelj and B. D. Moore, Nanoparticle-coated microcrystals. Chem. Commun. 21, 2677–2679 (2005) 16. Y. Fujiki, N. Tokunaga, S. Shinkai, K. Sada, Anisotropic decoration of gold nanoparticles onto specific crystal faces of organic single crystals. Angew. Chem. 45(29), 4764–4767 (2006) 17. S. Rodríguez-Llamazares, N. Yutronic, P. Jara, M. Noyong, J. Bretschneider, U. Simon, Face preferred deposition of gold nanoparticles on a-cyclodextrin/octanethiol inclusion compound. J. Colloid Interface Sci. 316(1), 202–205 (2007) 18. Y. Fujiki, S. Shinkai and K. Sada, Selective deposition of metal complex nanocrystals onto the surfaces of organic single crystals bearing pyridine moieties. Cryst. Growth Des. 9(6), 2751–2755 (2009) 19. V.T. D’Souza, K.B. Lipkowitz, Cyclodextrins: introduction. Chem. Rev. 98(5), 1741–1742 (1998) 20. T. Loftsson, D. Duchêne, Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11 (2007) 21. S. Rodríguez-Llamazares, N. Yutronic, P. Jara, M. Noyong, J. Bretschneider, U. Simon, The structure of the first supramolecular a-cyclodextrin complex with an aliphatic monofunctional carboxylic acid. Eur. J. Org. Chem. 2007(26), 4298–4300 (2007) 22. Z. Liu, M. Frasconi, J. Lei, Z.J. Brown, Z. Zhu, D. Cao, J. Iehl, G. Liu, A.C. Fahrenbach, Y.Y. Botros, O.K. Farha, C.A. Hupp Mirkin, J.F. Stoddart, Selective isolation of gold facilitated by second-sphere coordination with a-cyclodextrin. Nat. Commun. 4, 1855–1863 (2013) 23. B. Herrera, C. Adura, N. Yutronic, M. Kogan, P. Jara, Selective nanodecoration of modified alphacyclodextrin inclusion compounds crystals with gold nanorods. J. Colloid Interface Sci. 389(1), 42–45 (2013) Page 12 of 14

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24. K. Harata, Structural aspects of stereo differentiation in the solid state. Chem. Rev. 98, 1803–1827 (1998) 25. G. Wenz, B.-H. Han, A. M€ uller, Cyclodextrin rotaxanes and polyrotaxanes. Chem. Rev. 106, 782–817 (2006) 26. M.C. Daniel, D. Astruc, Gold nanoparticles: assembly, supramolecular chemistry, quantum-sizerelated properties, and applications toward biology, catalysis, and nanotechnology. Chem. Rev. 104, 293–346 (2004) 27. M. Díaz, N. Silva, N. Yutronic, E. Peña, B. Chornik, P. Jara, g-Cyclodextrin/alkylthiol inclusion compounds crystals as substrates for the formation and immobilization of gold nanoparticles produced by magnetron sputtering. J. Incl. Phenom. Macrocycl. Chem. 80, 133–138 (2014) 28. Y. Wang, J.F. Wong, X.W. Teng, X.Z. Lin, H. Yang, “Pulling” nanoparticles into water: phase transfer of oleic acid stabilized monodisperse nanoparticles into aqueous solutions of alpha-cyclodextrin. Nano Lett. 3(11), 1555–1559 (2003) 29. N. Lala, S. Lalbegi, S. Adyanthaya, M. Sastry, Phase transfer of aqueous gold colloidal particles capped with inclusion complexes of cyclodextrin and alkanethiol molecules into chloroform. Langmuir 17(12), 3766–3768 (2001) 30. Y. Liu, K.B. Male, P. Bouvrette, J.H.T. Luong, Control of the size and distribution of gold nanoparticles by unmodified cyclodextrins. Chem. Mater. 15(22), 4172–4180 (2003) 31. J. Liu, W. Ong, E. Roman, M. Lynn, A. Kaifer, Cyclodextrin-modified gold nanospheres. Langmuir 16(7), 3000–3002 (2000) 32. A.V. Kabashin, M. Meunier, C. Kingston, J.H.T. Luong, Fabrication and characterization of gold nanoparticles by femtosecond laser ablation in an aqueous solution of cyclodextrins. J. Phys. Chem. B 107(19), 4527–4531 (2003) 33. L. Barrientos, P. Allende, C. Orellana, P. Jara, Ordered arrangements of metal nanoparticles on alphacyclodextrin inclusion complexes by magnetron sputtering. Inorg. Chim. Acta 380, 372–377 (2012) 34. P. Jara, L. Barrientos, B. Herrera, I. Sobrados, Inclusion compounds of a-cyclodextrin with alkylthiols. J. Chil. Chem. Soc. 53(2), 1399–1401 (2008) 35. S. Rodríguez-Llamazares, P. Jara, N. Yutronic, N. Noyong, U. Simon, Chemical adhesion of silver nanoparticles onto crystal faces of alpha cyclodextrin/carboxylic acids inclusion compounds. J. Nanosci. Nanotechnol. 12(12), 8929–8934 (2012) 36. P. Jara, M. Justiniani, N. Yutronic, I. Sobrados, Syntheses and structural aspects of cyclodextrin/ dialkylamine inclusion compounds. J. Incl. Phenom. 32(1), 1–8 (1998) 37. B. Nikoobakht, M.A. El-Sayed, Preparation and growth mechanism of gold nanorods (NRs) using seed-mediated growth method. Chem. Mater. 15, 1957–1962 (2003) 38. D.K. Smith, B.A. Korgel, The importance of the CTAB surfactant on the colloidal seed-mediated synthesis of gold nanorods. Langmuir 24, 644–649 (2008) 39. L. Tong, Q. Wei, A. Wei, J.-X. Cheng, Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects. Photochem. Photobiol. 85(1), 21–32 (2009) 40. J. Pérez-Juste, I. Pastoriza-Santos, L.M. Liz-Marzán, P. Mulvaney, Gold nanorods: synthesis, characterization and applications. Coord. Chem. Rev. 249, 1870–1901 (2005) 41. T.K. Sau, C.J. Murphy, Self-assembly patterns formed upon solvent evaporation of aqueous cetyltrimethylammonium bromide-coated gold nanoparticles of various shapes. Langmuir 21, 2923–2929 (2005) 42. K. Ishii, High‐rate low kinetic energy gas‐flow‐sputtering system. J. Vac. Sci. Technol. A 7(2), 256–258 (1989)

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43. A. Reznickova, Z. Novotna, N.S. Kasalkova, V. Svorcik, Gold nanoparticles deposited on glass: physicochemical characterization and cytocompatibility. Nanoscale Res. Lett. 8, 252–259 (2013) 44. Y. Hatakeyama, K. Onishi, K. Nishikawa, Effects of sputtering conditions on formation of gold nanoparticles in sputter deposition technique. RSC Adv. 1, 1815–1821 (2011) 45. X. Zhou, Q. Wei, K. Kai Sun, L. Wang, Formation of ultrafine uniform gold nanoparticles by sputtering and redeposition. Appl. Phys. Lett. 94, 133107–133110 (2009) 46. B. Herrera, T. Bruna, D. Guerra, N. Yutronic, M.J. Kogan, P. Jara, Silver nanoparticles produced by magnetron sputtering and selective nanodecoration onto alpha- cyclodextrin/carboxylic acid inclusion compounds crystals. Adv. Nanopart. 2(2), 112–119 (2013) 47. R.G. Pearson, Hard and soft acids and bases. J. Am. Chem. Soc. 85(22), 3533–3539 (1963) 48. R.K. Swarnkar, S.C. Singh, P. Gopal, Effect of aging on copper nanoparticles synthesized by pulsed laser ablation in water: structural and optical characterizations. Bull. Mater. Sci. 34(7), 1363–1369 (2011) 49. N. Silva, S. Moris, B. Herrera, M. Díaz, M. Kogan, L. Barrientos, N. Yutronic, P. Jara, Formation of copper nanoparticles supported onto inclusion compounds of a-cyclodextrin: a new route to obtain copper nanoparticles. Mol. Cryst. Liq. Cryst. 521, 246–252 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Nanoparticle Arrays M. A. Mangolda*, A. W. Holleitnerb,c*, J. S. Agustssond and M. Calamed a IRsweep GmbH, c/o ETH Zurich, Institute f€ ur Quantum Electronics, Z€urich, Switzerland b Walter Schottky Institut and Physik-Department, Technische Universit€at M€unchen, Garching, Germany c Nanosystems Initiative Munich (NIM), Munich, Germany d Department of Physics and Swiss Nanoscience Institute, University of Basel, Basel, Switzerland

Abstract Arrays of metal nanoparticles in an organic matrix have attracted a lot of interest due to their diverse electronic and optoelectronic properties. By varying parameters such as the nanoparticle material, the matrix material, the nanoparticle size, and the interparticle distance, the electronic behavior of the nanoparticle array can be substantially tuned and controlled. For strong tunnel coupling between adjacent nanoparticles, the assembly exhibits conductance properties similar to the bulk properties of the nanoparticle material. When the coupling between the nanoparticles is reduced, a metal insulator transition is observed in the overall assembly. Recent work demonstrates that nanoparticle arrays can be further utilized to incorporate single molecules, such that the nanoparticles act as electronic contacts to the molecules. Furthermore, via the excitation of the surface plasmon polaritons, the nanoparticles can be optically excited and electronically read out.

Keywords Nanoparticle array; Electronic and optoelectronic properties; Surface plasmon resonance; Coulomb blockade; Metal insulator transition; Plasmonic; Bolometric; Molecular photoconductance

Introduction Well-ordered metal nanoparticle arrays are model systems for granular materials and they exhibit a rich variety of electronic and optoelectronic phenomena. At the nanometer scale, the electronic structure of metal aggregates shows an exquisite sensitivity to size. The physical properties of arrays can therefore be adjusted by controlling the nanoparticles size and by their electronic coupling in close-packed configurations. As a flexible platform to understand fundamental transport mechanisms, nanoparticle arrays have for instance helped studying metal–insulator transitions. Nanoparticle assemblies have also found their way into various applications [1–3] and bear potential for further developments, which include conductive coatings, catalytic surfaces, chemical and biological sensors, energy conversion devices, as well as information storage platforms or even computing networks, thanks to a defect-tolerant architecture. This chapter focuses on the properties of two-dimensional arrays of metal nanoparticles. The section “Preparation and Structure of Nanoparticle Arrays” describes methods to fabricate well-ordered nanoparticle assemblies and reviews aspects related to the structure of the arrays. It shows the importance of the organic matrix in controlling the properties and providing cohesion to the system. The electrical *Email: [email protected] *Email: [email protected] Page 1 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Table 1 Overview on nanoparticle array preparation methods Method Drying-mediated assembly

Langmuir–Blodgett assembly

Drying on water surface

Assembly mechanism Assembly at liquid–air interface during slow solvent evaporation Assembly on water surface controlled by movable barrier Assembly on water surface mediated by convective flow

Nanoparticle ordering Usually disordered arrays; high ordering demonstrated with small particles Long-range ordering demonstrated for a range of particle sizes and different ligands Highly ordered domains of several mm size

Interparticle distance Defined by nanoparticle ligand

Controlled by surface pressure applied by movable barrier Defined by nanoparticle ligand

References [8–15, 29, 32, 33, 41, 43, 46, 47, 78]

[16–20, 29, 30, 44]

[21, 22, 26, 31, 34–38, 54, 55, 58, 74, 81, 83, 86, 88]

Table 2 Overview on previous work regarding electrical and optoelectronic properties of nanoparticle arrays Section Electrical transport properties

Optoelectronic properties of nanoparticle arrays

Topic Energy scales Transport mechanisms Linear and nonlinear electrical response Nanoparticle arrays functionalized with molecules Optical excitation of isolated metal spheres Effective medium theory of nanoparticle arrays Plasmonically enhanced photoconductance Photoconductance in the Coulomb blockade regime Functionalized nanoparticle arrays

References [28, 35, 39–42] [28, 39, 42, 45–51] [34, 45, 52–56] [38] [36, 59–69] [36, 60, 70, 73] [36, 74–81] [83] [84–88]

transport properties are discussed in the section “Electrical Transport Properties of Two-Dimensional Nanoparticle Arrays,” starting with a brief overview of the fundamental transport mechanisms. The particular properties of molecular place-exchange in two-dimensional arrays are discussed before focusing on their linear and nonlinear transport properties. Functionality emerging at the array level due to active molecular compounds is then addressed. In the section “Optoelectronic Properties of Nanoparticle Arrays,” optoelectronic properties are reviewed. Building on Mie theory, the discussion is extended to include interactions between adjacent nanoparticles. The interplay between plasmonic excitations in the nanoparticles and the conductance of the arrays are addressed. A discussion of arrays embedding more complex molecules, such as optoelectronic molecular switches, closes the section (Tables 1 and 2).

Preparation and Structure of Nanoparticle Arrays In the following section, ways of controlling the structural and by this the electronic and optical properties of nanoparticle arrays are introduced. In the first section, several ways of producing metal nanoparticle arrays are described.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

a

b

50 nm

c

20 nm

100 nm

Fig. 1 (a) Transmission electron microscope (TEM) image of a two-dimensional array of gold nanoparticles with 5.5 nm diameter produced by drying-mediated assembly (Reprinted with permission from J. Phys. Chem. B 105, 3353 (2001) [15]. Copyright 2001 American Chemical Society) (b) TEM image of a 2.8 nm silver particle array produced by the Langmuir–Blodgett technique (Reprinted with permission from J. Phys. Chem. B 101, 189 (1997) [19]. Copyright 1997 American Chemical Society) (c) Scanning electron microscope (SEM) image of an array produced from 9 nm gold particles using the drying-mediated assembly on a water surface method

Preparation Methods A prerequisite for the preparation of well-ordered two-dimensional assemblies of metal nanoparticles is the synthesis of nanoparticles with a narrow size distribution. Nanoparticles are typically stabilized by a layer of organic ligand molecules. The synthesis and stabilization of nanoparticles is discussed in several reviews and is not the subject of the present article [4–7]. An ordered array of nanoparticles is then formed by self-assembly. Three widely used nanoparticle array assembly methods are discussed in the following. Drying-Mediated Assembly The easiest way of producing two-dimensional arrays of metal nanoparticles is by simply casting a droplet of a colloidal solution on a substrate. Drying of the solvent leads to precipitation of the nanoparticles on the surface. By this method, disordered two-dimensional assemblies of nanoparticles were produced [8–11]. The observation of small domains of highly ordered nanoparticle array in such disordered assemblies stimulated research on the mechanism of array formation [12]. Using in situ small-angle x-ray spectroscopy (SAXS) [13] and modeling of the assembly process [14], a thorough understanding of the array self-assembly was obtained. It was understood that uncontrolled dewetting of the substrate leads to rupture of the arrays and therefore to poor ordering. Adding a slowly evaporating substance to the solvent enables the assembly of the nanoparticles at the liquid–air interface of the evaporating droplet. After the self-assembly process, controlled dewetting by application of vacuum results in two-dimensional nanoparticle arrays with long-range order over macroscopic distances. In Fig. 1a, a transmission electron microscope (TEM) image of such an array is shown. Defect free ordering extends over several micrometers as is seen from the real-space image as well as from the very sharp pattern in the 2-d fast Fourier transform of the image (inset) [15]. Langmuir–Blodgett Technique A very successful route toward forming two-dimensional arrays of nanoparticles is the Langmuir–Blodgett technique [16–18]. The technique was initially used to compress a monolayer of fatty acids on a water surface using a movable barrier [20]. The monolayer formation is controlled by measuring the surface pressure of the monolayer with a Wilhelmy plate. The advantages of the technique include the high uniformity of the produced monolayers over macroscopic distances and the possibility to control the surface pressure and by this the nanoparticle distance. In an extensive study, Heath and coworkers could relate the two-dimensional structure of the assembly to the degree by which the organic ligands of the nanoparticles could interpenetrate each other [19]. While very strong interpenetration leads to uncontrolled agglomeration and therefore a disordered assembly, very weak interpenetration results in Page 3 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

c a

b

hexagonally close packed

evaporation

chloroform water

water

water

Fig. 2 (a) For drying-mediated assembly on a water surface, a solution of nanoparticles is cast on a convex water surface. (b) The evaporation of the chloroform results in a convective flow which assembles the nanoparticles. (c) The nanoparticles form stable two-dimensional layers on the water surface

irreversible koalition of the particles under pressure. Only in an intermediate regime, reversible assembly into highly ordered arrays is obtained (Fig. 1b). Drying-Mediated Assembly on Water Surface Drying-mediated assembly on a water surface is a combination of the above presented methods [21, 22]. It relies on the high mobility of the nanoparticles at an air–water interface, but it abandons the movable barrier to compress the particles. For this method, nanoparticles with a hydrophobic capping layer, which are dissolved in an organic solvent, are spread on a convex water surface. The self-assembly of the array is a three-step process: (i) A convective flow caused by the evaporation of the solvent moves the nanoparticles to the surface of the solvent layer (Fig. 2a). (ii) At the boundaries of the solvent layer, the convective flow pushes the nanoparticles into close contact to each other (Fig. 2b). (iii) The nanoparticles stabilize each other due to their hydrophobic interaction on the water surface (Fig. 2c). This leads to the formation of stable two-dimensional gold nanoparticle layers (Fig. 1c). Using this assembly method, reproducible formation of mono- or multilayer nanoparticle arrays was shown [22].

Structural Analysis of Nanoparticle Arrays Due to the nanometer size of nanoparticles, their structure cannot be investigated by optical means. A straightforward replacement for optical microscopy is the investigation of the array structure with electron microscopy. Electron microscopy generates real-space images of the arrays as shown by the TEM images in Fig. 1a, b and the scanning electron microscopy (SEM) image in Fig. 1c. A very high resolution alternative to electron microscopy is the examination of nanoparticle arrays with X-ray scattering. In conventional X-ray scattering, the intensity of an X-ray beam transmitted through a sample is recorded as a function of its deflection angle. Thereby, conventional X-ray scattering is sensitive to the bulk properties of a sample [23]. In grazing incidence small-angle X-ray scattering (GISAXS), the transmission geometry is replaced by a reflection geometry. This results in a surface sensitivity of the scattered X-ray beam which is advantageous for the examination of thin films or monolayered materials [24, 25]. The structure of a nanoparticle array is investigated with GISAXS in reciprocal space. Figure 3 shows the two-dimensional scattering patterns of (a) a GISAXS measurement of a gold particle array produced by the dryingmediated assembly on a water surface method [26] and (b) of the simulation of this data using IsGISAXS [27]. Concerning the most prominent features (positions and shapes of Yoneda peak and side maxima), there is a good agreement between data and simulation (line cut in Fig. 3c). The best modeling is obtained using a two-particle-type model (inset of Fig. 3c). One particle type has spheroid geometry with an occurrence probability of 98 %. Its average radius (height) is 4.6 nm (9.1 nm). The second particle type has cylindrical geometry and occurs with a probability of 2 %. Its average radius (height) is 9.8 nm (11.5 nm). Both particle types are placed on a hexagonal two-dimensional paracrystal with a lattice Page 4 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

1.8

1.8 q z [nm−1]

b 2.2

q z [nm−1]

a 2.2

1.4 1.0

1.0

0.6

0.6 −1.0

−0.5

0 qy

Intensity [arb. u.]

c

1.4

0.5

−1.0

1.0

[nm−1]

−0.5

0 qy

0.5

1.0

[nm−1]

d

104

Two particle model: spheroid

103

cylinder

102 101 50 nm 0

0.4

0.8 qz [nm−1]

1.2

1.6

Fig. 3 (a) Two-dimensional GISAXS spectrum of an array of gold nanoparticles: the specular reflection is blocked with a small beamstop. (b) Simulated two-dimensional GISAXS pattern shown on the same intensity scale and in the same q-range as the measurement. (c) Example of a horizontal line cut from the two-dimensional GISAXS data (circles) shown together with the simulation (solid line). The inset sketches the model used for fitting the GISAXS data. (d) Scanning electron micrograph of a gold nanoparticle array. White circles highlight clustered nanoparticles (Reprinted with permission from Phys. Status Solidi RRL 5, No. 1, 16 (2011) [26]. Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

constant of 11.25 nm. The spheroid particles from the model can be attributed to the gold nanoparticles, and the cylindrical particles can be explained by the appearance of clusters of gold nanoparticles (circles in Fig. 3d). The successful interpretation of the data demonstrates the suitability of GISAXS measurements to determine the size, shape, and the interparticle distance of nanoparticles in an array with very high accuracy.

Controlling the Interparticle Distance in Nanoparticle Arrays A very important parameter determining the physical properties of an array is the distance between adjacent nanoparticles. While at large distances, the nanoparticles act as isolated metallic islands, they start to interact strongly at small distances leading to coherent electronic transport in the array [28]. Compression of Langmuir–Blodgett Films In addition to the outstanding long-range order, nanoparticle assembly in a Langmuir–Blodgett trough grants control on the interparticle spacing in an array. While measuring the surface pressure of the monolayer, the nanoparticles can be controllably compressed from a widely dispersed particle assembly to a strongly interacting array. By this, it was possible to bring the electrical conductivity of a monolayer of 2.7 nm diameter silver particles from an insulating to a metallic state [29]. The continuous tunability of physical properties could also be directly observed in reflectivity measurements of an array of silver nanoparticles during compression in a Langmuir–Blodgett trough [30]. In the low compression state, the reflectivity of the assembly is dominated by the diffractive coupling of surface plasmons caused by the in-plane periodicity. The reflectivity maximum could be continuously blue-shifted by increasing the packaging density of the array. Aggregation of the particles then gives rise to higher-order plasmon modes Page 5 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Fig. 4 TEM images (upper panel) and the corresponding fast Fourier transform of nanoparticle arrays using octane, dodecane, and hexadecane thiol molecules (from left to right) as ligands for the nanoparticles [31])

which are directly observed as an increased reflectivity in the long-wavelength region of the spectrum. This experiment nicely illustrates the versatile optical behavior of nanoparticle assemblies. Capping Molecules as Spacers Other than by compression of the nanoparticle assembly, the distance of nanoparticles in an array can also be controlled by the length of the organic ligand attached to the nanoparticles. Typically, alkanethiols (HS-(CH2)n-H) are attached to gold particles prior to self-assembly. Varying the number n of methylene groups allows continuously varying the distance between the nanoparticles. In the upper panel of Fig. 4, TEM images of a series of nanoparticle arrays are shown with n = 8, 12, and 16 from left to right. From the fast Fourier transform of the images shown in the lower panel, one deduces an average center-to-center distance of 2.6, 2.8, and 3.0 nm [31]. In an X-ray photoelectron spectroscopy study, the electron density at the Fermi level of gold particle arrays was found to be reduced due to Coulomb blockade. When the interparticle distance is reduced to below 1 nm, the density of states at the Fermi edge is restored due to screening of the blockade [32]. This behavior is directly reflected by a metal to insulator transition of such arrays. When the separation between particles is large (n
5), the overall assembly exhibits an insulating character with a vanishing conductance at low temperatures. Using short alkane spacer molecules (n < 5), the strong interaction of adjacent nanoparticles leads to a metallic behavior of the overall assembly [33].

The Organic Matrix Embedding the Nanoparticles

The organic matrix can further be used to introduce function into arrays. In sections “Electrical Transport Properties of Two-Dimensional Nanoparticle Arrays” and “Optoelectronic Properties of Nanoparticle Arrays” of this chapter, examples of redox and optically active matrices will be presented. Here, it is shown how the molecules composing the organic matrix can be exchanged without disturbing the order of the array. By immersion of the nanoparticle array in a solution of the desired molecules, the reversible incorporation of single molecules into a nanoparticle array was shown [34]. The nanoparticles are covalently bound to the thiol end group of the molecules. Figure 5a schematically depicts the process of the molecular exchange for oligo(phenylene vinylene) (OPV) molecules. The nanoparticles are initially coated with alkanethiols. In the course of the exchange, a part of the alkanes is replaced by OPV Page 6 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

a

OPV =

HS

SH

~2 nm

b C8

c

OPE

d

G[nS]

100

10 0

4 8 12 sample number

Fig. 5 (a) Sketch of a nanoparticle array and how the nanoparticles are interlinked by OPV molecules in a molecular exchange. (b) SEM image of nanoparticle array before (left) and after (right) molecular exchange (exemplarily shown for OPE). (c) SEM image of a contact strip of nanoparticle array with width w and length l. (d) Conductance of 14 individual nanoparticle arrays before (full circles) and after (open circles) the molecular exchange with OPV ((a) and (d): Adapted with permission from the Journal of the American Chemical Society 133, 12185 (2011) [88]. Copyright 2011 American Chemical Society). ((b) and (c): Reprinted with permission from Advanced Materials 18, 2444 (2006) [34]. Copyright 2006 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim)

molecules. This process does not disturb the crystalline order of the nanoparticle array (Fig. 5b). Due to the higher conductivity of OPV compared to alkanes, the overall conductivity increases in the exchange process. This can be studied in a configuration where a strip of nanoparticle array is contacted by two gold electrodes (Fig. 5c). Figure 5d depicts the conductivity of 14 such contacted nanoparticle arrays before (full circles) and after (open circles) the molecular exchange. The introduction of OPV increases the conductivity by approximately one order of magnitude [35]. Further insight into the exchange process and the molecular composition of the arrays can be inferred from Fourier transform infrared spectroscopy (FTIR) [36]. Figure 6 displays a series of spectra corresponding to three stages of the exchange between alkanes and oligo(phenylene ethynylene) (OPE): (1) initial array (only alkanes), (2) after molecular exchange with OPE, (3) after back-exchange where OPE is again replaced by alkanes. Spectra for pure octane thiols (top) and pure OPE (bottom) are also shown. The optical response of the as-prepared array (1) exhibits the typical features of alkane chains, i.e., the methylene (CH2) and methyl (CH3) stretching vibrations around 3,000 cm1 and deformation around 1,450 cm1. Spectrum 2 unambiguously reveals the coexistence of alkane and OPE molecules. Whereas one can still identify alkane stretching features, the C = C at 2,200 cm1 and C-C at Page 7 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

x5

1 2

CH3vs CH2vs

3 CH3va CH2va

Absorbance [arb. u.]

C8

OPE

3000

2900

2800

2000 −1 K[cm ]

1500

Fig. 6 FTIR spectra, from top to bottom: pure octanethiol, as-prepared array with alkane ligands (1), same array after OPE exchange (2), same array after alkane back-exchange (3), OPE embedded in a KBr matrix (solid). The thicker gray traces on the left side of spectra 1–3 are Lorentzian multi-peak fits. The arrows point to specific signatures of the OPE compound (Reprinted with permission from Bernard et al., J. Phys. Chem. C 101, 18445 (2007) [20]. Copyright 2007 American Chemical Society)

1,500 cm1 ring vibrations of the OPE molecules appear clearly (arrows). This observation indicates the insertion of OPE within the array. That the alkane vibrations are still strongly present after exchange indicates the partial character of molecular exchange. After back-exchange (3), the OPE signature is no longer observed, indicating that OPE can be inserted and fully removed from the array. From Lorentzian fits to the absorption peaks (gray line), a relative change in intensity between spectra 1 and 2 ranging from 20 % to 30 % is inferred. From this, one can estimate that approximately one fifth to one third of the molecules on the nanoparticle surface is exchanged during the molecular exchange process [21].

Electrical Transport Properties of Two-Dimensional Nanoparticle Arrays The electrical transport properties of ordered arrays of metallic nanoparticles are governed by the different energy scales and geometrical parameters characterizing their structure. Transport through nanoparticle arrays is also affected by a partial randomization of the electrical potential landscape due to quenched charge disorder. Extensive discussions of the electrical transport properties of granular systems and nanoparticle arrays can be found in Refs. [28] and [39].

Energy Scales and Transport Mechanisms Energy Scales A sketch of a two-dimensional nanoparticle array is depicted in Fig. 7a. Below the sketch, three nanoparticles are represented by their electronic levels (Fig. 7b) [35]. The three bars indicate filled electronic states. Due to quantum confinement, these states are separated by a mean level spacing d = (Vn)1 where V is the volume of the nanoparticle and n is the density of states at Fermi energy EF [28]. For gold particles with a 10 nm diameter, the level spacing is d  0.13 meV which corresponds to the thermal energy kBT at T = 1.5 K [40]. For the particular devices discussed here, quantum confinement effects will therefore not play a significant role in transport measurements. A second energy scale is defined by the charging energy EC of a nanoparticle

Page 8 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

a

b E

kBT

EC

G

d EF

eVbg eVsd r

Fig. 7 (a) Sketch of a two-dimensional assembly of nanoparticles. (b) Schematic representation of the energy scales in a nanoparticle assembly. The three bars indicate filled electronic states for three nanoparticles. The thermal energy kBT, the single electron charging energy EC, and the level spacing d caused by quantum confinement are indicated on the three different particles. The electronic states of adjacent particles are coupled to each other by the tunnel coupling G. The Fermi energies EF of different particles are offset due to a random background potential Vbg and an externally applied bias Vsd

e2 EC ¼ ; 2C

(1)

where C is the capacitance of an isolated particle. EC corresponds to the electrostatic energy required to add one elementary charge e to the nanoparticle. Using the capacitance of a sphere with radius r in vacuum (C = 4pe0r with the vacuum permittivity e0), the single charging energy of an isolated particle with r = 5 nm can be estimated to EC = 144 meV. For a particle in a dielectric medium, the charging energy is reduced by the relative permeability of the medium. In an array geometry, however, EC is substantially reduced and typically amounts to only 10 meV for 10 nm diameter particles [41]. At room temperature, charging effects will therefore not be perceptible, starting to play a role only at lower temperatures. In a close-packed array, the electronic wave functions of adjacent nanoparticles will partially overlap, leading to a finite tunneling conductance Gt. The resulting coupling energy ħG can be written in terms of the tunneling conductance Gt and the mean energy level spacing of the nanoparticles d ħG ¼

Gt d; G0

(2)

where ħ = h/2p is the reduced Planck constant and G0 = 2e2/h is the conductance quantum. When the coupling energy exceeds the level spacing, (Gt > G0), the overall assembly shows metallic transport properties. For ħG < d, the assembly behaves like an insulator [28]. The transport properties of a nanoparticle assembly can be strongly influenced by a random background electrostatic potential e  Vbg (Fig. 7b). Localized charges in the organic matrix or in the sample substrate can introduce random relative energy shifts in the electronic levels of the system [42]. This effect modifies the potential landscape experienced by the nanoparticles and adds up to the externally applied bias voltage Vsd.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Transport Mechanisms The parameters above determine the electron transport regime for nanoparticle arrays. In terms of conductance, the coupling energy plays a dominant role: at large coupling, i.e., for ħG > d, arrays exhibit metallic properties. Here, the charge diffusion across the array results in an ohmic conductance behavior with a conductivity s0 independent of Vsd [28]: s0 ¼ 2e2 nDeff ;

(3)

with Deff = Gd2 an effective diffusion constant given by the coupling constant G and the diameter d of the particles. In the intermediate regime (ħG  1), a metal–insulator transition is observed at a critical conductance value Gc that can be written in terms of the charging energy Ec and level spacing d [28] Gc ¼

G0 E c ln  G0 ; 2pD d

(4)

where D is the dimensionality of the nanoparticle array. This transition was observed in arrays where the interparticle distance was varied for instance by annealing [43], compression [33], or ligand exchange [44]. For Gt < G0, i.e., for ħG < d, EC dominates the transport behavior, resulting in an insulating behavior. For a small applied bias voltage Vsd and a thermal energy kBT « EC, the conductivity can be expressed by [28] s ¼ 2s0 eEC =k B T :

(5)

For electrons with energies smaller than EC, transport is exponentially suppressed. This situation corresponds to a Coulomb blockade regime. At T = 0 K and in an assembly with negligible electrostatic disorder, i.e., Vbg = 0 V, this gives rise to a threshold bias voltage V th ¼ 2N E C =e, where N is the number of nanoparticles along the width of the array [39]. For Vsd > Vth , the current is expected to linearly increase with Vsd. The presence of a nonzero background potential Vbg introduces a random distribution of conductance thresholds for adjacent nanoparticles. The conductance through the overall nanoparticles assembly raises as soon as more and more percolating electron paths develop through the array. This scenario leads to a power-law dependence of the current I as a function of threshold voltage Vth [45]:
0, f or jV sd j < V th I ðV sd Þ / : (6) x ðV sd  V th Þ , f or jV sd j > V th The exponent x is predicted to be 1 (5/3) for infinite one-dimensional (two-dimensional) arrays. Measurements as well as simulations of finite two-dimensional assemblies yield however larger values: 2 < x < 3 [42, 46, 47]. The value of the exponent x will be further discussed in section “Nonlinear Response.” In the presence of electrostatic disorder (Vbg 6¼ 0), the threshold voltage has to be renormalized by a constant factor a, with a = 0.226 for a triangular two-dimensional array of nanoparticles [42]. Increasing the temperature thermally activates more electrons, progressively overcoming the Coulomb blockade. The threshold voltage thus effectively depends on temperature [42]:   4:8k B T 1 ; (7) V th ðT Þ ¼ V th ð0Þ  1  pc E eff c

Page 10 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

where pc is the percolation threshold, with pc = sin(p/18)  0.35 for bond percolation in a two-dimensional triangular network [48]. The ratio kBT/Eeff c corresponds to a probability to overcome , an effective charging energy. Equation 7 predicts a vanishing threshold the Coulomb blockade with Eeff c eff for T > T c ¼ pc E c =4:8k B, resulting in a finite conductance of the array at zero bias. At temperatures T > Tc, the IV characteristic still follows a power-law dependence due to the random distribution of threshold voltages. As the bias voltage increases, more percolating paths develop across the array. In this regime, the model still describes the conductance of the array albeit with a negative effective voltage threshold [47]. pffiffiffiffiffiffiffiffi Weaker temperature dependences of the form s / e T 0 =T have been experimentally observed [49, 50]. This temperature dependence has been predicted for disordered semiconductors in the regime of variable range hopping [28, 51]. In principle, this process requires (i) a finite tunneling probability beyond nearest neighbors, which is unlikely for metallic nanoparticles due to screening effects and (ii) a nonvanishing electronic density of states at the Fermi energy, which is a priori not the case because of the Coulomb blockade. The presence of a background electrostatic potential Vbg, however, can lead to a random local lifting of the Coulomb blockade giving rise to a finite density of states at the Fermi energy [28, 50]. Taking additionally into account elastic and inelastic co-tunneling effects to mediate tunneling beyond nearest neighbors leads to an exponential dependence of the current I as a function of bias voltage Vsd I / e

pffiffiffiffiffiffiffiffiffiffiffi V 0 =V sd

;

(8)

with V0 a characteristic voltage of the variable range hopping mechanism.

Linear Response

In this paragraph, arrays consisting of a large number of nanoparticles (typically 106) with contacts as shown in Fig. 5c are considered. The bias voltage drop between neighboring nanoparticles is small as 0.4

I (mA)

0.2

1010 4

1,3

0

109 I (nA)

−0.2 −0.4

b

2

−10

−5

1

108 1,3

−1

0 V (V)

R˙ (W)

a

5

10

0

180 t (min)

360

Fig. 8 Electrical characterization of nanoparticles arrays before and after molecular place-exchange. (a) Typical current–voltage (IV) curves measured at different stages in a molecular exchange experiment: (1) as-prepared octanethiol array, (2) after OPE exchange (first time), (3) after octanethiol exchange, (4) after OPE exchange (second time). Inset: curves 1 and 3 shown at lower current values. (b) Sheet resistance (R□) of a device as a function of immersion time (t) in an OPE solution during the course of molecular exchange (from stage 1 to 2) (Reprinted with permission from Adv. Mater., vol. 18, p. 2444 (2006) [34]. Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

compared to molecular energy levels separation. The current–voltage characteristic (IV) of the array is thus dominated by the charging energy of the particles and the interparticle tunneling. At room temperature and for arrays based on 10 nm diameter particles, the thermal energy kBT ffi 25 meV is larger than the charging energy which amounts to about 10 meV as discussed above. Figure 8a shows typical DC IV measurements at different stages during a molecular exchange experiment [34]. Typically, the conductance of the devices reaches G  108 S after exchange with OPE molecules. This corresponds to a weak coupling regime, since the tunneling conductance between adjacent particles is much smaller than G0. The ohmic behavior observed reveals a diffusive regime due to thermal activation. Room Temperature Characterization and Exchange Curve 1 in Fig. 8a shows the measurement of an as-prepared device (octane thiol ligands) with a resistance of R1 = 4.4  1010 O. In order to be able to compare devices with slightly different geometries, it is convenient to use the sheet resistance R□ = Rw/l, with l and w, the length and width of the device, respectively, and R, the measured resistance. In the graphs, the sheet resistance of the devices is reported, unless otherwise specified. The sheet resistance of one device can be related to a single junction resistance RJ, i.e., the resistance of two interconnected neighboring nanoparticles. This resistance can be seen as the inverse of the tunneling conductance Gt described above, i.e., RJ  1/Gt. For a typical hexagonal geometry, one obtains RJ = (2/√3)  R□ [34]. In other words, a measurement of the IV response of a device comprising thousands of junctions provides the typical, average response of a single junction. After a first exchange, the sheet resistance has substantially decreased to R2 = 6.3  107 O (curve 2). This is attributed to the interlinking of neighboring particles by the conjugated molecules which results in the formation of conducting pathways. The time evolution of the sheet resistance for one device during the exchange process is shown in Fig. 8b. The exchange was interrupted at regular time intervals and the resistance of the device measured after rinsing and drying. A rapid decrease of the sheet resistance is observed in the first 40 min followed by a saturation of the resistance. This behavior is consistent with the place-exchange behavior observed for monolayer-protected clusters [52]. As shown by FTIR measurements, the exchange process is reversible. After the back-exchange process, from conjugated compounds back to alkanethiols, the DC IV measurements showed a similar conductance as in the as-prepared devices with R3 = 5.4  1010O (Fig. 8a, curve 3). An additional exchange with OPE molecules results again in a lower resistance, as measured after the first OPE insertion (Fig. 8a, curve 4), showing the reproducibility of the process and flexibility of the nanoparticles platform.

0.3

Counts (arb. units)

0.3

AcS

SAc

AcS

0.2

0.2

0.1

0.1

0.0

0.0 1.0

1.5

2.0

2.5

log(Gf/Gi)

3.0

1.0

1.5

2.0

2.5

3.0

log(Gf/Gi)

Fig. 9 Histograms of log(Gf /Gi), where Gf is the final sheet conductance after exchange and Gi the initial conductance before exchange, for OPE-dithiol (left) and OPE-monothiol (right) (Adapted from Reference New J. Phys., 10, 065019 (2008) [54] with permission. # IOP Publishing Ltd and Deutsche Physikalische Gesellschaft. Published under a CC BY-NC-SA license)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Interlinking of Neighboring Particles To create a truly interconnected network of nanoparticles, the inserted molecular compounds need to bridge neighboring nanoparticles by forming a chemical bond at both ends of the compound. That this happens during a molecular exchange process is not trivial as various local geometries might appear which may still notably contribute to increase the device conductance. For instance, p  p interactions between neighboring conjugated molecules can lead to the formation of stable molecular bridges resulting in a significant conductance increase of metal–molecule–metal junctions [53]. Strong evidence that molecules bearing two anchor groups do interlink neighboring nanoparticles is provided in Fig. 9 [54]. Histograms of the ratio of the final conductance Gf after exchange to the initial conductance Gi before exchange are considered. The experiments were performed for OPE compounds bearing one anchor group at each end (OPE-dithiol, left panel) and for OPE compounds with a single anchor group (OPE-monothiol, right panel). A sharper distribution of conductance ratio and larger average conductance increase upon exchange can be observed for OPE-dithiol. These experiments demonstrate that for any given initial conductance value, the final conductance of the arrays after insertion of the conjugated compounds is systematically larger for OPE-dithiol than for OPE-monothiol up to only very few exceptions [54]. Performing a molecular exchange in nanoparticle arrays therefore leads to the formation of chemically interconnected networks of molecular junctions.

Nonlinear Response At temperatures lower than room temperature, the charging energy in arrays based on 10 nm nanoparticles becomes relevant and the IV characteristics start to deviate from a linear behavior. Figure 10 illustrates this effect, showing typical IV characteristics at different temperatures. The observed power-law dependence of the IV curves is typical for activated charge transport characterized by a response of the type (see Eq. 6):  I/

x V sd 1 : V th

(9)

Disorder and finite-size effects influence the value of x. Using a simple rescaling of the data obtained at low temperatures, one can extract Vth and x. Figure 11 shows such a scaling for seven different arrays [55]. The measured voltage V and current I have been scaled to account for arrays size effects and normalized using the threshold voltage. The rescaled voltage Vn and current In are respectively given by

Fig. 10 Current (I) versus applied voltage (Vsd) characteristic of a two-dimensional gold nanoparticle (∅ 9.2 nm) array in vacuum (106 mbar) with exchanged OPV molecules. (a) IV measured at T = 13.7 K. (b) IV characteristics at T = 13.7 K (bottom curve), T = 25 K (middle curve), and T = 43 K (top curve). White lines are fitting curves according to Eq. 6 (Reprinted with permission from ACS Nano 6, 4181 (2012). Copyright 2012 American Chemical Society)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

101

100 0.5 Vth 100

100

10−1 10−1

In= I / (NGiVth)

1.5 Vth

In = I / (GiVth) · 1/N

ξ=2

ξ=1.3

10−1 101

ξ=5/3 ξ=1.3

ξ=1

Vn= (V - Vth) / Vth

100 Vn = (V - Vth) / Vth

101

Fig. 11 Scaled IV curves from seven different devices illustrating the exponent x = 1.3 observed in small nanoparticles arrays. The different lines show possible x values from different models (see text). As illustrated on one measurement (inset), changing the threshold voltage Vth by up to 50 % does not significantly affect the slope of the curve at high bias voltages. The middle curve is the reference data and the top and bottom curves were plotted for 1.5 Vth and 0.5 Vth, respectively. The line shows a calculated curve for an exponent x = 1.3

Vn = (V  Vth)/Vth and In = I/(GiVth)1/N where Vth is the threshold voltage, N is the number of nanoparticles along the width of the device, and Gi is the initial conductance of each device. At high voltages (Vn > 1), the slope of the normalized data in Fig. 11 (log–log plot) provides the exponent x. The black solid line corresponds to a slope of x = 1.3, following well the data. This value lies between the values predicted by Middleton and Wingreen [45] of x = 1 for a one-dimensional array and x = 5/3 for a two-dimensional array (black dotted lines). The discrepancy between observed and expected value may originate from the influence of topological disorder within the array and/or from a contribution by the substrate (SiO2/Si) that can introduce a random background electrostatic potential Vbg. Šuvakov and Tadić [56] have calculated the exponent x for different levels of disorder in the nanoparticle assembly. Their simulations of regular, close-packed arrays with weak topological disorder give an exponent x = 2 (black dashed line). A further reduction of the exponent is observed for arrays with added quenched charge disorder. This typically corresponds to a background potential that can originate from random trapped charges in the oxide layer of the substrate. The calculated exponent in this case is similar to the measured value x = 1.3. Liao et al. [37] investigated the influence of the substrate on x by comparing freestanding nanoparticle arrays with nanoparticle arrays on a substrate. They observed a value of x = 2 for free-standing arrays and x = 2.4 for arrays on a substrate. While the exponent values are larger, those measurements support the idea that the substrate does influence the exponent x, possibly due to trapped charges in the substrate leading to quenched disorder. The existing spread in the exponent values reported to date shows that a full understanding and control of nanoparticles assemblies on substrates remains a challenging task. A better insight may emerge from combined theoretical approaches taking into account the multiple time scales involved in electron transport in these systems [57].

From Switching Molecules to Functional Arrays In the previous paragraphs, nanoparticles arrays have been shown to form a useful architecture to create networks of molecular junctions and study their transport properties. Here, it is demonstrated that inserting functional molecules in nanoparticles arrays can result in an overall functionality at the array

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

a

b

S

reduction +2e S S

S S

S S S

oxidation -2e S S

TTF red

S

C8

S

TTF ox

102

TTF

S

G ® / G®

S

TTF initial

S

101

S

TTF Ox1 Re1 Ox2 Re2 Ox3 Re3 Ox4 Process step

Fig. 12 Redox-switching devices based on networks of nanoparticles with dithiolated tetrathiafulvalene molecules (TTFdTs). (a) Schematics of the redox-active TTFdT molecule which can be oxidized or reduced in situ. (b) Average normalized conductance G□TTF/G□C8 during four oxidation-reduction cycles. ●, immediately after exchange; ~, after oxidation; ▼, after reduction (Adapted with permission from Nano Letters 10, 759 (2010) [38]. Copyright 2010 American Chemical Society)

scale. As an example, the implementation of cyclic conductance switching, thanks to redox-active molecules, is briefly discussed [38]. Starting from octanethiol (C8) covered gold nanoparticles arrays, dithiolated tetrathiafulvalene derivatives (TTFdTs) (Fig. 12a) were inserted in the array by molecular place-exchange in organic solvents. The molecule has a redox-active TTF group in its center and (3-thiopropyl) groups on each side. At both ends, the thiol group enables bridging two neighboring nanoparticles. The solution contains two isomers (Fig. 12a). As verified by UV-visible absorption spectroscopy, oxidation and reduction of the TTFdT compound can be achieved via iron chloride (FeCl3) and ferrocene (Fe(C5H5)2), respectively. The molecule can be reversibly switched between its neutral state (Fig. 12a, top) and its oxidized, dication state (Fig. 12a, bottom). For all devices, the sheet conductance G□C8 was first measured before the molecular exchange for as-prepared arrays. Immediately after the exchange with TTFdTs, the conductance was again measured and normalized by the conductance before the exchange. The measurements were performed for 24 devices, and the average ratio G□TTF/ G□C8 was determined for all devices. The initial ratio G□TTF initial/G□C8 was around 10, the insertion of TTFdTs thus increasing initially the conductance of the devices by about one order of magnitude. To investigate the influence of the oxidation state of the molecule on the conductance, the devices were measured during four consecutive oxidation-reduction processes (Fig. 12b). The conductance systematically increased after oxidation and it decreased after reduction. Note that the switching amplitude decays as the number of cycles increases. This may be due (i) to the breaking of Au-S bonds between the TTFdT compound and the nanoparticles by the oxidant and (ii) to the coordination of unbound end groups with iron ions present in the oxidant. The formation of dimers or oligomers via disulfide bond formation during the redox cycles might also affect the switching. Interestingly, it is in principle possible to artificially enhance the on–off ratio of a switchable molecular device further, provided the device is brought in the regime of multiple inelastic co-tunneling, e.g., by using smaller nanoparticles [58]. Overall, these experiments demonstrate that nanoparticle arrays can be used as a “nanoscale breadboard” to assemble molecular junction networks showing active functionality at the network level.

Optoelectronic Properties of Nanoparticle Arrays A distinctive optical effect of nanoparticle arrays is the collective surface plasmon resonance comprising more than one nanoparticle. Here, it is demonstrated that photoconductance measurements allow characterizing this fingerprint of a metal nanoparticle array. They further allow analyzing the optically induced Page 15 of 31

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

potential redistribution of an array in the Coulomb blockade. The section closes with the photoconductance and optically induced conductance changes of arrays functionalized with single molecules.

Optical Excitation of Isolated Spheres

The mathematical description of the interaction of light with an isolated metal sphere was first described by Gustav Mie in 1908 by analytically solving the Maxwell equations [59]. The three main assumptions of the Mie theory are (i) the particle is strictly spherical, (ii) the material of the particles as well as its surrounding is homogeneous, and (iii) the bulk dielectric properties of the materials can be applied. The appropriate boundary conditions are applied at the surface of the sphere, and the incoming electric and magnetic fields are described by a multipole expansion. Hereby, the extinction and the scattering cross section are obtained as [60] sext ¼

1 2p X ð2n þ 1Þ½Reðan þ bn Þ ; k 2 n¼1

(10)

ssca ¼

1  2  2p X 2 ; ð 2n þ 1 Þ ja j þ jb j n n k 2 n¼1

(11)

with k the wavenumber of the incoming light. The scattering coefficients of the electric and the magnetic modes are given by [60] mjn ðmxÞ½jn ðxÞ 0  ½jn ðmxÞ 0 jn ðxÞ ; mjn ðmxÞ½hn ðxÞ 0  ½jn ðmxÞ 0 hn ðxÞ

(12)

mjn ðmxÞ½jn ðxÞ 0  m½jn ðmxÞ 0 jn ðxÞ ; mjn ðmxÞ½hn ðxÞ 0  m½jn ðmxÞ 0 hn ðxÞ

(13)

an ¼

bn ¼

where jn and hn are Bessel functions of the first and second kind and m is the relative refractive index given pffiffiffiffiffiffiffiffiffi by m ¼ e=em with e and em the dielectric permittivities of the metal and the surrounding medium, respectively. The derivation is valid for an arbitrary size of the metal sphere. The size is included by the dimensionless size parameter x given by pffiffiffiffiffi 2p em r ; x¼ l

(14)

with r the radius of the sphere and l the wavelength of the light in vacuum. The above expressions can be greatly simplified for metal spheres with a diameter much smaller than the wavelength of the incoming light, i.e., x 10 V. The observed behavior can be explained by a lifted Coulomb blockade due to a local temperature increase in the nanoparticle array. Figure 19b depicts a sketch of a nanoparticle array irradiated by a laser beam. The sample is at temperature T0. At the laser position, the temperature is locally increased to T1. Generally, the increased temperature leads to a bolometrically increased conductance of the nanoparticle array. Without irradiation, the potential U drops linearly between the two contacts (dashed line in the second panel of Fig. 19b). Under irradiation, the potential drop in the irradiated area is reduced due to the locally increased conductance. Consequently, the potential drop in the nonirradiated area must increase such that the overall potential drop equals the applied bias Vsd (solid line in the second panel of Fig. 19b). Accordingly, the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

Iphoto [nA]

a

0.4

Icalc

b

0.8

Au SiO2

13.7 K 25 K

Au T0

T1

U 0 −0.4

y

E

−0.8 −15 −10 −5 0 5 Vsd (V)

c

10 15

3 2

Icalc [nA]

y

13.7 K 25 K

1 0 −1 −2 −3 −15 −10 −5

0

5

10 15

Vsd (V)

Fig. 19 (a) Iphoto as a function of Vsd measured at T0 = 13.7 K (black symbols) and T0 = 25 K (grey) (Ephoton = 2.07 eV, Iopt = 0.7 kW/cm2, and fchop = 1605 Hz). (b) Sketch of a nanoparticle array at bath temperature T0 on a SiO2 substrate contacted by gold electrodes and irradiated by a focused laser beam increasing the local temperature to T1. Second and third panel represent the potential U and the electric field E as a function of position in the irradiated (solid line) and the nonirradiated (dashed line) array. (c) Calculated optically induced current Icalc as a function of Vsd for T0 = 13.7 K, T1 = 16.2 K (black symbols) and T0 = 25 K, T1 = 26.6 K (grey) (Reprinted with permission from ACS Nano 6, 4181 (2012). Copyright 2012 American Chemical Society)

electric field is constant along the nonirradiated array (dashed line in the third panel of Fig. 19b). Under irradiation, however, the electric field is reduced in the irradiated sample part, while it is increased in the nonirradiated sample part (solid line). According to this scheme, the current Icalc across the nanoparticle array can be calculated from the measured temperature dependence of the conductance of the nonirradiated array (Fig. 19c). Since the calculation and the measurements nicely agree, the experiments verify that the photoconductance in the Coulomb blockade can be understood in terms of a locally bolometrically induced conductance in combination with a potential redistribution in the nanoparticle arrays [83].

Functionalized Nanoparticle Arrays: A Platform for Molecular Optoelectronics There have been several attempts to resolve the photocurrent signal of single molecules in molecular junctions [84, 85]. However, the molecular photoconductance is typically overlaid by bolometric or plasmonic effects induced in the metallic electrodes of the molecular junctions [84]. A promising approach to photocurrent spectroscopy of organic molecules contacted to metal electrodes consists in the use of metal nanoparticles as nanoscopic electrodes to the molecules. The advantage of such a configuration is that the molecules can easily be accessed by optical means. It was shown that diarylethene molecules contacted in gold nanoparticle arrays maintain their optical switching activity when they are

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

a Au

S

S

S

UV

Au

S

S

S

Au

Vis

S

S

Au

D Vis UV

b 3.2

G (nS)

3.0 2.8 2.6 2.4 2.2 0

1000

2000

3000

t (s)

Fig. 20 (a) Switchable diarylethene molecules embedded into an array of gold nanoparticles: top, closed, “on” form; bottom, open, “off” state. Switching from on to off is possible by illumination with visible light. The reverse is achieved by UV irradiation. (b) Repeated conductance switching. The conductance G is plotted vs. illumination time t. In the dark, the sample conductance is constant (t < 0). At t = 0, illumination with visible light is commenced (Vis in colored top bar), leading to an immediate conductance decrease. Upon UV irradiation (e.g., at t = 245 s, UV in top bar), G increases again. The illumination is alternated from visible (245 s) to UV irradiation (125 s), as indicated by the colored bar. For 2,095 < t < 2,650 s, the sample is left in the dark. The experiment was done in an argon flow cell at room temperature (Adapted with permission from Nano Letters 9, 76 (2009) [86]. Copyright 2009 American Chemical Society)

incorporated into a nanoparticle array (Fig. 20) [86]. Hereby, a single-molecule based optoelectronic switch was realized in nanoparticle arrays. Furthermore, the photoconductance of oligo(phenylene vinylene) (OPV) (Fig. 21a) incorporated in gold nanoparticle arrays was presented [88]. A pronounced photoconductance arises upon resonant excitation of the OPV molecules. Figure 21b shows the absorbance spectrum of OPV molecules dissolved in tetrahydrofuran (THF). The molecules are transparent for photon energies Ephoton below 3 eV. For a photon energy of 3.4 eV, the absorbance reaches a maximum due to a resonant excitation of an electron in the highest occupied molecular orbital (HOMO) to the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

SH

b Absorbance [arb. u.]

a

SH

0 2.0

d

4 2

Gphoto [pS]

Iphoto [pA]

c

Ephoton,OPV

1

0 −2

2.5 3.0 3.5 Ephoton [eV] 5.0 4.0 3.0 2.0 1.0

−4 −4

−2

0 0 Vsd [V]

2

4

0

0.5

1.0 Iopt

1.5

2.0

[kW/cm2]

Fig. 21 (a) Schematic representation of the OPV. (b) Absorbance spectrum of the OPV molecule dissolved in THF. The two arrows indicate the photon energies used in subsequently presented experiments [88] (c) Iphoto of a nanoparticle array as a function of Vsd measured with Ephoton = 3.35 eV, Iopt = 0.48 kWcm2, and fchop = 1533 Hz. (d) The photoconductance as a function of irradiation intensity with Ephoton = 3.35 eV, Vsd = 1 V, and fchop = 71 Hz. Lines represent fits to the data. Dotted line represents linear contribution. Dashed line describes nonlinear photoconductance which is only detected at photon energies Ephoton,OPV at which OPV absorbs (Adapted with permission from Journal of the American Chemical Society 133, 12185 (2011). Copyright 2011 American Chemical Society)

lowest unoccupied molecular orbital (LUMO) [87]. The arrow in Fig. 21b indicates the photon energy EPhoton,OPV used for the experiments shown in Fig. 21c, d. A sublinear power dependence of the photoconductance is observed for small light intensities with a typical time constant of  ms (Fig. 21d), which vanishes for all Ephoton < 3 eV. For Ephoton < 3 eV, a strictly linear dependence of Gphoto on Iopt was found as described, e.g., by the bolometric contribution Eq. 33. Based on the observations, the sublinear increase of Gphoto can be understood in terms of a molecular phototransistor such that electrons, which are photogenerated in the OPV molecules, directly participate in the charge transport across the functionalized nanoparticle array [88].

Conclusion In this overview of the electronic and optoelectronic properties of well-organized nanoparticles arrays, we show, the versatility of this platform for fundamental studies is shown. Granularity is rather ubiquitous in nature, and nanoparticle arrays represent a flexible model system to better understand materials with particular geometrical arrangements with and without disorder. Nanoparticles made out of noble metals are discussed, but there is a variety of physical regimes than can already be addressed. The possibility to control the organic matrix consolidating the metal nanoparticles array using for instance molecular exchange brings an additional lever arm to tune the electrical and optoelectronic properties of the arrays

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_27-1 # Springer International Publishing Switzerland 2015

and even add functionality to them. This aspect together with a low-cost fabrication scheme makes nanoparticles arrays particularly interesting for a number of applications.

Acknowledgments Numerous colleagues have contributed to the work presented here. Particular thanks goes to Claire Barrett, Laetitia Bernard, Jianhui Liao, Marcel Mayor, Sense Jan van der Molen, and Christian Schönenberger. For critical reading and comments, we thank Jianhui Liao, Sense Jan van der Molen, Ralph Stoop, Martin Niedermeier, and Anton Vladyka. Following agencies are acknowledged for financial support: the Swiss NCCR “Nanoscale Science,” the Swiss National Science Foundation (SNSF), the European Science Foundation (ESF) through the Eurocores Program on Self-Organized Nanostructures (SONS), the Gebert R€ uf Foundation, the DFG excellence cluster “Nanosystems Initiative Munich” (NIM), and the European Commission (EC) via the FP7 projects – “FUNMOLS” (ITN) no. 212942, “FUNMOL” no. 213382, “HYSENS” no. 263091, “NanoREAL” (ERC grant) no. 306754, “SYMONE” no. 318597, and “MOLESCO” (ITN) no. 606728.

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61. L. Novotny, B. Hecht, Principles of Nano Optics (Cambridge University Press, Cambridge, 2006) 62. R.C. Weast, D.R. Lide (eds.), Handbook of Chemistry and Physics, 70th edn. (CRC, Boca Raton, 1990) 63. S.K. Ghosh, T. Pal, Interparticle coupling effect on the surface plasmon resonance of gold nanoparticles: from theory to applications. Chem. Rev. 107, 4797 (2007) 64. U. Kreibig, L. Genzel, Optical absorption of small metallic particles. Surf. Sci. 156, 678 (1985) 65. L. Genzel, T.P. Martin, U. Kreibig, Dielectric function and plasma resonances of small metal particles. Zeitschrift f€ ur Physik B Condensed Matter 21, 339 (1975) 66. L. Genzel, U. Kreibig, Dielectric function and infrared absorption of small metal particles. Zeitschrift f€ ur Physik B Condensed Matter 37, 93 (1980) 67. M. Quinten, Optical constants of gold and silver clusters in the spectral range between 1.5 eV and 4.5 eV. Zeitschrift f€ ur Physik B Condensed Matter 101, 211 (1996) 68. J. Cao, Y. Gao, H.E. Elsayed-Ali, R.J.D. Miller, D.A. Mantell, Femtosecond photoemission study of ultrafast electron dynamics in single crystal Au(111) films. Phys. Rev. B 58, 10948 (1998) 69. N.W. Ashcroft, N.D. Mermin, Solid State Physics (Thomson Learning, London, 2003) 70. J.C. Garnett, Colours in metal glasses and in metallic films. Philos. Trans. R. Soc. Lond. A 203, 385 (1904) 71. L. Genzel, T.P. Martin, Infrared absorption by surface phonons and surface plasmons in small crystals. Surf. Sci. 34, 33 (1973) 72. T. Ung, L.M. Liz-Marzán, P. Mulvaney, Gold nanoparticle thin films. Colloids Surf. A Physicochem. Eng. Asp. 202, 119 (2002) 73. N.E. Christensen, B.O. Seraphin, Relativistic band calculation and the optical properties of gold. Phys. Rev. B 4, 3321 (1971) 74. M.A. Mangold, C. Weiss, M. Calame, A.W. Holleitner, Surface plasmon enhanced photoconductance of gold nanoparticle arrays with incorporated alkane linkers. Appl. Phys. Lett. 94, 161104 (2009) 75. P. Banerjee, D. Conklin, S. Nanayakkara, T.H. Park, M.J. Therien, D.A. Bonnell, Plasmon-induced electrical conduction in molecular devices. ACS Nano 4, 1019 (2010) 76. H. Chen, G.C. Schatz, M.A. Rattner, Experimental and theoretical studies of plasmon–molecule interactions. Rep. Prog. Phys. 75, 096402 (2012) 77. A.O. Govorov, H. Zhang, Y.K. Gun’Ko, Theory of photo-injection of hot plasmonic carriers in metal–semiconductor nanostructures and surface molecules. J. Phys. Chem. C 117, 16616 (2013) 78. H. Nakanishi, K.J.M. Bishop, B. Kowalczyk, A. Nitzan, E.A. Weiss, K.V. Tretiakov, M.M. Apodaca, R. Klajn, J.F. Stoddart, B.A. Grzybowski, Photoconductance and inverse photoconductance in films of functionalized metal nanoparticles. Nature 460, 371 (2009) 79. A.O. Govorov, H.H. Richardson, Generating heat with metal nanoparticles. Nano Today 2, 30 (2007) 80. A.O. Govorov, W. Zhang, T. Skeini, H. Richardson, J. Lee, N.A. Kotov, Gold nanoparticle ensembles as heaters and actuators: melting and collective plasmon resonances. Nanoscale Res. Lett. 1, 84 (2006) 81. M.A. Mangold, C. Weiss, B. Dirks, A.W. Holleitner, Optical field-enhancement in metal nanoparticle arrays contacted by electron beam induced deposition. Appl. Phys. Lett. 98, 243108 (2011) 82. Q. Park, Optical antennas and plasmonics. Contemp. Phys. 50, 407 (2009) 83. M.A. Mangold, M. Calame, M. Mayor, A.W. Holleitner, Negative differential photoconductance in gold nanoparticle arrays in the Coulomb blockade regime. ACS Nano 6, 4181 (2012) 84. D.C. Guhr, D. Rettinger, J. Boneberg, A. Erbe, P. Leiderer, E. Scheer, Influence of laser light on electronic transport through atomic-size contacts. Phys. Rev. Lett. 99, 086801 (2007)

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85. G. Noy, A. Ophir, Y. Selzer, Response of molecular junctions to surface plasmon polaritons. Angew. Chem. Int. Ed. 49, 5734 (2010) 86. S.J. van der Molen, J. Liao, T. Kudernac, J.S. Agustsson, L. Bernard, M. Calame, B.J. van Wees, B.L. Feringa, C. Schönenberger, Light-controlled conductance switching of ordered metal-moleculemetal devices. Nano Lett. 9, 76 (2009) 87. E.I. López-Martínez, L.M. Rodríguez-Valdez, N. Flores-Holguín, A. Márquez-Lucero, D. GlossmanMitnik, Theoretical study of electronic properties of organic photovoltaic materials. J. Comput. Chem. 30, 1027 (2009) 88. M.A. Mangold, M. Calame, M. Mayor, A.W. Holleitner, Resonant photoconductance of molecular junctions formed in gold nanoparticle arrays. J. Am. Chem. Soc. 133, 12185–12191 (2011)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Electrochemistry of Metal Nanoparticles and Quantum Dots Antonio Doménech-Carbóa*, Raquel E. Galianb, Jordi Aguilera-Sigalatb and Julia Pérez-Prietob a Departamento de Química Analítica, Universidad de Valencia, Burjassot, Valencia, Spain b Departamento Química Organica/Instituto de Ciencia Molecular (ICMol), Universidad de Valencia, Paterna, Valencia, Spain

Abstract Metal nanoparticles, with a wide range of applications in catalysis and sensing, have structural and electronic properties that differ from those of their bulk macroscopic counterparts. Electrochemical techniques are of particular interest in the study of metal nanoparticles because electrons may undergo quantum confinement effects which are reflected in their electrochemical behavior, resulting, ultimately, in three distinguishable voltammetric regimes: bulk continuum, quantized double-layer charging, and molecule-like. Similarly, semiconductor nanoparticles (quantum dots, QDs) are receiving considerable attention due to their high fluorescence, which makes them of interest for biological and medical applications, among others. The semiconductor bulk materials possess defect states that originate from impurities, divacancies, or surface reactions as a result of their synthesis. Voltammetric features provide information on bandgap energy, the position of conduction and valence band edges, and the position of defect sites as well as on the interaction with the capping ligand. This chapter is devoted to provide a critical view of the current state of the art in the electrochemistry of such systems.

Introduction Metal and semiconductor nanoparticles, nanowires, nanopores, and other systems of dimensions at the nanometric scale have structural and electronic properties that differ from those of their bulk macroscopic counterparts. The study of the electrochemistry of such systems, i.e., that of the processes involving interfacial charge transfer between nanosized systems and electron-conducting electrodes, possesses a great importance by either its ability to yield relevant information on the structure and composition of nanoparticulate entities and their applications in catalysis and sensing [1, 2]. Here, the attention will be focused on nanoparticulate systems constituted by a core of metal atoms, surrounded or not by a coating of metal compounds, and stabilized by a monolayer (capping) of organic ligands that prevent agglomeration; the electrochemistry of nanoparticulate films, nanoelectrodes, and nanopores will be treated only tangentially here. In principle, the term nanoparticle electrochemistry refers to that of metal and semiconductor colloids, also termed colloidal microelectrodes [3, 4], differing from conventional colloids by their ability to act as electron donors and acceptors [5, 6]. Typically, the electrochemistry of solutions of metal nanoparticles and quantum dots in electrolytes is studied by means of voltammetric methods. Several general aspects should be underlined [7, 8]:

*Email: [email protected] Page 1 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Table 1 Earlier insights into the development of nanoparticles electrochemistry Matter Electron donor/acceptor properties of metal and semiconductor colloids Metal nanoparticles and water splitting Stabilizing nanoparticles by means of organic ligands Role of metal and semiconductor colloids as redox mediators Quantum dots Modeling molecular capacitance Chemical linking of metal nanoparticles to electrodes Bulk-continuum voltammetry of metal nanoparticles Quantized double-layer charging of metal nanoparticles Quantum confinement effects Electrodeposition of metal nanoparticles

Citation(s) Henglein [5]; Kiwi and Gratzel [6] Miller et al. [11] Schmid et al. [12] Henglein [4] Bawendi et al. [13] Weaver and Gao [14] Chumanov et al. [15]; Grabar et al. [16] Ung et al. [17] Ingram et al. [18] Chen et al. [19] Finot et al. [20]

(a) The voltammetric response of the nanoparticulate systems can be superimposed to that of electroactive ligands. (b) Measurements can be performed both on nanoparticulate solutions (or dispersions) and on thin films of nanoparticles deposited on the electrode surface. (c) In contrast with, for instance, spectroscopic techniques which provide information on the “bulk” nanoparticle composition, electrochemical methods mainly probe the surface properties of those systems [9, 10]. (d) There is a number of applications for sensing, photoelectrochemical functional devices, electrosynthesis, anticorrosion, and environmental remediation, involving nanoparticulate systems with different nanoarchitectures and/or involving different types of functionalization and/or forming a variety of nanocomposites. The earlier historical development of nanoparticle electrochemistry can be summarized in a series of insights, some of which are listed chronologically in Table 1. Nanoparticles electrochemistry can be viewed as a new field located at an intermediate-size scale between molecular electrochemistry and solid state electrochemistry [21]. Figure 1 shows a schematic view of the position of nanoparticle electrochemistry and its previously mentioned aspects.

Electrochemical Techniques Conventional electrochemical techniques have been used in the chemistry of nanomaterials to characterize the nanomaterial surface. Electrochemical techniques are particularly interesting by their capability of yielding information by using standard instrumentation. Regarding to the sample experimental condition, the electrochemical measurements can be done in a colloidal solution or in a film. In the first case, the in general low solubility of the nanoparticles in the media reduces the electrochemical signal and the sensibility of the system. The deposition of the nanoparticle on the electrodes has been used to overcome this problem [7]. In general, electrochemical techniques are used for analytical purposes, but they can also be used for preparative ones, for instance, for electrodeposition of nanoparticles on substrates [22] and liquid–liquid interfaces [23]. The most used electrochemical techniques can be divided into static and dynamic, depending on the type of electrochemical processes occurring at the electrode/electrolyte interface. As summarized in Fig. 2, the main static methods are potentiometry, electrochemical noise, and impedance Page 2 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Molecular electrochemistry

Solid state electrochemistry

Electrochemistry of macromolecules and supramolecular aggregates

Electrochemistry of colloidal systems

Nanoparticles electrochemistry

Metal nanoparticles

Semiconductor nanoparticles

Nanoarchitecturees (core@shell, nanorods, etc.), functionalization, etc.

Nanoparticles in solution

Nanoparticlemodified electrodes

Fig. 1 Scheme of possible relationships among topics typically involved in nanoparticles electrochemistry

measurements (electrochemical impedance spectroscopy in particular). Dynamic methods involve faradaic processes recorded by means of coulometry, chronoamperometry, chronopotentiometry and, particularly, voltammetry. Chronoamperometric and chronocoulometric techniques can be used conjointly with voltammetric ones, whereas electrochemical impedance spectroscopy is of application in the analysis of microparticulate films. Several of both static and dynamic techniques can be hyphenated with optical (X-ray diffraction, spectroelectrochemistry) and microscopy imaging techniques such as atomic force microscopy (AFM). In the particular case of semiconductor quantum dots, the most used electrochemical techniques can be grouped into voltammetric Electrochemical methods Static

Dynamic

Electrochemical impedance spectroscopy

Coulometry

Electrochemical noise

Chronoamperometry and chronocoulometry

Potentiometry

Voltammetry

Electrochemiluminiscence

Spectroelectrochemistry

Electrochemical imaging techniques (SECM)

Hyphenated techniques (AFM, XRD)

Fig. 2 Scheme illustrating the main electrochemical techniques used in nanoparticle electrochemistry Page 3 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

eNanoparticle Nanoparticle eFermi level

Fermi level

Electron-conducting electrode

Electron-conducting electrode

Fig. 3 Schematic representation of electrochemical processes involving nanoparticles. Left: injection of an electron from the Fermi level of the metal electrode to the conduction band of the particle; right: electron extraction from the particle to the Fermi level of a metal electrode (equivalent to the injection of a hole into the valence band of the nanoparticle)

(cyclic, differential pulse, square wave voltammetry), electrochemiluminescence, and spectroelectrochemistry [8]. Electrochemical imaging techniques are increasingly used to study nanoparticle films on electrodes. The scanning electrochemical microscopy technique (SECM), developed by Bard et al. [24], uses a tip microelectrode as a local probe providing spatially resolved information on the redox reactivity of surfaces and has been used for measurement on electron transfer dynamics [25] and local deposition of nanoparticles [22, 26]. Recent developments involve the use of optical signals of the electrode, namely, surface plasmon resonance [27], and combination with AFM in order to probe individual metal nanoparticles [28]. Spectroelectrochemistry techniques combine spectroscopic and electrochemical methods, thus facilitating the interpretation of electron transfer reactions. For example, they can give valuable information in photoinduced electron transfer processes by providing static-state products analogous to those that are generated in transient spectroscopy. Among the spectroscopic techniques, the steady-state and time-resolved optical ones are having a special relevance in nanoparticle spectroelectrochemistry. For these measurements, the electrochemical cell, housing a working, a reference, and a counter electrode, is designed to be simultaneously used for electrochemistry and spectroscopy, and consequently, the spectra are recorded while the potential is stepped to a desired value. Thus, the design of the cell for electrochemiluminescence is such that it can be inserted into the sample compartment of an emission spectrophotometer.

Electrochemical Behaviors Quantum Confinement Effects In a solid metal or semiconductor, electronic energy levels are distributed forming quasi-continuum bands. When the size of the particle is reduced to few nanometers, quantum confinement effects appear and the band structure of the semiconductor changes into discrete levels. As a result, the optical and electrical properties become dependent on its physical dimension; in particular, the

Page 4 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Metallic continuum

Molecule-like behavior

Metal-like quantized charging

0.2 eV Au225

0.3 eV

0.7 eV

1.2 eV

1.8 eV

Au140 Au75 Au38 Au13

Fig. 4 Schematic representation of the variation of the electrochemical response of Au nanoparticles showing optical HOMO-LUMO energy gaps (Adapted from Ref. [7] using data from Refs. [14, 32–37])

electrochemical response becomes size dependent. For our purposes it is pertinent to remark that electronic levels separate into conduction and valence bands and the energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) widens as the particle size decreases [29–31]. This yields an energy gap which can be optically and/or electrochemically detected (vide infra). Then, the nanoparticulate system behaves similarly to semiconductor electrochemistry. Figure 3 shows a schematic representation of the basic electron transfer processes between an electron-conducting electrode and a nanoparticle having a band gap. Electrochemical reduction processes can be described as the injection of an electron from the Fermi level of the metal electrode to the conduction band of the particle. Electrochemical oxidation can be represented by an extraction of an electron from the valence levels of the particle to the Fermi level of a metal electrode. This process can be considered as similar to the injection of a hole into the valence band of the nanoparticle. Roughly speaking, there is a continuous-like transition from the metal (or semiconductor) “bulk” state to the molecule-like behavior, so that following Murray [7], three electrochemical regimes can be differentiated by means of voltammetric methods, namely, bulk continuum, quantized doublelayer charging, and molecule-like. When the organic ligand monolayer of the nanoparticles contains electroactive groups, the electrochemical response of such groups can be recorded, thus incorporating additional signals to the voltammetry response of the nanoparticulate system. Figure 4 shows a schematic representation for the shift from the continuum electrochemical response to the molecule-like behavior for Au nanoparticles [7, 14, 32–36]. In the case of semiconductors, the bandgap of the bulk material can be increased by nanostructuring the material via quantum confinement effects, and the band-edge energies can be subsequently tuned by passivating the surface with dipolar ligands [37].

Bulk-Continuum Response The bulk-continuum behavior is typical of nanoparticles having sizes larger than 3–4 nm. Such systems behave as capacitors with double-layer capacitance CNP, directly related to the change in electrochemical potential (DV) associated to the transfer of z electrons from/to the nanoparticle to/from the electrode:

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Fig. 5 Differential pulse voltammetry of 0.07 mM ethanol-soluble hexanethiolate-MPCs at (a) 279 and (b) 230 K in dichloromethane/0.05 M Bu4NClO4 at 1.6-mm diameter Pt working electrode, Pt coil counter electrode, and Ag wire quasireference electrode (0.05 V pulse, 50-ms pulse width, 200-ms period, 0.02 V/s scan rate) [40]. The asterisks mark the peaks used for determining the capacitance of the nanoparticles (Reprinted with permission from Miles and Murray [40]. Copyright (2003) American Chemical Society)

DV ¼ ze=C NP

(1)

If DV is of the same order of magnitude or lower than the Boltzmann thermal energy distribution factor (kBT), successive electron transfers from/to the particle will result in a continuous change in the particles potential. In these circumstances, the capacitive charging currents are under mass transport control and can be distinguished from double-layer charging and faradaic reactions at the electrode/electrolyte interface using conventional chronoamperometric, chronocoulometric, and/or rotating disk voltammetric experiments. In the case of Ag nanoparticles capped with polyacrylic acid, application of anodic potentials produced currents for the oxidative dissolution of nanoparticles (vide infra) while applying negative potentials yields featureless, progressively rising currents under mass transfer control so that for sufficiently negative potentials ca. 1,600 electrons/ nanoparticle were transferred, corresponding to a capacity of 80 mF/cm2 [37], clearly higher than those typically obtained at conventional metal electrodes under equivalent conditions.

Quantized Double-Layer Charging This electrochemical regime is characterized by the record of multiple peak features corresponding to quantized double-layer charging. First reported by Ingram et al. [18], these features have been intensively studied, as can be seen in recent reviews [38, 39]. A typical example can be seen in Fig. 5, where differential pulse voltammograms for monolayer alkanethiolate-protected Au nanoclusters at different temperatures are shown [40]. The voltammogram consists of a series of peaks almost equally spaced, which can be attributed to quantized charge processes [41].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Such systems can be described as a concentric spherical capacitor assuming that the metal core, of radius r, is surrounded by a monolayer of capping (typically, thiolate compounds) of thickness d, of effective dielectric permittivity e. The capacity of this system is r C ¼ 4pe ðr þ d Þ d

(2)

Charging processes can be viewed as sequential reversible one-electron transfers on metal nanoparticles, M, represented as Mn þ e ! Mn1

(3)

where n = 0, 1, 2, etc. The simplest theoretical approach considers the metal nanoparticles to be a conducting sphere with the energetics of electron addition determined by classical electrostatics [14, 42, 43]. This model predicts the appearance of identical voltammetric waves corresponding to the successive transfer of electrons giving rise to successive z, z1, z2, etc., charge states [44, 45]. The formal electrode potential of the z/z1 charge state change is given by E oz, z1 ¼ E PZC þ

ðz  1=2Þe C

(4)

where EPZC is the potential of zero charge for the nanoparticle core. Deviations from the expected uniform potential spacing between voltammetric peaks appear at high charge states and are dependent on the solvent, on the electrolyte composition, and, in particular, on the length of the alkanethiolate chain [41]. These features can be mainly attributed to the variations in the permittivity of the capping monolayer. The peak spacing is also conditioned by the length and flexibility of the protecting (typically alkanethiolate) molecules, allowing for a more or less profound penetration of the solvent between them. Apart from the above effects, diffuse layer effects associated to the Helmholtz double-layer surrounding the nanoparticles also influence the observed peak spacing [32]. Supporting electrolyte anion-dependent effects can be interpreted as the result of different ion-pairing effects [46]. Ultimately, the incipient influence of the moleculetype response can also distort the uniform peak spacing response. Doublet oxidation peaks, a typical feature of electron transfer at molecular species, often appear, but the interpretation of such features still remains controversial [47, 48].

Molecule-Type Behavior For sufficiently small nanoparticles, there is an energy bandgap which can be detected, but not equivalently, by means of optical and electrochemical measurements. The optical bandgap corresponds to transitions between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), detectable as absorption band edges in the visible or nearinfrared region. The electrochemical energy gap is the difference between the electrochemical potentials for the first oxidation and first reduction wave for a parent species. The electrochemical bandgap is in general in good agreement with the difference between them, increasing the importance of the quantum confinement effects (i.e., for small particles), resulting in an increased Coulombic electron–hole interaction term (i.e., the energy associated to the generation of separated charges). Then, DE op ¼ DE el  J e, h

(5) Page 7 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014 0.06

a

0.04 0.02 0.00 −0.02

I (mA)

−0.04 CV DPV

0.04 0.03

b

0.02 0.01 0.00 −0.01 −0.02 −0.03 −0.04 −1.5

−1.0

−0.5

0.5 1.0 0.0 E (V vs Ag/AgCl)

1.5

2.0

Fig. 6 Cyclic (cvS) and differential pulse voltammograms (DPVs) of Au11Cl3(PPh3)7 nanoparticles before (a) and after (b) exchange reactions with n-dodecanethiols at a Pt microelectrode (25 mm). The particle solutions were prepared in CH2Cl2 with 0.1 M TBAP at a concentration of 0.5 mM (a) and 1.2 mM (b), respectively. CV potential scan rate 20 mV/s; in DPV measurements, dc potential ramp 20 mV/s, pulse amplitude 50 mV. Arrows indicate the first positive and negative voltammetric peaks [49] (Reprinted with permission from Yang and Chen [49]. Copyright (2003) American Chemical Society)

The value of Je,h for the smaller particles can be calculated as ca. 0.1 eV. This term does not apply for optical HOMO–LUMO transitions, where no change in the overall charge of the nanoparticle occurs. In the case of alkanethiol-capped metal nanoparticles, appearance of a HOMO–LUMO energy gap is reflected by an enlarged potential spacing between the current peaks for the first one-electron loss and the first one-electron gain of the parent nanoparticle (Fig. 6) [50]. The molecule-like behavior appears to be dependent on the electronic interactions between the particle core and capping ligands. Thus, electron-donating cappings such as phosphines would lead to an increase of the particle core electron density and hence a negative (upward) shift of the Fermi level. Opposite behavior is expected from electron-acceptor cappings, typically thiol-protecting ligands, resulting in a decrease of the electron density of the Au core [49]. It is pertinent to note that uncertainty remains about the so-called formulaic composition of the nanoparticulate system, expressed in terms of [metal]x[stabilizing ligands]y,z [7], so that, in general, nanoparticulate systems are designed by their diameter, which is typically estimated from TEM images. An interesting, directly related case is that of metal nanoparticles covered by a metal oxide shell. Voltammetric experiments suggest that oxidation of Pd@PdO nanoparticle in aqueous alkaline electrolyte could proceed via formation of Pd(OH)x adsorbed species further evolving to Pd oxides

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

a

10 μA

b

2 μA

+1.4

+0.2

−1.0

−2.2

−3.4

E / V vs. Fc+/Fc

Fig. 7 Cyclic voltammograms at glassy carbon electrode of (a) 1 mM N-(2-mercaptoethyl)-1,8-naphthalimide, (b) 6 mM CdSe/ZnS QDs capped with that ligand in 0.10 M Bu4NPF6 solution in 1/1 toluene/MeCN (v/v). Potential scan rate 50 mV/s. The dotted line separates the region of largely negative potentials where electrolyte signals appear (Reprinted with permission from Aguilera-Sigalat et al. [58]. Copyright (2013) American Chemical Society)

and/or Pd2+ ions in solution [51], similarly to the growth of porous PdO films on Pd electrodes [52]. Solid state electrochemistry of nanoheterogeneous deposits of Pd nanoparticles covered by PdO shell on graphite electrodes in contact with aqueous permits a direct estimation of the thickness of the PdO shell and the size of the palladium core by using electrochemical data alone [51]. In the case of CdSe and CdTe quantum dots, nanocrystals are usually endowed with surface monolayers composed of ligands such as trioctylphosphine oxide (TOPO), n-decanethiol, and TOPO/n-hexadecylamine. Cyclic voltammetric experiments on QD dispersions [52] and adsorbed on electrode surfaces [53] have been used for determining energy band gaps, the relationship between optical and electrochemical band gaps being expressed by Eq. 5. It has been reported that the electrochemical bandgap energy of n-decanethiol-coated samples decreases on increasing the core diameter of the QD, the electrochemical bandgap being consistently 0.4–0.5 eV smaller than the optical bandgap [8]. This discrepancy, which is clearly larger than that estimated for the Coulombic interaction energy, has been attributed to the presence of surface defects that act as local trap states for electrons and holes [8, 54]. The presence of additional peaks in the voltammograms of quantum dots has been attributed to inter-band trap states. This assignment is consistent with the presence of a broad band on the low-energy side of the band-edge photoluminescence or the appearance of a new band at longer wavelengths [55]. In the case of CdSe/ZnS QDs, electrochemical data suggest that the ZnS shell does not affect the charge injection to the CdSe core. This has been attributed to the occurrence of electron injection at potentials below those corresponding to the conduction energy level for ZnS [56]. Replacing usual capping ligands by electroactive ones results in shifts in the peak potentials for QD oxidation and reduction, but also in the modification of the electrochemical response of the ligand [57]. It is pertinent to note that in general it is difficult to discern between the genuine signals of the nanoparticle system and those due to the “free” electroactive cappings (such as thiolate species) and even those due to the supporting electrolyte/solvent system. An example can be seen in Fig. 7, where

Page 9 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

a 1 µA

b

+1.4

+0.2

−1.0

−2.2

E / V vs. Fc+/Fc

Fig. 8 Square-wave voltammograms at glassy carbon electrode of 6 mM solution of CdSe/ZnS QDs capped with long chain primary amine in 1/1 (v/v) toluene/MeCN (0.10 M Bu4NPF6). Potential scan initiated at (a) +0.80 V in the negative direction and (b) 2.7 V in the positive direction. Potential step increment 4 mV; square wave amplitude 25 mV; frequency 5 Hz. Extreme QD signals are marked by solid arrows while intermediate QD-localized ones are marked by dotted arrows [58] (Reprinted with permission from Aguilera-Sigalat et al. [58]. Copyright (2013) American Chemical Society)

cyclic voltammograms at glassy carbon electrode of N-(2-mercaptoethyl)-1,8-naphthalimide and of CdSe/ZnS nanoparticles capped with this ligand in 1/1 toluene/MeCN (v/v) solution [58]. The ligand displays an irreversible, thiol-localized oxidation at largely positive potentials and an essentially reversible couple at ca. 1.8 V vs. Fc+/Fc, ascribed to the reduction of the carbonyl unit. This couple is considerably diminished in the naphthalimide-capped QD and is accompanied by a series of additional voltammetric features which can be assigned to the QDs signals, formally represented in terms of the CdSe/Se (oxidation) and CdSe/Cd (reduction) couples. Figure 8 permits to observe intermediate signals accompanying extreme QD signals defining the electrochemical band gap. Such signals have been interpreted in terms of charge transfer processes involving defect states of the QDs. Intermediate oxidation processes would correspond to cappingmediated electron release from defect sites of the QDs, whereas intermediate reduction would correspond to the electron transfer to empty energy levels of the QD. Interestingly, the separation of the intermediate QD-localized voltammetric peaks relative to the extreme QD peaks appears to be coincident with the position of the different trap energy levels for the different types of defect sites reported in the literature [59]. However, the relative intensity of the intermediate peaks is clearly capping dependent, so that the role of the ligand would be, to some extent, the “activation” of the trap states [58].

Electrochemical Characterization of Nanoparticles The oxidative dissolution of metal nanoparticles is also a size-dependent process, so that the standard electrode potential for the oxidation of, for instance, Ag nanoparticles, EoM,NP, differs from that for the oxidation of the bulk metal, EoM,bulk, by one term including the surface tension, s; the molar volume, vM; the lowest valence state, z; and the nanoparticle radius, r [60, 61]:

Page 10 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

5

calculated experimental

e

4

I / μA

a

b

c

d

3

2 1 0 0.6

0.7

0.8

0.9

1.0 E/ V

1.1

1.2

1.3

1.4

Fig. 9 Experimental (circle) and calculated (triangular) voltammograms of the gold particles electrooxidation in 0.1 M HCl; potential scan rate 50 mV/s. Calculation parameters: Q = 10.07 mC, d = 1 (a); Q = 11.30 mC, d = 1 (c); Q = 14.57 mC, d = 1 (b); Q = 49.42 mC, d = 0.3 (d) [65] (Reprinted with permission from Brainin et al. [65]. Copyright (2011) American Chemical Society)

EoM, NP ¼ E oM, bulk  2zvM =zFr

(6)

Recently, Brainina et al. have proposed a size-dependent model for the oxidative dissolution of metal nanoparticles based on the above considerations, showing an excellent agreement with experimental data [62–65]. Here, the peak profile for metal nanoparticle oxidation is made dependent on the fraction of particles of a certain size, d, and the surface tension of gold on the boundary with air. An excellent agreement was obtained between theory and experiment, as shown in Fig. 9. It should be noted that, in general, electrochemical oxidation of metal nanoparticles can lead not only to metal ions in solution but also to the formation of metal oxides via, in the case of Pt, the following processes: Pt ! Pt2þ ðaqÞ þ 2e

(7)

Pt þ H2 O ! PtOðsÞ þ 2Hþ ðaqÞ þ 2e

(8)

The electrochemical stability under “thermodynamic” conditions would be size dependent, so that particle size-dependent potential vs. pH diagrams such as in Fig. 10 can be constructed [67]. Compton et al. have provided theoretical modeling of charge diffusion on the surface of immobilized spherical particles [67], voltammetry at random microparticle arrays [68], and dissolution of microparticle arrays [69] and nanoparticle detection [70]. Direct oxidation of the Ag nanoparticles during collision events was monitored by the presence of a spike under oxidative current. The onset potential of the spike changes with the potential and can be used to determine the size of the nanoparticle. This method can be used to identify Ag NPs (onset spike potential vs. anodic stripping voltammetry of the NPs) and to analyze their size by taking into account the charge passed per current spike [70]. Surface agglomeration of Ag nanoparticle has been recently described using the anodic stripping voltammetry. New analytical expressions were reported for the stripping voltammetry, and they demonstrate that the oxidation peak potential for the stripping of the metallic nanoparticle should be below the formal potential for the oxidation. Changes in the response of the stripping peak potential as a function of the surface coverage give information about the nanoparticle

Page 11 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014 1.5 Pt2+

E (V) NHE

1

0.5

A’

−1

PtO

B’

0

−0.5

C’

Pt Planar surface D = 10.0 nm D = 3 nm D = 2 nm D = 1.5nm D = 1.0 nm

4

0

8

12

16

pH

Fig. 10 Particle-size-dependent potential-pH diagram for Pt/106 M, Pt2+ [66] (Reprinted with permission from Tang et al. [66]. Copyright (2010) American Chemical Society)

distribution and can be related to the surface agglomeration of the NPs [71]. Electrodeposition of monolayers [72] or multilayers [73] of a second metal on a metal nanoparticle has also been reported. Bard et al. [74] have proposed a new and simple methodology for the study of the nanoparticles at the single particle level (single-molecule electrochemistry). It is well known that only few electrons can be transferred between the nanoparticle and the electrode, and consequently, a small current can be determined, resulting in a small signal that can be confused with the background noise. The proposed methodology is based on the large current amplification (“staircase”) generated in an electroactive redox probe whose oxidation or reduction is catalytically enhanced at nanoparticulate films on electrodes. This methodology has been applied to the reduction of proton and hydrogen peroxide at very low concentrations as well as to the oxidation of hydrazine occurring in Pt nanoparticle solutions. The electrocatalytic effect occurs (see scheme in Fig. 11) when the nanoparticles collide with the inert electrode [75]. These single nanoparticle collisions are characterized as current transients (electrocatalytic amplification) and are used to estimate the nanoparticle size. Single IrOx nanoparticles can also be detected on the basis of the increase of the signal (“spike”) produced when the IrOx nanoparticle and the Pt electrode are in contact for the hydrogen production, which does not occur in absence of the nanoparticle [76]. Stochastic electrochemistry with metal and

H2O

H2

Electrode

Fig. 11 Electrochemical water oxidation in the nanoparticle surface occurs when the nanoparticles are in contact with an electrode Page 12 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

a QD annihilation-based ECL CB VB anode

cathode

QD - e

QD

QD + e

QD

QD + QD

QD* + QD

+

QD*

b coreactant-based ECL cathodic

cathode

anode

QD

CR + e

SOx

QD + SOx

CR CR

CR

CR

QD + e

QD*+SF

CR: S2O82–, O2, CH2Cl2 anodic

SOx

SRed SF

SF

QD – e

QD

CR – e

SRed

QD + SRed

QD*+SF

CR: Pr3N, (But)2NCH2CH2OH, SO32– QD*

Fig. 12 Schemes for (a) annihilation-based and (b) coreactant based ECL

metal oxide nanoparticles at inert electrodes has been modeled in terms of NP collisions, differing from the usual model for ensemble-based electrochemical behavior [77]. The role of counterions into the electrochemical response of gold nanoparticle on a monolayer films has been reported. Electrochemical charging was observed with small counterions like BF4, ClO4, and PF6 and not with larger ones as bis(trifluoromethylsulfonyl)amide Tf2N, among others. This has been explained as due to the proximity of the counterion to the monolayer-protected layer (MPC) that allowed the alkanethiolate to get charge compensation, and this was propose as a new way to modulate the electronic-charging response of the film [78]. Monolayer metal deposition at the electrochemical interface has proved the halide–metal interaction [79].

Page 13 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

F

ECL

F

ECL

Fig. 13 Schemes for band gap-based ECL (left) and surface state-based ECL (right)

Electrochemiluminescence and Spectroelectrochemistry Electrochemiluminescence (ECL) consists of the radiative deactivation of excited states that have been generated electrochemically. In QDs, this process can occur via an annihilation process involving only QD radical ions (QD-annihilation-based ECL), or it can require a coreactant (coreactant-based ECL), both schematized in Fig. 12. In QD-annihilation-based ECL, under electrochemical conditions, an individual QD can accept an electron in its conduction band while another donates an electron from its valence band, thus leading to the QD radical anion/QD radical cation couple (QD/QD+). Subsequent collision of the radicals produces the ground state of one of them and the excited state (QD*) of the other, which finally reaches the ground state after emitting light. The stepwise removal or addition of charge from QDs by an electrochemical method can give information on the energy needed for electron transfer and, consequently, for ECL emission. This type of electrochemiluminescence has been exhibited by QDs with a superlattice structure, but it has not been detected in QDs capped with electrochemically inert ligands, such as mercaptoalkanes. In coreactant-based ECL, a coreactant (CR) and a QD can be electrochemically reduced, eventually leading to an oxidized species (SOx) and QD, and then the SOx/QD couple reacts to lead to an unreactive product (SF) and the QD excited state (QD*), which partially decays via a radiative process. Alternatively, the CR and the QD are electrochemically oxidized, eventually leading to a reduced form (SRed) and QD+ and then the SRed/QD+ couple reacts yielding QD*. These processes are further classified as cathodic- and anodic-based ECL depending on the role of the CR as an oxidant or reductant, respectively, that will rely on the oxidation or reduction potential of the resulting SOx or SRed intermediate. The coreactant-based ECL possesses several advantages over the QD annihilation-based ECL, in particular when either the QD radical cation or the radical anion is not quite stable or the electrode or the solvent has a narrow potential window so that neither of these radical ions can be generated. The coreactants can be (i) amines, such as tri-n-propylamine and triethanolamine); (ii) peroxides, such as O2, H2O2, S2O82; (iii) other species like SO32, CH2Cl2; and (iv) other nanoparticles. A number of considerations have to be taken into account for choosing the right coreactant, such as its solubility, stability, electrochemical activity, direct ECL, as well as suitability to be easily oxidized or reduced at or near the electrode and its capacity to leading rapidly to the corresponding reactive intermediate. There are a considerable number of examples of ECL in QDs such as CdSe, CdS, and CdTe. It has been recently demonstrated that water dispersible, blue-luminescent graphene QDs exhibit an ECL behavior similar to CdSe QDs. These QDs present anodic ECL when using H2O2 as the coreactant, and this emission is strong and appears at low potential (ca. 0.4 V vs. Ag/AgCl) [80]. The ECL emission can originate from recombination of an electron and a hole at the conduction and valence band edges of the QD core, respectively, and it matches the band-edge fluorescence and is size dependent. Alternatively, the ECL can involve transition levels caused by defect states at the QD surface, and, consequently, energy relaxation and recombination dynamics in QDs strongly Page 14 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

electrolyte

CB

ktrans1

krel

EFermi kpot

ktrans2

krec trap state

kr trap state knr

VB

Fig. 14 Schematic representation of the plausible processes occurring after QD illumination under potentiostatic control

depend on passivation of the QD surface (Fig. 13). Consequently, the QD ECL can be classified as band gap based or surface state based. Because electron/hole injection in QDs is assumed to occur via the surface states, the surface state-based ECL has been considered as the main process for QD ECL, but there are increasing reports showing that QDs can exhibit band gap-based ECL or both types of ECL, the contribution of the first increasing by progressive passivation of the QD surface. In addition, it has to be taken into account that the introduction of coreactants can have an impact on surface state-based QD ECL and a “dual peak” can appear. Metallic nanoparticles can be used to improve the ECL performance of QDs due to their excellent conductivity. Thus, they can reduce the electron-relay barrier between the QD and the electrode, accelerating the electron/hole injection, thus enhancing ECL intensity and moving ECL onset and the peak potential toward zero. For example, ECL of CdS–CdSe QDs was drastically enhanced by placing a large number of silica-coated AuNPs on their surface [81]. Furthermore, silver and gold nanoclusters can also exhibit their own ECL. Metal nanoclusters differ from their corresponding nanoparticles in that the continuous density of states breaks into discrete energy levels and as a consequence they can exhibit molecule-like properties, such as luminescence. Thus, nanoclusters with a small number of Ag atoms can show a considerable fluorescence quantum yield as well as ECL under strong cathodic polarization using K2S2O8 as the coreactant. The ECL spectrum of the nanoclusters matched that of their photoluminescence [82]. In the case of gold, Au25 nanoclusters protected by bovine serum albumin can exhibit ECL by using triethylamine as the coreactant, but in this case the ECL spectrum matched the surface-state fluorescence that appeared as a weak shoulder on the main peak in the Au25 nanocluster fluorescence spectrum [83]. By contrast, the ECL spectrum of similar Au25 nanoclusters immobilized on hydroxylated indium tin oxide (ITO) and using K2S2O8 as the coreactant was similar to that of the photoluminescence spectrum [83]. These optical spectroelectrochemistry techniques have been recently used to obtain information on the relationship between the emissive properties of QDs and their intrinsic structure features. Thus, the absolute energetic position of trap levels can be determined by using an electrochemical method which is particularly useful for QD electrodes [84], once the energy of the bandgap edges is known. It consists of the control of the population of the energy states involved in fluorescence by potentiostatic control of the Fermi level in the material, thus enhancing or quenching the fluorescence depending on the energy state involved (Fig. 14). It should be emphasized that semiconductor materials possess defect states that originate from substitutional and interstitial impurities,

Page 15 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Type-B blinking 1Pe k intra

1Se

k intra knr and kr > krec an increase in the surface-state emission would be observed. As a result, it was demonstrated that the green fluorescence of thin films of ZnO QDs is caused by a transition from an upper trap level, at 0.35  0.03 eV below the conduction band edge, to a deep trap within the bandgap and that the position of this upper level shifts with the size of the QD in the same way as the conduction band. Although this did not happen in these QDs, this method could alternatively induce the quenching of the QD fluorescence by applying more negative potentials than that of the upper trap level via competitive population of a deep, electron-acceptor trap-state (ktrans2), if this process is fast enough. In addition, optical spectroelectrochemistry techniques have been applied to obtain information on the basis of QD photoluminescence blinking, which is a random switching between states of high (ON) and low (OFF) emissivities. The OFF periods are often explained by using a charging model Page 16 of 25

ele c co tro n d de an uct tig ing en b rid ge

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

analyte

antibody

QDs/carrier

ECL

Fig. 16 Scheme for ECL immunoassays based on labeling of biological molecules

(additional charge causing photoluminescence quenching by non-radiative recombination, Auger mechanism). However, time-resolved photoluminescence studies of individual QDs have been carried out by controlling the QD charging electrochemically and suggest that there are two types of blinking (i) A-type blinking (Auger mechanism) in which the lower photoluminescence intensity is accompanied by a short luminescence lifetime and (ii) B-type blinking, due to charge fluctuations in the electron-accepting surface states, in which the lower emission is not accompanied by a significant change in the QD emission lifetime. In B-type blinking, unoccupied surface states intercept hot electrons before they relax into emitting core states (Fig. 15). Both blinking mechanisms can be suppressed by application of the appropriate potential. These types of studies have been conducted on single CdSe/CdS QDs, by performing timetagged, time-resolved, single photon counting measurements in a three-electrode electrochemical cell. At E = 0 V and E = +0.8 V, periods of low luminescence intensity and a considerable shortening of lifetime was observed. These effects can be attributed to a low Fermi level, increasing the relative time spent by the trap in the unoccupied state, and consequently having the capacity of trapping hot electrons which eventually recombine non-radiatively with a VB hole, thus resulting in a neutral QD. These B-type blinking events usually coexist with A-type fluctuations. For negative potentials (E = 1 V), the fluorescence lifetime was typical of a neutral exciton, but the blinking was suppressed by increasing the energy of the Fermi level that led to population of the trap states. At more negative potentials, the photoluminescence decay became biexponential and the QD lifetime was drastically reduced. This has been attributed to charging the QD with extra electron and emission from negative trions. The different origin of A- and B-type blinking of QDs became patent by increasing the shell thickness. While type-B blinking is reduced and even suppressed, by adding an incrasing number of shell monolayers, A-type can still be detected in the case of highly thick shells. Interestingly, it has been shown that hollow spherical CdSe assemblies generate intense ECL using persulfate as the

Page 17 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

coreactant. The aggregation has a protective effect on the electrogenerated reduced species, facilitating a more competitive radiative charge recombination process [85]. Graphene-QD composites are being used increasingly for accelerating the electron transfer on the electrode surface and amplifying the ECL of QDs [86, 87]. Moreover, ECL immunoassays have become a smart analytical tool; they make use of ECL-active species as labels on biological molecules and of the high affinity of antibodies for their corresponding antigens (Fig. 16). Thus, it has recently been shown that ZnO nanospheres can be used to increase the loading of CdTe QDs, leading to QD/carrier nanocomposites with higher ECL intensity and better ECL stability than that of the CdTe QDs [88]. For the construction of the ECL immunosensor, the biomolecule is immobilized on a sensing surface (conducting bridge). For example, Au-Pt bimetallic nanoparticles are deposited on a glassy carbon electrode and the resulting nanocomposite is more effective than pure Pt nanoparticles for accelerating the electron transfer. Finally, upconverting nanoparticles (UCNPs), such as NaYF4/Yb3+,Er3+, are peculiar ECL nanoemitters, since they exhibit anti-Stokes fluorescence. Examples of UCNP ECL are rare, but recently UCNP@SiO2 core-shell nanohybrids modified with polyoxometalates have shown ECL dependence on the applied potential [89] whereas there are ECL biosensors whose sensing is based on the combination of ECL and energy transfer (ECL-ET). Thus, the ECL of CdSeTe/CdS/ZnS QDs can be modulated in the presence of Au nanorods and this strategy has been applied to build a sensitive ECL-ET based sensor of a biomarker [90].

Nanoparticles as Redox Mediators Electrocatalytic Effects Electrocatalysis has been performed by attaching nanoparticles to the electrode surfaces, forming different types of films/deposits/nanocomposites. The nanoparticle-modified electrodes have several advantages compared to bulk electrodes, such as fast electron transfer kinetics, lower overpotential, and enhancement of electro-active surface area, thus facilitating kinetically hindered redox reactions. Metal nanoparticles such as Pt, Pd, Au and Fe have demonstrated good electrocatalytic performance toward different electrochemical processes [91]. Electrochemical reduction of oxygen dissolved in aqueous electrolytes (oxygen reduction reaction, ORR) can be taken as a paradigmatic example of reactions catalyzed by metal nanoparticles [92]. The electrocatalytic effect exerted by gold nanoparticles on ORR depends on the shape and size of the NPs [93, 94], and the number of electrons exchanged during the ORR is dependent on the nanoparticle shape [95]. The efficiency of the catalytic process can be improved by combination with other nanomaterials and may be photochemically assisted. Semiconductor nanoparticles, such as TiO2, have shown interesting photoelectrocatalytic activity [91]. A plethora of multifunctional electro- and photoelectrocatalysts have been reported with applications in the fields of sensing, fuel cells, and water splitting. Among them are bimetallic nanoparticles with different core-shell compositions and architecture [95, 96] and nanocomposites of metal nanoparticles with semiconductor materials. In addition, both types of nanoparticles can be associated with other material, such as polymers or graphene to form nanocomposites which present catalytic and sensing applications, thus improving those displayed for the separated components. The electrocatalytic performance of metal nanoparticles on different kinds of graphite surfaces has recently been reviewed [96, 97]. Regarding the nanoparticle-polymer combination, nanocomposites

Page 18 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

Active site for hydrogen evolution

hν > Egap

C.B

H+

e– H2

Egap V.B O2

h+ Photocatalyst

H2O

Active site for hydrogen evolution

Fig. 17 Scheme for photoelectrocatalytic water splitting using semiconductor nanoparticles by means of the semiconductor liquid junction approach [102]

of poly(amidoamine)-encapsulated platinum nanoparticles and phosphotungstic acid have been used as an electrocatalyst for the hydrogen evolution reaction (HER) [98]. An important group of applications deals with photoelectrocatalytic water splitting where either photovoltaic cells or semiconductor-liquid junctions, or both, have been combined [99]. In general, water splitting can be achieved effectively when a cocatalyst is added together with the photocatalyst, for example, a metal and semiconductor nanoparticle [100, 101]. Figure 17 shows a scheme for the photoelectrochemical water splitting by means of a semiconductor-liquid junction cell. The photocatalytic activity of the process depends on the physicochemical properties of the photocatalyst, the nature of the active sites (usually known as cocatalyst), and the conditions of the reaction [102]. Another interesting application of electrocatalysis and photoelectrocatalysis is that of removing of organic pollutants via electrooxidation. Among different compositional and architectural varieties, Cu2O/TiO2 composite nanotubes improve the separation of photogenerated electrons and holes so that Cu2O/TiO2 heterojunction photoelectrodes exhibit a more effective photoconversion capability than TiO2 nanotubes alone for oxidative degradation of pollutant probes [103]. Multifunctional photocatalysts are receiving considerable attention because of their potential ability for promoting oxidation and reduction processes simultaneously. In particular, metal and semiconductor nanoparticles have been anchored to different carbon nanostructures, such as single or multiwall carbon nanotubes and graphene oxide/reduced graphene oxide. Reduced graphene oxide has been used as a two dimensional support for semiconductor nanoparticles like TiO2 on one side of the material and the metal ions on the other. After light irradiation the electrons generated in the semiconductor are transported through the graphene to reduce silver ions into silver nanoparticles localized on the other side of the material [104, 105].

Sensing at Nanoparticulate Films and Composites Electrocatalysis can also be used for sensing purposes. The development of an electrochemical sensor has the following steps (i) synthesis of the nanoparticle, (ii) modification of the electrode with the nanoparticles, and (iii) characterization of the nanoparticle-modified electrodes. After the synthesis of the nanoparticle, following well-known methodologies, the electrode surface should be modified with those nanoparticles using different physical or chemical techniques, such as a simple mixture of the NPs with additives (enzymes), solvent evaporation, chemical covalent bonding, NP growth in the sol–gel network, electro-aggregation, and so on. Electrodeposition of Page 19 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014 hν1

ET

a

b Current

A e–

ET

FR

h+

b

c

F hν3

hν2

Fig. 18 Schematic representation of a QD-based sensor using: (a) electron transfer to an acceptor molecule, (b) photocurrent generation, (c) fluorescence, and (d) FRET

the nanoparticle on the electrode surface seems to be one of the most used techniques due to their simplicity; however, one limitation is the size distribution of the NP, which depends on the deposition time, deposition potential, electrolyte solution and salt concentration, and the non-uniform distribution of the nanoparticles on the electrode. The previous modification of the nanoparticle surface can overcome this problem. The functionalization of nanoparticles with molecules or biomolecules plays a key role in their sensing applications because the functionality can induce changes on the photophysical properties of the nanoparticle and modify their immobilization on the electrode [106, 107]. For instance, the organothiolate capped Au25 nanoparticle clusters have good electrocatalytic activity toward the electrochemical oxidation of ascorbic and uric acids, where Au25 plays a dual role as an electronic conductor and redox mediator. Electron transfer studies showed a correlation between the electronic conductivity of Au nanoparticles and the sensing sensitivity. The proposed mechanism is initiated by the oxidation of Au25 NPs, the oxidized form producing the electrocatalytical oxidation of the analyte and the generation of Au25, which increases the anodic current as the analyte concentration increase. The electrocatalytic activity of the Au25 NPs has been attributed to the electron-deficient Au12 shell and to the low-coordinated surface gold atoms [108]. Direct DNA detection is usually obtained following the redox behavior of bases or sugar residues; however, indirect detection can be determined by using nanoparticles. The DNA hybridization sensing has been studied from the electrochemical detection of DNA by the catalytic silver cluster formed on the DNA strand. The Ag+ ions on the immobilized DNA are subsequently reduced by hydroquinone to form the aggregates that after acidic solution addition are solubilized and detected by stripping potentiometric detection. This is a powerful electroanalytical technique for trace metal measurements, attributed to the built-in preconcentration step as a consequence of the metal accumulation in the working electrode. Detection of DNA, protein, and biomolecules of interest by using enzyme-nanoparticle hybrids has also been reviewed [109]. In addition, enzyme/protein –nanoparticle based sensors have also been used for sensing of small molecules, such as peroxide, colesterol, glucose, phenolic compounds, gallic acid, and others. Moreover, the detection of gaseous components that can be responsible of air pollution, such as H2S, ozone, H2, NOx, NH3, is currently receiving a great interest. Chemical modification of nanoparticles can help to prepare nanoparticlemodified electrodes for gas sensing [110]. Also relevant is the detection of biological systems used

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-1 # Springer International Publishing Switzerland 2014

for clinical diagnostic (cancer biomarkers, proteins, bacterias, and cancer cells) by using sensors based on gold nanoparticles [111]. Nucleic acid/semiconductor nanoparticle hybrid systems have been used for optical and electrochemical sensing taking advantage of the recognition and catalytic properties of nucleic acid and the photophysical properties of QDs [112]. The strategy of detection can be based on different mechanisms, such as fluorescence resonance energy transfer (FRET), chemiluminiscence energy transfer, electron transfer, among others (Fig. 18). In general, the design of polyelectrolyte gold nanoparticule composite films requires to consider the following factors (i) the nanoparticle film density, (ii) the electronic inter-nanoparticle coupling and also between the film assembly, (iii) the analyte accessibility within the film to the electrode, and (iv) the stabilizer layer of the nanoparticle [113]. Interestingly, synergetic effects obtained in a variety of nanocomposites involving different kinds of nanoparticles, for instance, graphene-Au nanoparticles [114], are extensively studied for sensing purposes. These include a variety of nanoarchitectures (core and core@shell nanoparticles, nanorods, nanowires, etc.) able to be deposited on inert electrodes displaying voltammetric and amperometric sensing with enhanced sensitivity and selectivity with respect to the unmodified electrodes. Similar strategies are being developed in the case of quantum dots, accompanied by functionalization and doping [115], with applications in biochemical [116], and biomedical [117] analysis. Nanoparticle modified-electrode is a promising methodology in electrochemistry for future miniaturization of opto-electronic and for the development of electrochemical bio-nanochip. More specific and selective sensors would benefit from the design of new hybrid materials and better understanding of the detection principle and performance of electrochemical techniques.

Conclusion Metal and semiconductor nanoparticles possess distinctive electrochemical and photoelectrochemical responses that differ from those of their macroscopic equivalents. Electrochemical techniques can give significant information on the structure, composition, and quantum confinement effects of microparticulate systems reflected in different electrochemical regimes. Voltammetric features provide information on bandgap energy, the position of conduction and valence band edges, and defect sites of the nanoparticulate systems, as well as on the inter-particle interaction and binding to capping ligands. Electrocatalytic and photoelectrocatalytic phenomena involving metal nanoparticles and quantum dots, as well as different nanostructured materials with a variety of architectures, can be used for a variety of applications from water splitting to removal of pollutants and they are extensively used for electrochemical sensing. In summary, both from the fundamental and applied point of view, the electrochemistry of nanoparticulate systems can be considered as an important research field whose expansion will probably continue during the next years.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Electrochemistry of Metal Nanoparticles and Quantum Dots Antonio Doménech-Carbóa*, Raquel E. Galianb, Jordi Aguilera-Sigalatb and Julia Pérez-Prietob a Departamento de Química Analítica, Universidad de Valencia, Burjassot, Valencia, Spain b Instituto de Ciencia Molecular (ICMol), Universidad de Valencia, Paterna, Valencia, Spain

Abstract Metal nanoparticles, with a wide range of applications in catalysis and sensing, have structural and electronic properties that differ from those of their bulk macroscopic counterparts. Electrochemical techniques are of particular interest in the study of metal nanoparticles because electrons may undergo quantum confinement effects which are reflected in their electrochemical behavior, resulting, ultimately, in three distinguishable voltammetric regimes: bulk continuum, quantized double-layer charging, and molecule-like. Similarly, semiconductor nanoparticles (quantum dots, QDs) are receiving considerable attention due to their high fluorescence, which makes them of interest for biological and medical applications, among others. The semiconductor bulk materials possess defect states that originate from impurities, divacancies, or surface reactions as a result of their synthesis. Voltammetric features provide information on bandgap energy, the position of conduction and valence band edges, and the position of defect sites as well as on the interaction with the capping ligand. This chapter is devoted to provide a critical view of the current state of the art in the electrochemistry of such systems.

Keywords Electrochemical techniques; Metal nanoparticles; Quantum dots; Electrocatalysis

Introduction Metal and semiconductor nanoparticles, nanowires, nanopores, and other systems of dimensions at the nanometric scale have structural and electronic properties that differ from those of their bulk macroscopic counterparts. The study of the electrochemistry of such systems, i.e., that of the processes involving interfacial charge transfer between nanosized systems and electron-conducting electrodes, possesses a great importance by either its ability to yield relevant information on the structure and composition of nanoparticulate entities and their applications in catalysis and sensing [1, 2]. Here, the attention will be focused on nanoparticulate systems constituted by a core of metal atoms, surrounded or not by a coating of metal compounds, and stabilized by a monolayer (capping) of organic ligands that prevent agglomeration. The electrochemistry of nanoparticulate films, nanoelectrodes, and nanopores will be treated only tangentially. In principle, the term nanoparticle electrochemistry refers to that of metal and semiconductor colloids, also termed colloidal microelectrodes [3, 4], differing from conventional colloids by their ability to act as electron donors and acceptors [5, 6]. Typically, the electrochemistry of solutions of

*Email: [email protected] Page 1 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Table 1 Earlier insights into the development of nanoparticles electrochemistry Matter Electron donor/acceptor properties of metal and semiconductor colloids Metal nanoparticles and water splitting Stabilizing nanoparticles by means of organic ligands Role of metal and semiconductor colloids as redox mediators Quantum dots Modeling molecular capacitance Chemical linking of metal nanoparticles to electrodes Bulk-continuum voltammetry of metal nanoparticles Quantized double-layer charging of metal nanoparticles Quantum confinement effects Electrodeposition of metal nanoparticles

Citation(s) Henglein [5]; Kiwi and Gr€atzel [6] Miller et al. [11] Schmid et al. [12] Henglein [4] Bawendi et al. [13] Weaver and Gao [14] Chumanov et al. [15]; Grabar et al. [16] Ung et al. [17] Ingram et al. [18] Chen et al. [19] Finot et al. [20]

metal nanoparticles and quantum dots in electrolytes is studied by means of voltammetric methods. Several general aspects should be underlined [7, 8]: (a) The voltammetric response of the nanoparticulate systems can be superimposed to that of electroactive ligands. (b) Measurements can be performed both on nanoparticulate solutions (or dispersions) and on thin films of nanoparticles deposited on the electrode surface. (c) In contrast with, for instance, spectroscopic techniques which provide information on the “bulk” nanoparticle composition, electrochemical methods mainly probe the surface properties of those systems [9, 10]. (d) There is a number of applications for sensing, photoelectrochemical functional devices, electrosynthesis, anticorrosion, and environmental remediation, involving nanoparticulate systems with different nanoarchitectures and/or involving different types of functionalization and/or forming a variety of nanocomposites. The earlier historical development of nanoparticle electrochemistry can be summarized in a series of insights, some of which are listed chronologically in Table 1. Nanoparticles electrochemistry can be viewed as a new field located at an intermediate-size scale between molecular electrochemistry and solid state electrochemistry [21]. Figure 1 shows a schematic view of the position of nanoparticle electrochemistry and its previously mentioned aspects.

Electrochemical Techniques Conventional electrochemical techniques have been used in the chemistry of nanomaterials to characterize the nanomaterial surface. Electrochemical techniques are particularly interesting by their capability of yielding information by using standard instrumentation. Regarding to the sample experimental condition, the electrochemical measurements can be done in a colloidal solution or in a film. In the first case, the in general low solubility of the nanoparticles in the media reduces the electrochemical signal and the sensibility of the system. The deposition of the nanoparticles on the electrodes has been used to overcome this problem [7]. In general, electrochemical techniques are used for analytical purposes, but they can also be used for preparative ones, for instance, for electrodeposition of nanoparticles on substrates [22] and liquid–liquid interfaces [23]. Page 2 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Molecular electrochemistry

Solid state electrochemistry

Electrochemistry of macromolecules and supramolecular aggregates

Electrochemistry of colloidal systems

Nanoparticles electrochemistry

Metal nanoparticles

Semiconductor nanoparticles

Nanoarchitecturees (core@shell, nanorods, etc.), functionalization, etc.

Nanoparticles in solution

Nanoparticlemodified electrodes

Fig. 1 Scheme of possible relationships among topics typically involved in nanoparticles electrochemistry

Electrochemical methods Static

Dynamic

Electrochemical impedance spectroscopy

Coulometry

Electrochemical noise

Chronoamperometry and chronocoulometry

Potentiometry

Voltammetry

Electrochemiluminiscence

Spectroelectrochemistry

Electrochemical imaging techniques (SECM)

Hyphenated techniques (AFM, XRD)

Fig. 2 Scheme illustrating the main electrochemical techniques used in nanoparticle electrochemistry

The most used electrochemical techniques can be divided into static and dynamic, depending on the type of electrochemical processes occurring at the electrode/electrolyte interface. As summarized in Fig. 2, the main static methods are potentiometry, electrochemical noise, and impedance measurements (electrochemical impedance spectroscopy in particular). Dynamic methods involve faradaic processes recorded by means of coulometry, chronoamperometry, chronopotentiometry and, particularly, voltammetry. Chronoamperometric and chronocoulometric techniques can be used conjointly with voltammetric ones, whereas electrochemical impedance spectroscopy is of

Page 3 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

application in the analysis of microparticulate films. Several static and dynamic techniques can be hyphenated with optical (X-ray diffraction, spectroelectrochemistry) and microscopy imaging techniques such as atomic force microscopy (AFM). In the particular case of semiconductor quantum dots, the most used electrochemical techniques can be grouped into voltammetric (cyclic, differential pulse, square wave voltammetry), electrochemiluminescence, and spectroelectrochemistry [8]. Electrochemical imaging techniques are increasingly used to study nanoparticle films on electrodes. The scanning electrochemical microscopy technique (SECM), developed by Bard et al. [24], uses a tip microelectrode as a local probe providing spatially resolved information on the redox reactivity of surfaces and has been used for measurement on electron transfer dynamics [25] and local deposition of nanoparticles [22, 26]. Recent developments involve the use of optical signals of the electrode, namely, surface plasmon resonance [27], and combination with AFM in order to probe individual metal nanoparticles [28]. Spectroelectrochemistry techniques combine spectroscopic and electrochemical methods, thus facilitating the interpretation of electron transfer reactions. For example, they can give valuable information in photoinduced electron transfer processes by providing static-state products analogous to those that are generated in transient spectroscopy. Among the spectroscopic techniques, the steady-state and time-resolved optical ones are having a special relevance in nanoparticle spectroelectrochemistry. For these measurements, the electrochemical cell, housing a working, a reference, and a counter electrode, is designed to be simultaneously used for electrochemistry and spectroscopy, and consequently, the spectra are recorded while the potential is stepped to a desired value. Thus, the design of the cell for electrochemiluminescence is such that it can be inserted into the sample compartment of an emission spectrophotometer.

Electrochemical Behaviors Quantum Confinement Effects In a solid metal or semiconductor material, electronic energy levels are distributed forming quasicontinuum bands. When the size of the particle is reduced to few nanometers, quantum confinement effects appear and the band structure of the semiconductor changes into discrete levels. As a result, the optical and electrical properties become dependent on its physical dimension; in particular, the electrochemical response becomes size dependent. For our purposes it is pertinent to remark that electronic levels separate into conduction and valence bands and the energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) widens as the particle size decreases [29–31]. This yields an energy gap which can be optically and/or electrochemically detected (vide infra). Then, the nanoparticulate system behaves similarly to semiconductor electrochemistry. Figure 3 shows a schematic representation of the basic electron transfer processes between an electron-conducting electrode and a nanoparticle having a band gap. Electrochemical reduction processes can be described as the injection of an electron from the Fermi level of the metal electrode to the conduction band of the particle. Electrochemical oxidation can be represented by an extraction of an electron from the valence levels of the particle to the Fermi level of a metal electrode. This process can be considered as similar to the injection of a hole into the valence band of the nanoparticle. Roughly speaking, there is a continuous-like transition from the metal (or semiconductor) “bulk” state to the molecule-like behavior, so that following Murray [7], three electrochemical regimes can be differentiated by means of voltammetric methods, namely, bulk continuum, quantized doublelayer charging, and molecule-like. When the organic ligand monolayer of the nanoparticles contains Page 4 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

eNanoparticle Nanoparticle eFermi level

Fermi level

Electron-conducting electrode

Electron-conducting electrode

Fig. 3 Schematic representation of electrochemical processes involving nanoparticles. Left: injection of an electron from the Fermi level of the metal electrode to the conduction band of the particle; right: electron extraction from the nanoparticle to the Fermi level of a metal electrode (equivalent to the injection of a hole into the valence band of the nanoparticle)

Metallic continuum

Molecule-like behavior

Metal-like quantized charging

0.2 eV Au225

0.3 eV

0.7 eV

1.2 eV

1.8 eV

Au140 Au75 Au38 Au13

Fig. 4 Schematic representation of the variation of the electrochemical response of Au nanoparticles showing optical HOMO-LUMO energy gaps (Adapted from Ref. [7] using data from Refs. [14, 32–37])

electroactive groups, the electrochemical response of such groups can be recorded, thus incorporating additional signals to the voltammetry response of the nanoparticulate system. Figure 4 shows a schematic representation for the shift from the continuum electrochemical response to the molecule-like behavior for Au nanoparticles [7, 14, 32–36]. In the case of semiconductors, the bandgap of the bulk material can be increased by nanostructuring the material via quantum confinement effects, and the band-edge energies can be subsequently tuned by passivating the surface with dipolar ligands [37].

Page 5 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Fig. 5 Differential pulse voltammetry of 0.07 mM ethanol-soluble hexanethiolate-MPCs at (a) 279 and (b) 230 K in dichloromethane/0.05 M Bu4NClO4 at 1.6-mm diameter Pt working electrode, Pt coil counter electrode, and Ag wire quasireference electrode (0.05 V pulse, 50-ms pulse width, 200-ms period, 0.02 V/s scan rate) [40]. The asterisks mark the peaks used for determining the capacitance of the nanoparticles (Reprinted with permission from Miles and Murray [40]. Copyright (2003) American Chemical Society)

Bulk-Continuum Response The bulk-continuum behavior is typical of nanoparticles having sizes larger than 3–4 nm. Such systems behave as capacitors with double-layer capacitance CNP, directly related to the change in electrochemical potential (DV) associated to the transfer of z electrons from/to the nanoparticle to/from the electrode: DV ¼ ze=C NP

(1)

If DV is of the same order of magnitude or lower than the Boltzmann thermal energy distribution factor (kBT), successive electron transfers from/to the particle will result in a continuous change in the particles potential. In these circumstances, the capacitive charging currents are under mass transport control and can be distinguished from double-layer charging and faradaic reactions at the electrode/electrolyte interface using conventional chronoamperometric, chronocoulometric, and/or rotating disk voltammetric experiments. In the case of Ag nanoparticles capped with polyacrylic acid, application of anodic potentials produced currents for the oxidative dissolution of nanoparticles (vide infra) while applying negative potentials yields featureless, progressively rising currents under mass transfer control so that for sufficiently negative potentials ca. 1,600 electrons/ nanoparticle were transferred, corresponding to a capacity of 80 mF/cm2 [37], clearly higher than those typically obtained at conventional metal electrodes under equivalent conditions.

Page 6 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Quantized Double-Layer Charging This electrochemical regime is characterized by the record of multiple peak features corresponding to quantized double-layer charging. First reported by Ingram et al. [18], these features have been intensively studied, as can be seen in recent reviews [38, 39]. A typical example can be seen in Fig. 5, where differential pulse voltammograms for monolayer alkanethiolate-protected Au nanoclusters at different temperatures are shown [40]. The voltammogram consists of a series of peaks almost equally spaced, which can be attributed to quantized charge processes [41]. Such systems can be described as a concentric spherical capacitor assuming that the metal core, of radius r, is surrounded by a monolayer of capping (typically, thiolate compounds) of thickness d, of effective dielectric permittivity e. The capacity of this system is r C ¼ 4pe ðr þ d Þ d

(2)

Charging processes can be viewed as sequential reversible one-electron transfers on metal nanoparticles, M, represented as Mn þ e ! Mn1

(3)

where n = 0, 1, 2, etc. The simplest theoretical approach considers the metal nanoparticles to be a conducting sphere with the energetics of electron addition determined by classical electrostatics [14, 42, 43]. This model predicts the appearance of identical voltammetric waves corresponding to the successive transfer of electrons giving rise to successive z, z1, z2, etc., charge states [44, 45]. The formal electrode potential of the z/z1 charge state change is given by E oz, z1 ¼ E PZC þ

ðz  1=2Þe C

(4)

where EPZC is the potential of zero charge for the nanoparticle core. Deviations from the expected uniform potential spacing between voltammetric peaks appear at high charge states and are dependent on the solvent, on the electrolyte composition, and, in particular, on the length of the alkanethiolate chain [41]. These features can be mainly attributed to the variations in the permittivity of the capping monolayer. The peak spacing is also conditioned by the length and flexibility of the protecting (typically alkanethiolate) molecules, allowing for a more or less profound penetration of the solvent between them. Apart from the above effects, diffuse layer effects associated to the Helmholtz double-layer surrounding the nanoparticles also influence the observed peak spacing [32]. Supporting electrolyte anion-dependent effects can be interpreted as the result of different ion-pairing effects [46]. Ultimately, the incipient influence of the moleculetype response can also distort the uniform peak spacing response. Doublet oxidation peaks, a typical feature of electron transfer at molecular species, often appear, but the interpretation of such features still remains controversial [47, 48].

Molecule-Type Behavior For sufficiently small nanoparticles, there is an energy bandgap which can be detected, but not equivalently, by means of optical and electrochemical measurements. The optical band gap, DEop, corresponds to transitions between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), detectable as absorption band edges in the visible or nearinfrared region. The electrochemical energy gap, DEel, is the difference between the electrochemical Page 7 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015 0.06

a

0.04 0.02 0.00 −0.02

I (mA)

−0.04 CV DPV

0.04 0.03

b

0.02 0.01 0.00 −0.01 −0.02 −0.03 −0.04 −1.5

−1.0

−0.5

0.5 1.0 0.0 E (V vs Ag/AgCl)

1.5

2.0

Fig. 6 Cyclic (CVs) and differential pulse voltammograms (DPVs) of Au11Cl3(PPh3)7 nanoparticles before (a) and after (b) exchange reactions with n-dodecanethiols at a Pt microelectrode (25 mm). The particle solutions were prepared in CH2Cl2 with 0.1 M TBAP at a concentration of 0.5 mM (a) and 1.2 mM (b), respectively. CV potential scan rate 20 mV/s; in DPV measurements, dc potential ramp 20 mV/s, pulse amplitude 50 mV. Arrows indicate the first positive and negative voltammetric peaks [49] (Reprinted with permission from Yang and Chen [49]. Copyright (2003) American Chemical Society)

potentials for the first oxidation and first reduction wave for a parent species. The electrochemical bandgap is in general in good agreement with the difference between them, increasing the importance of the quantum confinement effects (i.e., for small particles), resulting in an increased Coulombic electron–hole interaction term (i.e., the energy associated to the generation of separated charges), Je,h. Then, DE op ¼ DE el  J e, h

(5)

The value of Je,h for the smaller particles can be calculated as ca. 0.1 eV. This term does not apply for optical HOMO–LUMO transitions, where no change in the overall charge of the nanoparticle occurs. In the case of alkanethiol-capped metal nanoparticles, appearance of a HOMO–LUMO energy gap is reflected by an enlarged potential spacing between the current peaks for the first one-electron loss and the first one-electron gain of the parent nanoparticle (Fig. 6) [50]. The molecule-like behavior appears to be dependent on the electronic interactions between the particle core and capping ligands. Thus, electron-donating cappings such as phosphines would lead to an increase of the particle core electron density and hence a negative (upward) shift of the Fermi level. Opposite behavior is expected from electron-acceptor cappings, typically thiol-protecting ligands, resulting in a decrease of the electron density of the Au core [49]. Page 8 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

a

10 μA

b

2 μA

+1.4

+0.2

−1.0

−2.2

−3.4

E / V vs. Fc+/Fc

Fig. 7 Cyclic voltammograms at glassy carbon electrode of (a) 1 mM N-(2-mercaptoethyl)-1,8-naphthalimide, (b) 6 mM CdSe/ZnS QDs capped with that ligand in 0.10 M Bu4NPF6 solution in 1/1 toluene/MeCN (v/v). Potential scan rate 50 mV/s. The dotted line separates the region of largely negative potentials where electrolyte signals appear (Reprinted with permission from Aguilera-Sigalat et al. [58]. Copyright (2013) American Chemical Society)

It is pertinent to note that uncertainty remains about the so-called formulaic composition of the nanoparticulate system, expressed in terms of [metal]x[stabilizing ligands]y,z [7], so that, in general, nanoparticulate systems are designed by their diameter, which is typically estimated from TEM images and spectral data. An interesting, directly related case is that of metal nanoparticles covered by a metal oxide shell. Voltammetric experiments suggest that oxidation of Pd@PdO nanoparticle in aqueous alkaline electrolyte could proceed via formation of Pd(OH)x adsorbed species further evolving to Pd oxides and/or Pd2+ ions in solution [51], similarly to the growth of porous PdO films on Pd electrodes [52]. Solid state electrochemistry of nanoheterogeneous deposits of Pd nanoparticles covered by PdO shell on graphite electrodes in contact with aqueous permits a direct estimation of the thickness of the PdO shell and the size of the palladium core by using electrochemical data alone [51]. In the case of CdSe and CdTe quantum dots, nanocrystals are usually endowed with surface monolayers composed of ligands such as trioctylphosphine oxide (TOPO), n-decanethiol, and TOPO/n-hexadecylamine. Cyclic voltammetric experiments on QD dispersions [52] and adsorbed on electrode surfaces [53] have been used for determining energy band gaps, the relationship between optical and electrochemical band gaps being expressed by Eq. 5. It has been reported that the electrochemical bandgap energy of n-decanethiol-coated samples decreases on increasing the core diameter of the QD, the electrochemical bandgap being consistently 0.4–0.5 eV smaller than the optical bandgap [8]. This discrepancy, which is clearly larger than that estimated for the Coulombic interaction energy, has been attributed to the presence of surface defects that act as local trap states for electrons and holes [8, 54]. The presence of additional peaks in the voltammograms of quantum dots has been attributed to inter-band trap states. This assignment is consistent with the presence of a broad band on the low-energy side of the band-edge photoluminescence or the appearance of a new band at longer wavelengths [55].

Page 9 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

a 1 µA

b

+1.4

+0.2

−1.0

−2.2

E / V vs. Fc+/Fc

Fig. 8 Square-wave voltammograms at glassy carbon electrode of 6 mM solution of CdSe/ZnS QDs capped with long chain primary amine in 1/1 (v/v) toluene/MeCN (0.10 M Bu4NPF6). Potential scan initiated at (a) +0.80 V in the negative direction and (b) 2.7 V in the positive direction. Potential step increment 4 mV; square wave amplitude 25 mV; frequency 5 Hz. Extreme QD signals are marked by solid arrows while intermediate QD-localized ones are marked by dotted arrows [58] (Reprinted with permission from Aguilera-Sigalat et al. [58]. Copyright (2013) American Chemical Society)

In the case of CdSe/ZnS QDs, electrochemical data suggest that the ZnS shell does not affect the charge injection to the CdSe core. This has been attributed to the occurrence of electron injection at potentials below those corresponding to the conduction energy level for ZnS [56]. Replacing usual capping ligands by electroactive ones results in shifts in the peak potentials for QD oxidation and reduction, but also in the modification of the electrochemical response of the ligand [57]. It is pertinent to note that in general it is difficult to discern between the genuine signals of the nanoparticle system and those due to the “free” electroactive cappings (such as thiolate species) and even those due to the supporting electrolyte/solvent system. An example can be seen in Fig. 7, where cyclic voltammograms at glassy carbon electrode of N-(2-mercaptoethyl)-1,8-naphthalimide and of CdSe/ZnS nanoparticles capped with this ligand in 1/1 toluene/acetonitrile (v/v) solution [58]. The ligand displays an irreversible, thiol-localized oxidation at largely positive potentials and an essentially reversible couple at ca. 1.8 V vs. Fc+/Fc, ascribed to the reduction of the carbonyl unit. This couple is considerably diminished in the naphthalimide-capped QD and is accompanied by a series of additional voltammetric features which can be assigned to the QD signals, formally represented in terms of the CdSe/Se (oxidation) and CdSe/Cd (reduction) couples. Figure 8 permits to observe intermediate signals accompanying extreme QD signals defining the electrochemical band gap. Such signals have been interpreted in terms of charge transfer processes involving defect states of the QDs. Intermediate oxidation processes would correspond to cappingmediated electron release from defect sites of the QDs, whereas intermediate reduction would correspond to the electron transfer to empty energy levels of the QD. Interestingly, the separation of the intermediate QD-localized voltammetric peaks relative to the extreme QD peaks appears to be coincident with the position of the different trap energy levels for the different types of defect sites reported in the literature [59]. However, the relative intensity of the intermediate peaks is clearly

Page 10 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

5

calculated experimental

e

4

I / μA

a

b

c

d

3

2 1 0 0.6

0.7

0.8

0.9

1.0 E/ V

1.1

1.2

1.3

1.4

Fig. 9 Experimental (circle) and calculated (triangular) voltammograms of the gold particles electrooxidation in 0.1 M HCl; potential scan rate 50 mV/s. Calculation parameters: Q = 10.07 mC, d = 1 (a); Q = 11.30 mC, d = 1 (c); Q = 14.57 mC, d = 1 (b); Q = 49.42 mC, d = 0.3 (d) [65] (Reprinted with permission from Brainina et al. [65]. Copyright (2012) Springer)

capping dependent, so that the role of the ligand would be, to some extent, the “activation” of the trap states [58].

Electrochemical Characterization of Nanoparticles The oxidative dissolution of metal nanoparticles is also a size-dependent process, so that the standard electrode potential for the oxidation of, for instance, Ag nanoparticles, EoM,NP, differs from that for the oxidation of the bulk metal, EoM,bulk, by one term including the surface tension, s; the molar volume, vM; the lowest valence state, z; and the nanoparticle radius, r [60, 61]: EoM, NP ¼ E oM, bulk  2zvM =zFr

(6)

Recently, Brainina et al. have proposed a size-dependent model for the oxidative dissolution of metal nanoparticles based on the above considerations, showing an excellent agreement with experimental data [62–65]. Here, the peak profile for metal nanoparticle oxidation is made dependent on the fraction of particles of a certain size, d, and the surface tension of gold on the boundary with air. An excellent agreement was obtained between theory and experiment, as shown in Fig. 9. It should be noted that, in general, electrochemical oxidation of metal nanoparticles can lead not only to metal ions in solution but also to the formation of metal oxides via, in the case of Pt, the following processes: Pt ! Pt2þ ðaqÞ þ 2e

(7)

Pt þ H2 O ! PtOðsÞ þ 2Hþ ðaqÞ þ 2e

(8)

The electrochemical stability under “thermodynamic” conditions would be size dependent, so that particle size-dependent potential vs. pH diagrams such as in Fig. 10 can be constructed [67]. Compton et al. have provided theoretical modeling of charge diffusion on the surface of immobilized spherical particles [67], voltammetry at random microparticle arrays [68], and dissolution of microparticle arrays [69] and nanoparticle detection [70]. Direct oxidation of the Ag

Page 11 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015 1.5 Pt2+

E (V) NHE

1

0.5

A’

−1

PtO

B’

0

−0.5

C’

Pt Planar surface D = 10.0 nm D = 3 nm D = 2 nm D = 1.5nm D = 1.0 nm

4

0

8

12

16

pH

Fig. 10 Particle-size-dependent potential-pH diagram for Pt/106 M, Pt2+ [66] (Reprinted with permission from Tang et al. [66]. Copyright (2010) American Chemical Society)

H2O

H2

Electrode

Fig. 11 Electrochemical water oxidation in the nanoparticle surface occurs when the nanoparticles are in contact with an electrode

nanoparticles during collision events was monitored by the presence of a spike under oxidative current. The onset potential of the spike changes with the potential and can be used to determine the size of the nanoparticle. This method can be used to identify Ag NPs (onset spike potential vs. anodic stripping voltammetry of the NPs) and to analyze their size by taking into account the charge passed per current spike [70]. Surface agglomeration of Ag nanoparticle has been recently described using the anodic stripping voltammetry. New analytical expressions were reported for the stripping voltammetry, and they demonstrate that the oxidation peak potential for the stripping of the metallic nanoparticle should be below the formal potential for the oxidation. Changes in the response of the stripping peak potential as a function of the surface coverage give information about the nanoparticle distribution and can be related to the surface agglomeration of the NPs [71]. Electrodeposition of monolayers [72] or multilayers [73] of a second metal on a metal nanoparticle has also been reported. Bard et al. [74] have proposed a new and simple methodology for the study of the nanoparticles at the single particle level (single-molecule electrochemistry). It is well known that only few electrons can be transferred between the nanoparticle and the electrode, and consequently, a small current can be determined, resulting in a small signal that can be confused with the background noise. The proposed methodology is based on the large current amplification (“staircase”) generated in an Page 12 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

electroactive redox probe whose oxidation or reduction is catalytically enhanced at nanoparticulate films on electrodes. This methodology has been applied to the reduction of proton and hydrogen peroxide at very low concentrations as well as to the oxidation of hydrazine occurring in Pt nanoparticle solutions. The electrocatalytic effect occurs (see scheme in Fig. 11) when the nanoparticles collide with the inert electrode [75]. These single nanoparticle collisions are characterized as current transients (electrocatalytic amplification) and are used to estimate the nanoparticle size. Single IrOx nanoparticles can also be detected on the basis of the increase of the signal (“spike”) produced when the IrOx nanoparticle and the Pt electrode are in contact for the hydrogen production, which does not occur in absence of the nanoparticle [76]. Stochastic electrochemistry with metal and metal oxide nanoparticles at inert electrodes has been modeled in terms of NP collisions, differing from the usual model for ensemble-based electrochemical behavior [77]. The role of counterions into the electrochemical response of gold nanoparticles on a monolayer films has been reported. Electrochemical charging was observed with small counterions like BF4, ClO4, and PF6 and not with larger ones as bis(trifluoromethylsulfonyl)amide Tf2N, among others. This has been explained as due to the proximity of the counterion to the monolayer-protected layer (MPC) that allowed the alkanethiolate layer to get charge compensation, and this was proposed as a new way to modulate the electronic-charging response of the film [78]. Monolayer metal deposition at the electrochemical interface has proved the halide–metal interaction [79].

Electrochemiluminescence and Spectroelectrochemistry Electrochemiluminescence (ECL) consists of the radiative deactivation of excited states that have been generated electrochemically. In QDs, this process can occur via an annihilation process involving only QD radical ions (QD-annihilation-based ECL), or it can require a coreactant (coreactant-based ECL), both schematized in Fig. 12. In QD-annihilation-based ECL, under electrochemical conditions, an individual QD can accept an electron in its conduction band while another donates an electron from its valence band, thus leading to the QD radical anion/QD radical cation couple (QD/QD+). Subsequent collision of the radicals produces the ground state of one of them and the excited state (QD*) of the other, which finally reaches the ground state after emitting light. The stepwise removal or addition of charge from QDs by an electrochemical method can give information on the energy needed for electron transfer and, consequently, for ECL emission. This type of electrochemiluminescence has been exhibited by QDs with a superlattice structure, but it has not been detected in QDs capped with electrochemically inert ligands, such as mercaptoalkanes. In coreactant-based ECL, a coreactant (CR) and a QD can be electrochemically reduced, eventually leading to an oxidized species (SOx) and QD, and then the SOx/QD couple reacts to lead to an unreactive product (SF) and the QD excited state (QD*), which partially decays via a radiative process. Alternatively, the CR and the QD are electrochemically oxidized, eventually leading to a reduced form (SRed) and QD+ and then the SRed/QD+ couple reacts yielding QD*. These processes are further classified as cathodic- and anodic-based ECL depending on the role of the CR as an oxidant or reductant, respectively, that will rely on the oxidation or reduction potential of the resulting SOx or SRed intermediate. The coreactant-based ECL possesses several advantages over the QD annihilation-based ECL, in particular when either the QD radical cation or the radical anion is not quite stable or the electrode or the solvent has a narrow potential window so that neither of these radical ions can be generated. The coreactants can be (i) amines, such as tri-n-propylamine and triethanolamine); (ii) peroxides, such as O2, H2O2, S2O82; (iii) other species like SO32, CH2Cl2; and (iv) other nanoparticles. Page 13 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

a QD annihilation-based ECL CB VB anode

cathode

QD - e

QD

QD + e

QD

QD + QD

QD* + QD

+

QD*

b coreactant-based ECL cathodic

cathode

anode

QD

CR + e

SOx

QD + SOx

CR CR

QD*+SF

CR: S2O82–, O2, CH2Cl2

CR

CR

QD + e

anodic SOx

SRed SF

SF

QD – e

QD

CR – e

SRed QD*+SF

QD + SRed

CR: Pr3N, (But)2NCH2CH2OH, SO32– QD*

Fig. 12 Schemes for (a) annihilation-based and (b) coreactant based ECL

F

ECL

F

ECL

Fig. 13 Schemes for band gap-based ECL (left) and surface state-based ECL (right)

A number of considerations have to be taken into account for choosing the right coreactant, such as its solubility, stability, electrochemical activity, direct ECL, as well as suitability to be easily oxidized or reduced at or near the electrode and its capacity to leading rapidly to the corresponding reactive intermediate.

Page 14 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

There are a considerable number of examples of ECL in QDs such as CdSe, CdS, and CdTe. It has been recently demonstrated that water dispersible, blue-luminescent graphene QDs exhibit an ECL behavior similar to CdSe QDs. These QDs present anodic ECL when using H2O2 as the coreactant, and this emission is strong and appears at low potential (ca. 0.4 V vs. Ag/AgCl) [80]. The ECL emission can originate from recombination of an electron and a hole at the conduction and valence band edges of the QD core, respectively, and it matches the band-edge fluorescence and is size dependent. Alternatively, the ECL can involve transition levels caused by defect states at the QD surface, and, consequently, energy relaxation and recombination dynamics in QDs strongly depend on passivation of the QD surface (Fig. 13). Consequently, the QD- based ECL can be classified as band gap or surface state ECL. Because electron/hole injection in QDs is assumed to occur via the surface states, the surface state-based ECL has been considered as the main process for QD ECL, but there are increasing reports showing that QDs can exhibit band gap-based ECL or both types of ECL, the contribution of the first increasing by progressive passivation of the QD surface. In addition, it has to be taken into account that the introduction of coreactants can have an impact on surface state-based QD ECL and a “dual peak” can appear. Metallic nanoparticles can be used to improve the ECL performance of QDs due to their excellent conductivity. Thus, they can reduce the electron-relay barrier between the QD and the electrode, accelerating the electron/hole injection, thus enhancing ECL intensity and moving ECL onset and the peak potential toward zero. For example, ECL of CdS–CdSe QDs was drastically enhanced by placing a large number of silica-coated AuNPs on their surface [81]. Furthermore, silver and gold nanoclusters can also exhibit their own ECL. Metal nanoclusters differ from their corresponding nanoparticles in that the continuous density of states breaks into discrete energy levels and as a consequence they can exhibit molecule-like properties, such as luminescence. Thus, nanoclusters with a small number of Ag atoms can show a considerable fluorescence quantum yield as well as ECL under strong cathodic polarization using K2S2O8 as the coreactant. The ECL spectrum of the nanoclusters matched that of their photoluminescence [82]. In the case of gold, Au25 nanoclusters protected by bovine serum albumin can exhibit ECL by using triethylamine as the coreactant, but in this case the ECL spectrum matched the surface-state fluorescence that appeared as a weak shoulder on the main peak in the Au25 nanocluster fluorescence spectrum [83]. By contrast, the ECL spectrum of similar Au25 nanoclusters immobilized on hydroxylated indium tin oxide (ITO) and using K2S2O8 as the coreactant was similar to that of the photoluminescence spectrum [83]. These optical spectroelectrochemistry techniques have been recently used to obtain information on the relationship between the emissive properties of QDs and their intrinsic structure features. Thus, the absolute energetic position of trap levels can be determined by using an electrochemical method which is particularly useful for QD electrodes [84], once the energy of the bandgap edges is known. It consists of the control of the population of the energy states involved in fluorescence by potentiostatic control of the Fermi level in the material, thus enhancing or quenching the fluorescence depending on the energy state involved (Fig. 14). It should be emphasized that semiconductor materials possess defect states that originate from substitutional and interstitial impurities, divacancies, surface reactions, etc., resulting from their synthesis. For example, the absolute energetic position of the trap levels involved in the green fluorescence of thin films of ZnO QDs has been determined [84]. Under illumination, the Fermi level in the QD increases due to the increase of electrons in the CB. Competitively with the recombination with the VB holes, the CB electrons can relax into a lower-lying, electron-acceptor trap state (krel) and by recombination with the electrolyte (krec) from the CB or from the trap state. Under potentiostatic control, the trap emission can increase due to the population of the trap state (ktrans1), subsequently increasing the Page 15 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

electrolyte

CB

ktrans1

krel

EFermi kpot

ktrans2

krec trap state

kr trap state knr

VB

Fig. 14 Schematic representation of the plausible processes occurring after QD illumination under potentiostatic control

probability for radiative and non-radiative recombination (kr and knr, respectively). If kr > > knr and kr > krec an increase in the surface-state emission would be observed. As a result, it was demonstrated that the green fluorescence of thin films of ZnO QDs is caused by a transition from an upper trap level, at 0.35  0.03 eV below the conduction band edge, to a deep trap within the bandgap and that the position of this upper level shifts with the size of the QD in the same way as the conduction band. Although this did not happen in these QDs, this method could alternatively induce the quenching of the QD fluorescence by applying more negative potentials than that of the upper trap level via competitive population of a deep, electron-acceptor trap-state (ktrans2), if this process is fast enough. In addition, optical spectroelectrochemistry techniques have been applied to obtain information on the basis of QD photoluminescence blinking, which is a random switching between states of high (ON) and low (OFF) emissivities. The OFF periods are often explained by using a charging model (additional charge causing photoluminescence quenching by non-radiative recombination, Auger mechanism). However, time-resolved photoluminescence studies of individual QDs have been carried out by controlling the QD charging electrochemically and suggest that there are two types of blinking (i) A-type blinking (Auger mechanism) in which the lower photoluminescence intensity is accompanied by a short luminescence lifetime and (ii) B-type blinking, due to charge fluctuations in the electron-accepting surface states, in which the lower emission is not accompanied by a significant change in the QD emission lifetime. In B-type blinking, unoccupied surface states intercept hot electrons before they relax into emitting core states (Fig. 15). Both blinking mechanisms can be suppressed by application of the appropriate potential. These types of studies have been conducted on single CdSe/CdS QDs, by performing timetagged, time-resolved, single photon counting measurements in a three-electrode electrochemical cell. At E = 0 V and E = +0.8 V, periods of low luminescence intensity and a considerable shortening of lifetime was observed. These effects can be attributed to a low Fermi level, increasing the relative time spent by the trap in the unoccupied state, and consequently having the capacity of trapping hot electrons which eventually recombine non-radiatively with a VB hole, thus resulting in a neutral QD. These B-type blinking events usually coexist with A-type fluctuations. For negative potentials (E = 1 V), the fluorescence lifetime was typical of a neutral exciton, but the blinking was suppressed by increasing the energy of the Fermi level that led to population of the trap states. At more negative potentials, the photoluminescence decay became biexponential and the QD lifetime

Page 16 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_28-2 # Springer International Publishing Switzerland 2015

Type-B blinking 1Pe k intra

1Se

k intra 10 nm) show a fluorescence enhancement of up to 100-fold [55–58]. The quenching properties of AuNPs have been applied in two approaches: molecular beacons, which rely on NPs functionalized with fluorescent-labeled hairpin structures, and AuNPs nanoprobes with ssDNA that hybridize to another fluorescent-labeled ssDNA probe [59]. Molecular beacons, i.e., AuNPs functionalized with fluorescent-labeled ssDNA where the NP act as a fluorescence quencher via the NP surface energy transfer occurring between the dye (donor molecule) and the NP’s surface (acceptor). On the other hand, noble metal nanoprobes rely on NPs functionalized with ssDNA hybridized to a complementary fluorescent-labeled ssDNA probe. Since ssDNA naturally adsorbs to the AuNPs, the proximity of the fluorophore with the nanoparticle is close enough for a 98 % of quenching efficiency. In the presence of a complementary target, dsDNA is formed resulting in a spatial separation of the fluorophore from the AuNPs, thus restoring the fluorescence signal (Fig. 6). The combination of AuNPs and semiconductor quantum dots (QDs) as a Förster resonance energy transfer (FRET) system has been used to develop fluorescence competition assays for nucleic acid, protein, and antibody/antigen detection where the dye is replaced by QDs [1]. Fluorescence modulation by AuNPs has been used to monitor specific nucleic acid hybridizations. Two different research groups have used this approach to detect synthetic DNA of Campylobacter and HCV synthetic RNA, respectively, with single-base mismatches detection capability [50, 60]. Deng Zhang et al. used a bio-barcode-type assay to obtain a fluorescence signal of PCR-amplified Salmonella enteritidis DNA [61]. In this type of assay, two types of nanoparticles are functionalized. Firstly, magnetic sulfo-SMCC-modified nanoparticles are functionalized with oligonucleotide sequence complementary to the sample DNA. Secondly, AuNPs are bi-functionalized with an oligonucleotide sequence specific for Page 12 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

a Hairpin probe

b Fluorescent Dye

Probe

Fluorescent-labeled target

Target (e.g. DNA/RNA) Noble metal NP (e.g. Au, Ag, etc.)

OR

Fluorescent-labeled Probe +

Fig. 6 Fluorescent-based noble metal NPs biosensing, (a) molecular nanobeacons, (b) direct hybridization of a fluorophorelabeled target or sandwich assay using fluorophore-labeled probe. Distances are not represented to the scale (Reproduced from Doria et al. [59])

the target (in lower percentage), and another sequence that contains a nucleotide sequence 30 modified with a fluorophore (in higher percentage). Both nanoparticles are mixed with the sample DNA and, in case of total complementarity, the sample DNA serves has linker of both nanoparticles. After the hybridization step, a magnetic field is generated to isolate hybridized NPs from non-hybridized ones, and the thiol bonds are broken releasing the fluorophore-labeled oligonucleotides (LOD of 21.5 fM). Ganbold et al. describe a similar method, but the synthetic probe is functionalized with a fluorophore whose fluorescence is quenched if the ssDNA is adsorbed to the particle but not if there is complementarity to the target [62]. Standard fluorescence signal is measured but there is also the possibility of using sub-aggregation conditions for Raman spectroscopic analysis. The method was tested with influenza A (H1N1) synthetic DNA and was able to discriminate single-base mismatches. In another application, Dubertret and coworkers used Au-nanobeacons to detect single-base mismatches with 100 more sensitivity than that of conventional molecular beacons [63]. Similarly, Beni et al. used Au-nanobeacons to successfully detect a mutation that occurs in 70 % of cystic fibrosis patients using nM concentrations of DNA target [64, 65]. In the second case, AuNPs can be combined with dye-labeled ssDNA probe and is used to detect specific DNA targets mediated by energy transfer mechanisms (FRET). The method consists in designing probes that identify complementary and contiguous sequences on the target, where hybridization forces the dye into close vicinity of the AuNPs’ surface and the fluorescence signal decreases [66]. More recently, Wang et al. proved that the fluorescence quenching/enhancement conferred by AuNP could be used as an SNP genotyping system suitable for point of care [67].

Gold Nanoparticles for Plasmonic-Based Sensing Plasmonic sensing here refers in the broader sense to detection based on light-scattering techniques, namely, SERS and LSPR spectroscopies. These techniques take advantage of the different size and shapes of AuNPs to detect the biding of molecules and alterations to conformation. Plasmonic nanoparticles act as signal transducers capable of converting minute changes to the local refractive index into sharp spectral shifts [68] (Fig. 2). Raman Scattering Raman scattering originates from the inelastic scattering of photons that interact with the analyte molecule, changing its vibrational states [59]. This interaction generates unique narrow spectrum bands that may be enhanced by metal nanostructures, allowing multiplex detection assays. Metallic nanosurfaces associated to SERS allow detection of specific biomolecules and is usually performed by means of a molecule with an intense and characteristic Raman signature (e.g., dye). SERS detection methods show great similarities to those previously described methods in colorimetric and fluorescent assays. Page 13 of 25

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Fig. 7 Time-dependent frequency changes of the circulating-flow QCM sensor, (a) addition of Probe 1 (1 mM; P1-30/12 T) for immobilization on the surface of the QCM sensor via self-assembly, (b) complementary target oligonucleotides [0.5 mM; T-104(AS)] are subsequently introduced for DNA hybridization, (c) additional treatment of the DNA hybridized QCM with Probe 2 (P2-30/12 T)-capped Au nanoparticles. The sequences of Probe 1 and Probe 2 are complementary to the two ends of the analyte DNA (i.e., target sequences) (Reproduced from Chen et al. [72] with permission from Elsevier)

The first proof of concept of this approach for pathogen detection was introduced by Cao et al., with a multiplexed detection of oligonucleotide targets with AuNPs labeled with oligonucleotides and Ramanactive dyes [69]. AuNPs help the formation of the silver coating, i.e., SERS promoter for the dye-labeled particles captured by the target molecules. This may be employed in a microarray format. Six DNA targets with six Raman-labeled NP probes were easily distinguished together with two RNA targets with single nucleotide polymorphism (LOD of 20 fM). This allowed for the multiplexed direct detection of hepatitis A virus, hepatitis B virus, HIV, Ebola virus, Variola virus, and Bacillus anthracis. Hu et al. developed a sensitive DNA–SERS biosensor based on multilayer metal–molecule–metal nanojunctions [70]. The sensor could detect as little as 0.1 atomolar of a HIV-1 DNA sequence. High sensitivity may be attained via a bio-barcode approach combined with a silver-enhanced spot test. Isola and coworkers explored a similar approach for HIV detection using Raman-active dye-labeled DNA on Ag or AuNPs [71]. Upon target recognition, the cross-linking cages the Raman reporter in “hot spots” between NPs and, thus, enhances the SERS signal.

Piezoelectric Sensors Using AuNPs for DNA/RNA Recognition Quartz crystal microbalances (QCM) have been extensively investigated as transducers for hybridizationbased DNA sensors, such as for the detection of gene mutations associated with disease and foodborne pathogens. Improving the sensitivity of QCM sensors has been based on probe immobilization and signal amplification strategies that include nanoparticles [72]. Nanoparticles are effective amplifiers for QCM DNA detection because they have a relatively large mass compared to that of DNA targets [73]. The use of AuNPs coupled to the DNA targets acts as “mass enhancers,” i.e., signal amplification, thus extending the limits of QCM DNA detection (Fig. 7). Page 14 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

Chen and coworkers introduced the first nanoparticle-amplified QCM DNA sensor for foodborne pathogens [72], using the sandwich hybridization of two specific probes: one specific to E. coli O157:H7 immobilized onto the piezoelectric surface and a second conjugated to the AuNPs as “mass enhancer” and “sequence verifier” by amplifying the frequency change of the piezoelectric part. The oscillation frequency of the piezoelectric sensor decreased with increasing weight at the sensor’s surface (i.e., sandwich hybridization involving the target oligo, the sensor’s probe, and the circulating DNA-functionalized AuNP). Thus, PCR products amplified from concentrations of 1.2  102 CFU/ mL of E. coli O157:H7 were easily detectable. Wang et al. also used AuNPs to functionalize QCM for E. coli DNA detection, employing two sizes of AuNPs to increase sensitivity [73]. First, 18-nm AuNPs were immobilized onto the QCM surface to support the ssDNA probes that will bind specifically to the biotinylated DNA of target bacteria. The gold layer binds a higher number of ssDNA molecules to the QCM, thus increasing sensitivity. The biotinylated DNA from the target organism binds to the sensor, which is recognized by avidin-functionalized 70-nm AuNPs to further amplify the signal. This scheme was capable of detecting bacteria without sample enrichment showing an LOD of 2.0  103 CFU/ mL. Recently, Hao et al. developed this method to detect Bacillus anthracis based on the recognition of a 168-bp fragment of the Ba813 gene and the 340-bp fragment of the pag gene in plasmid pXO1 [74]. A thiol DNA probe was immobilized onto the QCM gold surface to hybridize to the target ssDNA obtained by asymmetric PCR. The DNA-functionalized QCM biosensor could specifically recognize B. anthracis (and distinguish from its closest species, Bacillus thuringiensis) – LOD of 3.5  102 CFU/mL for B. anthracis vegetative cells without culture enrichment.

Electrochemical Detection of DNA/RNA Targets Using AuNPs Other physicochemical properties of AuNPs have also been used in detection protocols, such as electrochemical activity. AuNPs are also extremely useful in electrochemical bioassays, to bind enzymes to electrodes, mediate electrochemical reactions as redox catalysts, and amplify recognition signals of biological processes [1, 75, 76]. Examples of applications in DNA detection include direct detection of AuNPs anchored onto the surface of the genosensor, conductimetric detection, and AuNPs as carriers of other AuNPs or of other electroactive labels [77]. In general, electrochemical biosensors employ potentiometric, amperometric, or impedimetric transducers. Zhang et al. described an approach that makes use of the bio-barcode method to detect DNA from Salmonella enteritidis and Bacillus anthracis in a multiplex assay where the characteristic molecular signature sequences are labeled with cadmium and lead ions, respectively [78]. Following magnetic separation, the ions are cleaved from the oligonucleotides and the square–wave anodic stripping voltammetry analyzed on screen-printed carbon electrode (SPCE) chips. The differential signal of both ions allows the parallel read of either DNA signature. Further signal augmentation was attained via introduction of PCR amplification and the detection limit set at 0.5 ng/mL for Cd2+ and 50 pg/mL for Pb2+. Also using an electrochemical approach, it was possible to directly detect M. tuberculosis DNA with a detection limit of 1.25 ng/mL [79]. Firstly, AuNP are dual-labeled with a complementary sequence of target DNA and an enzyme alkaline phosphatase. Secondly, Au-nanoprobes are fixed onto indium tin oxide-coated glass plates that work as electrodes, and the extracted DNA followed by a second mix of dual-labeled AuNPs are then added and let to hybridize. Then, in the presence of paranitrophenyl phosphate, if both probes hybridize, the substrate is converted in paranitrophenol generating a signal that can be measured by differential pulse voltammetry. Vetrone et al. describe a bio-barcode-based assay in which, instead of using a signature DNA sequence, the amount of gold separated via the magnetic nanoparticles is measured [80]. Hydrochloric acid

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

a Sample pad

Conjugate padv Control line Test line

Membrane

b Sample + analyte

Absorbent pad

Plastic casing

Label

Negative control

Positive result

Fig. 8 Schematic representation of a LFA strip, (a) sample pad (sample inlet and filtering), conjugate pad (AuNP-antibody conjugates), incubation, and detection zone with test and control lines (antigen detection and functionality test) and final absorbent pad (liquid actuation); (b) sample is applied to the sample pad and the analyte binds to the AuNP-antibody conjugates and elutes with the buffer flow, and this analyte-AuNP-antibody conjugates bind to the test line (positive result). If the analyte is absent, the AuNP-antibody conjugates bind only to the control line (negative and control result) (Reprinted with permission from Gubala et al. [36]. Copyright 2011 American Chemical Society)

promotes dissolution on an SPCE’s plate that measures Au3+ ions. The method was capable to detect unamplified DNA specific of Salmonella enterica serovar Enteritidis (S. enteritidis) at an LOD of 7 ng/uL. Multiplex approaches have also been described. Li and colleagues used DNA arrays on gold surface combined with reporting silver nanoprobes to detect herpes simplex virus, Epstein–Barr virus, and cytomegalovirus by differential pulse voltammetry. The silver tag is allowed for the detection of as little as 5 aM of target DNA. Zhang et al. explored anodic stripping voltammetry using a screen-printed carbon electrode chip together with bio-barcoded AuNPs and magnetic NPs, to detect B. anthracis and S. enteritidis [78].

AuNPs for Diagnostics at Point of Care: Lateral Flow Devices

The lateral flow assay (LFA) or lateral flow immunochromatographic assay was introduced in 1988 by Unipath and is the most common commercially available POC diagnostic platform [81]. Most of the success of LFAs is due to the low cost and simplicity of operation. In fact, these devices are currently used in resource-poor or non-laboratory environments [37]. Generally, LFAs consist of a porous white membrane striped with a line of antibodies or antigens that interact with AuNP-antibody nanoprobes visible by the naked eye (Fig. 8). These types of platforms can support competitive or noncompetitive immunoassays. Competitive immunoassays are used for detection of low molecular weight target molecules like pesticides, hormones, and drugs, whereas competitive formats are used to detect high molecular weight targets with at least two binding sites [82]. With a suitably configured system, LODs in the picomolar range may be easily obtained.

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Many LFAs have been developed on the capillary test strip platform during the past 30 years. LFAs are easy to use, disposable, fast to perform, and relatively cheap [83]. Integration of such approaches with gold labels introduce several advantages in lateral flow designs, since they have been shown to be stable in liquid and dry without loss of signal [84]. Today, these platforms are “everywhere,” from pregnancy, heart attack, blood glucose, and metabolic disorders to small-molecule detection (e.g., narcotics, drugs, toxins, antibiotics, etc.) and even pathogens, such as anthrax, salmonella, and some viruses. LFAs have been applied to immunodiagnostics, RNA detection, and even identification of whole bacteria. Some of the more recent designs and publications show the detection of DNA without the need of amplification by PCR opening yet another vast field of new applications. In fact, Wilson and coworkers demonstrated how unlabeled PCR products can be detected with an antibody-free lateral flow device at room temperature [85]. Trials are being conducted for massive multi-parallel screening together with LFAs microarrays [86]. Recently several lateral flow strip-based devices have been developed. Chua et al. developed a typical design where the detector reagent recognizes the fluorescein haptens of PCR-amplified DNA target and produces visual red lines with a recorded LOD of 5 ng of DNA [87]. Rastogi et al. optimized this approach via the integration of locked nucleic acid conjugated Au-nanoprobes together with signal amplification protocols for as little as 0.4-nM DNA [40]. More recently, Rohrman et al. presented a lateral flow assay coupling NASBA RNA amplification with Au-nanoprobes and gold enhancement solution to quantitate amplified HIV RNA [88]. These results suggest that the lateral flow assay can be integrated with amplification and sample preparation technologies, allowing viral load testing to monitor therapy response in limited resource setting. Also, quantification of microRNA was demonstrated by Shao-Yi Hou et al. using of LFA nucleic acid test strips and AuNPs to detect miRNAs as low as 1 fmol [89]. LFAs evolved from a simple device into increasingly sophisticated platforms with internal calibrations and quantitative readouts. Nevertheless, single-use POC test devices are often affected by critical issues associated to dispersion of dried reagents into the sample, sample mixing with reagents, and effective control of incubation time and conditions. Several enabling technologies such as printing and laminating of components and microfluidic technologies are contributing to advances in LFAs. For a deeper perception on this technological perspective, including recent innovations in LFA technology, see the excellent review by Gubala et al. [36]. Some detection kits using AuNPs and their colorimetric sensing capability for human genetic tests can already be found in the market. For example, NanosphereTM offers FDA-approved assays aimed at identifying typical mutations in coagulation factors F5 (1691G > A), F2 (20210G > A), and MTHFR (677C > T) without the need for nucleic acid amplification or to genotype polymorphisms associated with the drug-metabolizing enzyme CYP450 [90, 91]. Samples are processed through a cartridge where the sample is analyzed via an automated processor and reader.

Conclusion AuNPs have become one of the most effective transducers and tags used in molecular diagnostics. In fact, the minimum number of AuNPs that can be detected by the naked eye against a white background is around roughly 1010. Assuming one molecule of target molecule per AuNP, ten femtomoles may be detected, which compares negatively to the amount of target analyte in a sample that is usually one million less [82]. An alternative to diminish this difference can combine detection with amplification techniques. These can either focus on the target, such as PCR or antigen concentration, or on the assay development, such as by silver enhancement. The conjugation of silver enhancement and microfluidics allows the Page 17 of 25

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exploitation of multiple protein and nucleic acid targets in a bio-barcode format. Nevertheless, the cost of manufacture of these microfluidic devices remains a problem, and the technology for POC use in detection protocols is still under development; thus, translation to the clinical setting remains a challenge.

Acknowledgments The authors acknowledge Fundação para a Ciência e Tecnologia (FCT/MEC) for funding: CIGMH (PEstOE/SAU/UI0009/2011); REQUIMTE (PEst-C/EQB/LA0006/2011); UCIBIO (UID/Multi/04378/2013); SFRH/BD/78970/2011 for BV; SFRH/BD/51103/2010 for FC.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

74. R.Z. Hao, H.B. Song, G.M. Zuo, R.F. Yang, H.P. Wei, D.B. Wang, Z.Q. Cui, Z. Zhang, Z.X. Cheng, X.E. Zhang, DNA probe functionalized QCM biosensor based on gold nanoparticle amplification for Bacillus anthracis detection. Biosens. Bioelectron. 26(8), 3398–3404 (2011). doi:10.1016/j. bios.2011.01.010 75. D. Astruc, Electron Transfer and Radical Processes in Transition Metal Chemistry (VCH, New York, 1995) 76. E. Katz, I. Willner, Integrated nanoparticle–biomolecule hybrid systems: synthesis, properties, and applications. Angew. Chem. Int. Ed. 43(45), 6042–6108 (2004). doi:10.1002/anie.200400651 77. M.T. Castañeda, S. Alegret, A. Merkoçi, Electrochemical sensing of DNA using gold nanoparticles. Electroanalysis 19(7–8), 743–753 (2007). doi:10.1002/elan.200603784 78. D. Zhang, M.C. Huarng, E.C. Alocilja, A multiplex nanoparticle-based bio-barcoded DNA sensor for the simultaneous detection of multiple pathogens. Biosens. Bioelectron. 26(4), 1736–1742 (2010). doi:10.1016/j.bios.2010.08.012 79. C. Thiruppathiraja, S. Kamatchiammal, P. Adaikkappan, D.J. Santhosh, M. Alagar, Specific detection of Mycobacterium sp. genomic DNA using dual labeled gold nanoparticle based electrochemical biosensor. Anal. Biochem. 417(1), 73–79 (2011). doi:10.1016/j.ab.2011.05.034 80. S.A. Vetrone, M.C. Huarng, E.C. Alocilja, Detection of non-PCR amplified S. enteritidis genomic DNA from food matrices using a gold-nanoparticle DNA biosensor: a proof-of-concept study. Sensors (Basel) 12(8), 10487–10499 (2012). doi:10.3390/s120810487 81. K. May, Home tests to monitor fertility. Am. J. Obstet. Gynecol. 165(6), 2000–2002 (1991). doi:10.1016/s0002-9378(11)90566-3 82. R. Wilson, The use of gold nanoparticles in diagnostics and detection. Chem. Soc. Rev. 37(9), 2028–2045 (2008). doi:10.1039/b712179m 83. V. Kumanan, S.R. Nugen, A.J. Baeumner, Y.F. Chang, A biosensor assay for the detection of Mycobacterium avium subsp. paratuberculosis in fecal samples. J. Vet. Sci. 10(1), 35–42 (2009). doi:10.4142/jvs.2009.10.1.35 84. P. Chun, Colloidal gold and other labels for lateral flow immunoassays, in Lateral Flow Immunoassay, ed. by R. Wong, H. Tse (Humana Press, Totowa, 2009), pp. 1–19. doi:10.1007/ 978-1-59745-240-3 85. J. Aveyard, M. Mehrabi, A. Cossins, H. Braven, R. Wilson, One step visual detection of PCR products with gold nanoparticles and a nucleic acid lateral flow (NALF) device. Chem. Commun. 41, 4251–4253 (2007). doi:10.1039/B708859K 86. D. Mark, S. Haeberle, G. Roth, F. von Stetten, R. Zengerle, Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications. Chem. Soc. Rev. 39(3), 1153–1182 (2010). doi:10.1039/b820557b 87. A. Chua, C.Y. Yean, M. Ravichandran, B. Lim, P. Lalitha, A rapid DNA biosensor for the molecular diagnosis of infectious disease. Biosens. Bioelectron. 26(9), 3825–3831 (2011). doi:10.1016/j. bios.2011.02.040 88. B.A. Rohrman, V. Leautaud, E. Molyneux, R.R. Richards-Kortum, A lateral flow assay for quantitative detection of amplified HIV-1 RNA. PLoS One 7(9), e45611 (2012). doi:10.1371/ journal.pone.0045611 89. S.Y. Hou, Y.L. Hsiao, M.S. Lin, C.C. Yen, C.S. Chang, MicroRNA detection using lateral flow nucleic acid strips with gold nanoparticles. Talanta 99, 375–379 (2012). doi:10.1016/j. talanta.2012.05.067 90. J.A. Lefferts, M.C. Schwab, U.B. Dandamudi, H.K. Lee, L.D. Lewis, G.J. Tsongalis, Warfarin genotyping using three different platforms. Am. J. Transl. Res. 2(4), 441–446 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

91. C.B. Maurice, P.K. Barua, D. Simses, P. Smith, J.G. Howe, G. Stack, Comparison of assay systems for warfarin-related CYP2C9 and VKORC1 genotyping. Clin. Chim. Acta 411(13–14), 947–954 (2010). doi:10.1016/j.cca.2010.03.005 92. M. Larguinho, P.V. Baptista, Gold and silver nanoparticles for clinical diagnostics – from genomics to proteomics. J. Proteomics 75(10), 2811–2823 (2012). doi:10.1016/j.jprot.2011.11.007 93. K. Sato, K. Hosokawa, M. Maeda, Non-cross-linking gold nanoparticle aggregation as a detection method for single-base substitutions. Nucleic Acids Res. 33(1), e4 (2005). doi: 10.1093/nar/gni007 94. W.J. Qin, L.Y. Yung, Nanoparticle-based detection and quantification of DNA with single nucleotide polymorphism (SNP) discrimination selectivity. Nucleic Acids Res. 35(17), e111 (2007). doi: 10.1093/nar/gkm602 95. H. Deng, Y. Xu, Y. Liu, Z. Che, H. Guo, S. Shan, Y. Sun, X. Liu, Gold nanoparticles with asymmetric polymerase chain reaction for colorimetric detection of DNA sequence. Anal. Chem. 84(3), 1253–1258 (2012). doi: 10.1021/ac201713t 96. Y.L. Jung, C. Jung, H. Parab, T. Li, H.G. Park, Direct colorimetric diagnosis of pathogen infections by utilizing thiol-labeled PCR primers and unmodified gold nanoparticles. Biosens. Bioelectron. 25 (8), 1941–1946 (2010). doi: 10.1016/j.bios.2010.01.010 97. J.J. Storhoff, R. Elghanian, R.C. Mucic, C.A. Mirkin, R.L. Letsinger, One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle probes. J. Am. Chem. Soc. 120(9), 1959–1964 (1998). doi: 10.1021/ja972332i 98. W.J. Qin, O.S. Yim, P.S. Lai, L.Y. Yung, Dimeric gold nanoparticle assembly for detection and discrimination of single nucleotide mutation in Duchenne muscular dystrophy. Biosens. Bioelectron. 25(9), 2021–2025 (2010). doi: 10.1016/j.bios.2010.01.028 99. J. Li, T. Deng, X. Chu, R. Yang, J. Jiang, G. Shen, R Yu, Rolling circle amplification combined with gold nanoparticle aggregates for highly sensitive identification of single-nucleotide polymorphisms. Anal. Chem. 82(7), 2811–2816 (2010). doi: 10.1021/ac100336n 100. D. Xi, X. Luo, Q. Ning, Detection of HBVand HCV coinfection by TEM with Au nanoparticle gene probes. J. Huazhong Univ. Sci. Technolog. Med. Sci. 27(5), 532–534 (2007). doi: 10.1007/s11596007-0514-2 101. Y.P. Bao, M. Huber, T.F. Wei, S.S. Marla, J.J. Storhoff, U.R. M€ uller, SNP identification in unamplified human genomic DNA with gold nanoparticle probes. Nucleic Acids Res. 33(2), e15 (2005). doi: 10.1093/nar/gni017 102. X. Mao, Y. Ma, A. Zhang, L. Zhang, L. Zeng, G. Liu, Disposable nucleic acid biosensors based on gold nanoparticle probes and lateral flow strip. Anal. Chem. 81(4), 1660–1668 (2009). doi: 10.1021/ ac8024653 103. I.K. Litos, P.C. Ioannou, T.K. Christopoulos, J. Traeger-Synodinos, E. Kanavakis, Multianalyte, dipstick-type, nanoparticle-based DNA biosensor for visual genotyping of single-nucleotide polymorphisms. Biosens. Bioelectron. 24(10), 3135–3139 (2009). doi: 10.1016/j.bios.2009.03.010 104. Y.N. Tan, K.H. Lee, X. Su, Study of single-stranded DNA binding protein-nucleic acids interactions using unmodified gold nanoparticles and its application for detection of single nucleotide polymorphisms. Anal. Chem. 83(11), 4251–4257 (2011). doi: 10.1021/ac200525a 105. C.C. Chang, S.C. Wei, T.H. Wu, C.H. Lee, C.W. Lin, Aptamer-based colorimetric detection of platelet-derived growth factor using unmodified gold nanoparticles. Biosens. Bioelectron. 42, 119–123 (2013). doi: 10.1016/j.bios.2012.10.072 106. M.M. Hussain, T.M. Samir, H.M. Azzazy, Unmodified gold nanoparticles for direct and rapid detection of Mycobacterium tuberculosis complex. Clin. Biochem. 46(7–8):633–637 (2013). doi: 10.1016/j.clinbiochem.2012.12.020

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_31-1 # Springer International Publishing Switzerland 2015

107. J. Rosa, J. Conde, J.M. de la Fuente, J.C. Lima, P.V. Baptista, Gold-nanobeacons for real-time monitoring of RNA synthesis. Biosens. Bioelectron. 36(1), 161–167 (2012). doi: 10.1016/j. bios.2012.04.006 108. M.Y. Sha, S. Penn, G. Freeman, W.E. Doering, Detection of human viral RNA via a combined fluorescence and SERS molecular beacon assay. NanoBiotechnol. 3(1), 23–30 (2007). doi: 10.1007/ s12030-007-0003-5 109. J. Hu, C.Y. Zhang, Single base extension reaction-based surface enhanced Raman spectroscopy for DNA methylation assay. Biosens. Bioelectron. 31(1), 451–457 (2012). doi: 10.1016/j. bios.2011.11.014 110. L. Sun, J. Irudayaraj, PCR-free quantification of multiple splice variants in a cancer gene by surfaceenhanced Raman spectroscopy. J. Phys. Chem. B 113(42), 14021–14025 (2009). doi: 10.1021/ jp908225f 111. W. Li, P. Wu, H. Zhang, C. Cai, Catalytic signal amplification of gold nanoparticles combining with conformation-switched hairpin DNA probe for hepatitis C virus quantification. Chem. Commun. (Camb) 48(63), 7877–7879 (2012). doi: 10.1039/c2cc33635a 112. M. Ozsoz, A. Erdem, K. Kerman, D. Ozkan, B. Tugrul, N. Topcuoglu, H. Ekren, M. Taylan, Electrochemical genosensor based on colloidal gold nanoparticles for the detection of Factor V Leiden mutation using disposable pencil graphite electrodes. Anal. Chem. 75(9), 2181–2187 (2003). doi: 10.1021/ac026212r 113. K.F. Low, A. Karimah, C.Y. Yean, A thermostabilized magnetogenosensing assay for DNA sequence-specific detection and quantification of Vibrio cholerae. Biosens. Bioelectron. 47, 38–44 (2013). doi:10.1016/j.bios.2013.03.004 114. P.J. Jannetto, B.W. Buchan, K.A. Vaughan, J.S. Ledford, D.K. Anderson, D.C. Henley, N.B. Quigley, N.A. Ledeboer, Real-time detection of influenza a, influenza B, and respiratory syncytial virus a and B in respiratory specimens by use of nanoparticle probes. J. Clin. Microbiol. 48(11), 3997–4002 (2010). doi: 10.1128/JCM.01118-10 115. B. Yang, K. Gu, X. Sun, H. Huang, Y. Ding, F. Wang, G. Zhou, L.L. Huang, Simultaneous detection of attomolar pathogen DNAs by Bio-MassCode mass spectrometry. Chem. Commun. (Camb). 46 (43), 8288–8290 (2010). doi: 10.1039/c0cc03156a

Page 25 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Nanoparticles for Mass Spectrometry Applications Miguel Larguinhoa, José Luís Capelob and Pedro V. Baptistaa* a UCIBIO, CIGMH, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal b UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal

Abstract Nanotechnology has led to the development of new and improved materials, and particular emphasis has been directed toward nanoparticles and their multiple bio-applications. Nanoparticles exhibit size-, shape-, and composition-dependent properties, e.g., surface plasmon resonance and photothermal properties, which may potentially enhance laser desorption/ionization systems for mass spectrometry-based analysis of biomolecules. Also, nanoparticles possess high surface to volume ratio that can be easily derivatized with a wide range of ligands with different functional groups. Surface modification makes nanoparticles advantageous for sample preparation procedures prior to detection by mass spectrometry. Moreover, it allows the synthesis of affinity probes, which promotes interactions between nanoparticles and analytes, greatly enhancing the ionization efficiency. This chapter provides a comprehensive discussion on the use of nanoparticles for mass spectrometryrelated applications, from sample preparation methodologies to ionization surfaces. Applications will focus on nanoparticle size, composition, and functionalization, as a comparative point of view on optimal characteristics toward maximization of bioassay efficiency.

Keywords Nanoparticles; Surface functionalization; Mass spectrometry; Affinity probes; SALDI

Introduction Nanoparticles have found extensive use in research and technology for biotechnology biomedical application mainly due to their ease of synthesis and surface functionalization and optical properties [1, 2]. Nanoparticles (or nanoclusters) are considered agglomerates of several atoms, structured into a particle with a size in the 1–100 nm range. These particles may possess different sizes, shapes (e.g., spheres, rods, stars), and composition (e.g., noble metal, graphite, oxide) which in turn modulate their properties. Nanoparticles (NPs) have been used for a wide variety of systems, either to improve existing approaches or to develop new ones. Mass spectrometry (MS) techniques allow the identification of molecules or metabolites of interest according to their mass/charge ratio. MS techniques are essentially composed of three integrated sequential events: ionization, analysis, and detection. Depending on the combination, nanoparticles may sometimes be introduced into the ionization step to boost the system capabilities in terms of detection. This is what happens in some laser desorption/ionization approaches (LDI) [80]. *Email: [email protected] Page 1 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Table 1 First reported applications of nanoparticles for mass spectrometry Surface 30 nm cobalt NPs 2–150 mm graphite particles Porous silicon Several different nanoparticles

Application LDI-TOF SALDI-TOF DIOS SALDI-TOF

Analytes Proteins, polymers Peptides, proteins, organic compounds Peptides, small drug molecules, glycolipids, carbohydrates Peptides, proteins

References [4] [5] [6] [7]

One of the most utilized and advantageous LDI-derived approaches is the matrix-assisted laser desorption/ionization (MALDI) technique. This MS approach was developed by Karas and Hillenkamp [3]. In MALDI analysis, a chemical compound, known as the matrix, is mixed with the sample. The mixture is allowed to dry on an appropriate plate, during which the matrix forms crystals, where the sample becomes embedded and (most likely) heterogeneously distributed. The matrix/sample mixture is then irradiated with a laser: the matrix absorbs the laser energy and transfers it to the sample, promoting a soft ionization. The ions thus formed are transported to the analyzer where they are separated and then detected. The main advantage of this technique is the utilization of a matrix, which allows for a more controlled energy transfer to the analyte, while protecting it from extensive fragmentation. MALDI is often coupled to time-of-flight (TOF) analyzers, providing a MALDI-TOF combination, suitable and most used for analyzing biomolecules, such as peptides or proteins. At the same time, Karas and Hillenkamp and Tanaka and co-workers [4] developed a distinct methodology for LDI analysis of high molecular weight proteins and polymers using 30 nm cobalt NPs (CoNPs) dispersed in glycerol to assist in the ionization process, instead of an organic matrix. This was the first report on LDI using an inorganic surface other than an organic matrix to absorb and transfer energy to the analyte (see Table 1). Later, Sunner et al. [5] followed the same idea and coined the term surface-assisted laser desorption/ionization (SALDI) for the first time applied to graphite, to distinguish desorption/ionization performed on an inorganic surface from organic used in MALDI. Four years later, Wei et al. [6] developed desorption/ ionization on silicon (DIOS), where the inorganic surface is composed of an array of silicon. Since then, employed many different NPs have been used as an inorganic surface to facilitate ionization, instead of the traditional organic matrix [7–9]. Different names have been used to define this approach, SALDI, nanoparticle-assisted laser desorption/ionization (nano-PALDI), etc., but all with the common purpose of finding an organic matrix-free alternative optimal for soft ionization of biomolecules with better sensitivity and reduced costs. Throughout this chapter, the term SALDI will be the only one used when referring to different types of nanoparticles, although it may include other inorganic surfaces.

General Aspects of Nanoparticles for Sample Preparation and Mass Spectrometry Applications Before mass spectrometry, sample treatment is mandatory. This step may serve to either isolate and purify the target analyte from a complex biological matrix or to increase its concentration to the limits of detection of the analysis technique. Nanoparticles have found plenty of use in protocols for sample preparation prior to detection, as their chemical properties often allow for simple surface modification with a wide variety of compounds, and these derivatized nanoparticles act as better affinity or capturing probes, isolating and pre-concentrating the analyte of interest. As mass spectrometry techniques are partially composed of integrated events of ionization and analysis, different ionization procedures, such as MALDI, fast atom bombardment (FAB), and electrospray ionization (ESI), may be combined with distinct analyzers, such as TOF, orbitrap, or triple quadrupole, to attain mass spectrometry approaches

Page 2 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Table 2 Nanoparticle-based strategies for sample preparation Nanoparticles AuNPs AuNPs

Strategy Trypsin digestion and adsorption of peptides Separation through adsorption

Analyte Peptides

AuNPs

Separation by gold–thiol bonding

Aptamer–AuNPs

Capture probes

AuNPs with magnetic particles

Capture probes

Thiolated biomolecules ATP and glutathione Thrombin

MNPs with TiO2

Capture probes

Phosphopeptides

MNPs

SPE extraction agents

Estrogens

Magnetic@SiO2 NPs Polydopamine-modified MNPs

SPE extraction agents SPE extraction agents

Magnetic SiO2 NPs

On-plate separation

Pesticides Hydrophobic pollutants Fatty acids

Zr-modified SiO2 NPs

Capture probes

Phosphopeptides

Cobalt oxide NPs

NP-based liquid–liquid extraction

Proteins

Nickel oxide NPs

Phosphopeptide

Zinc oxide NPs

Microwave-assisted peptide enrichment Bacterial pre-concentration

Cerium oxide NPs

NPs as mass tags

Polyarginine-, TiO2-coated nanodiamonds

Affinity probes

Serum proteins

Staphylococcus aureus Protein phosphorylation Phosphopeptides

Detection MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF LC-MS/ MS GC-MS MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF MALDITOF

References [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [83] [24] [91] [25]

with unique analytical characteristics. Depending on the combination, a mass spectrometry technique may be improved or altered by introducing nanoparticles somewhere into the system, usually for ionization.

Unmodified and Modified Nanoparticles for Sample Preparation Prior to Mass Spectrometry Detection MALDI-TOF is most often utilized for -omics applications, such as proteomics. Just so, many of the reported nanoparticle-based protocols for biomolecule concentration have been highly focused on peptides and proteins, particularly phosphopeptides, as these molecules are not very abundant, therefore somewhat troublesome to analyze, and are considered important cancer biomarkers [10, 11]. Protocols for biomolecular enrichment and pre-concentration may involve unmodified nanoparticles or derivatized nanoparticles (summarized in Table 2). According to the nanoparticle composition, different ligands may be chosen based on the affinity of specific functional groups toward the NP elements (e.g., thiol–gold bonding) [92]. Unmodified gold nanoparticles (AuNPs) have been used as concentrating agents, e.g., bovine serum albumin (BSA) Page 3 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

a Au Au

ATP

Au

Au

SALDI-TOF analysis

Au

Ammonium citrate

Au

Au

Au

AuNPs

Au

b Glucose, PDDA MMP

Thrombin-binding aptamer (TBA)

Digestion with trypsin

Thrombin

MMP

MMP

MMP

AuNPs

c

MALDI-TOF analysis

Target analyte Fe2O4

Fe2O4 Fe2O4

Fe2O4

Fe2O4

Fe2O4 Fe2O4

Fe2O4

Fe2O4

Magnetic separation

Fe2O4 Fe2O4 Fe2O4 Fe2O4 Fe2O4

SALDI-TOF analysis

Fe2O4

Fe3O4@PDA NPs

m/z

Fig. 1 Schematic representation of sample preparation methodologies using nanoparticles: (a) illustration of the interactions of ATP with apt–AuNPs and AuNPs, for SALDI-TOF analysis (Adapted with permission from [15]); (b) synthesis of AuNP-coated magnetic microparticles (MMPs), thrombin capture using a thrombin-binding aptamer (TBA), subsequent digestion with trypsin and MALDI-TOF analysis (Adapted with permission from [16]); (c) procedure of SALDI-TOF-MS based on Fe3O4@PDA NPs as adsorbent and surface for desorption/ionization (Adapted with permission from [20])

passively adsorbs to their surface. A trypsin digestion is carried out and resulting peptides interact with AuNP surface [12]. An internal standard allows product quantification, using a-cyano-4-hydroxicinnamic acid (CHCA) as an organic matrix for MALDI-TOF. Following a similar principle, López-Cortes et al. [13] have utilized AuNPs to separate serum proteins for subsequent fingerprinting identification by MALDI-TOF-MS. A mixture of 14 nm and 3.5 nm citrate-capped AuNPs was used for separation and analysis of biomolecules containing thiol groups, as the thiol groups show high affinity toward the gold surface and binding is strong and extremely likely to occur [14]. Aptamer–gold nanoparticle conjugates have also been used as affinity probes for SALDI-TOF analysis of adenosine triphosphate (ATP) and glutathione (GSH), improving sensitivity when compared to traditional matrices [15] – see Fig. 1a. A curious approach, using AuNPs adsorbed to the surface of magnetic microparticles (MMPs), was developed to facilitate functionalization with a thrombin-binding aptamer for capture of thrombin molecules (see scheme in Fig. 1b), which were subsequently digested with trypsin and analyzed by MALDI-TOF [16]. Magnetic nanoparticles (MNPs) have also been most utilized for sample preparation and pre-concentration, as their magnetic properties make them ideal for simple and fast separation of target analytes from complex samples. Thus, phosphopeptide enrichment was achieved by using magnetic carbon-encapsulated iron nanoparticles coated with titanium dioxide (TiO2) as affinity probes [17]. The use of titanium, which possesses elevated affinity for phosphate groups, ensures an efficient capture of phosphopeptides. This approach was used to isolate tryptic digests from HeLa cell lysates and allowed the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

identification of 1,415 unique phosphopeptides and 1,093 phosphorylation sites. Others have used MNPs functionalized with polypyrrole as solid-phase extraction (SPE) agents [18]. The p-conjugated structure and hydrophobicity of the polypyrrole coating are ideal for enhanced extraction of estrogens from milk samples without the need of protein precipitation, which allowed detection limits as low as 5 ng/L via liquid chromatography tandem–mass spectrometry (LC-MS/MS). Another example of MNPs as SPE agents was described by Xiong et al. [19], where C18-modified magnetic@silica core–shell nanoparticles were used for detection of low concentrations of pesticides in aqueous samples. This is one of the few applications of NP-based sample preparation for gas chromatography–mass spectrometry (GC-MS) detection. Polydopamine-modified MNPs were also employed for a magnetic SPE, toward pre-concentration of hydrophobic pollutants [20] – see scheme on Fig. 1c. A different approach describing magnetic silica nanoparticles (SiO2 NPs) coated with either aminopropyl or phenyl groups for on-plate separation was devised by Lim et al. [21]. This way, hydrophilic and hydrophobic sample components may be separated from each other and analyzed separately. Thus, the fatty acid fingerprint was obtained with lower sensitivity than with 2,5-dihydroxybenzoic (DHB) acid organic matrix due to the lack of interference from the polar amino acids in the sample (previously separated). Modified SiO2 NPs have also been used toward biomolecular enrichment [22]. Zirconium arsenate- and titanium arsenate-modified SiO2 NPs showed higher affinity for phosphate groups (due to Zr4+ and Ti4+ coordination sphere) and have thus been used to bind and capture phosphopeptides, for subsequent digestion and MALDI-TOF analysis. In addition to SiO2, other oxide NPs have been reported for extraction and concentration of biomolecules. Cobalt oxide nanoparticles (Co3O4 NPs) functionalized with cetyltrimethylammonium (CTA+) were successfully applied for NP-based liquid–liquid microextraction for protein enrichment in milk samples, allowing a highly sensitive analysis of a protein mixture of insulin, chymotrypsinogen, and lysozyme with MALDI-TOF-MS [23]. Nickel oxide nanoparticles (NiO NPs) are extremely effective in concentrating trace levels of phosphopeptides from previously digested samples through a microwaveassisted phosphopeptide enrichment approach where samples are digested using microwave energy and phosphopeptides are subsequently pre-concentrated using NiO NPs [83]. The system was applied to MALDI-TOF determination of a- and b-casein phosphopeptides 30 times less concentrated than the remaining sample components, with detection limits in the nanomolar range and good signal-to-noise (S/N) ratio. Also, zinc oxide nanoparticles (ZnO NPs) were utilized for pre-concentration of bacteria and applied on the MALDI plate together with the sinapinic acid (SA) organic matrix for mass signal enhancement, which allowed isolation and identification of the pathogen Staphylococcus aureus from laboratory ants [24]. A recently reported system [26] relies on tandem mass tags (TMTs) and the capacity of cerium oxide nanoparticles (CeO2 NPs) to efficiently dephosphorylate peptide chains [91]. A digest resulting from phosphoprotein trypsinization is equally divided, and CeO2 NPs are added to one half, to ensure a complete dephosphorylation. The different halves are then tagged with two isotopic different TMTs and pooled back together for MALDI analysis and isotope quantification through MS/MS (see Fig. 2). This method was used to quantify the absolute phosphorylation of the eukaryotic initiation factor 3H (eIF3H). Shiau and co-workers [25] reported a one-pot extraction of different types of phosphopeptides using polyarginine- and TiO2-coated nanodiamonds as affinity probes for multiply and singly phosphorylated peptides, respectively. The specificity of the approach was demonstrated by pre-concentrating b-casein digests in the presence of excess BSA (1:1,000), showing the capability to overcome suppression effects that occur during phosphopeptide MALDI analysis.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Fig. 2 Schematic overview using cerium oxide nanoparticles and tandem mass tags to measure protein phosphorylation levels (Reprinted with permission from [26]. Copyright 2012 American Chemical Society)

Nanoparticle-Based Mass Spectrometry Detection

Since the first application in 1988, NPs have been used as inorganic surfaces to overcome the main limitations of MALDI-MS, namely, due to three main aspects: homogeneity in crystallization preventing the formation of sweet spots, absence of matrix interference due to ionization of matrix-derived molecular ions, and efficiency of energy transfer to the analyte. Crystal orientation heterogeneity verified during crystallization of the matrix/analyte mixture will often originate sweet spots on the MALDI plate, which render the analysis more complicated and make Page 6 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

quantification very difficult to accomplish. The high surface area of nanoparticles allows better sample deposition and absorption and homogeneity in the mixture, preventing formation of sweet spots upon application [27, 78, 79]. What is more, spot-to-spot and shot-to-shot variability is considerably diminished for more accurate quantification approaches [14, 28]. In contrast to what happens in commonly used organic matrices, NPs in general are not so easily ionizable upon laser irradiation [29–31]. Laser incidence may cause fragmentation and desorption of matrix-derived molecular ions producing spectra with high background signal, thus rendering analysis of low molecular weight compounds rather ineffective [32, 33]. Depending on the NP composition and properties, the mass spectrum may present some signals corresponding to ionization of metal clusters, e.g., gold nanoparticles [8]. Considering that the size influences the NP ionization and mass signals, interference is greatly reduced when compared to conventional organic matrices. Due to their minimum size (1 ~ 100 nm), NPs possess excellent optical properties deriving from phenomena such as surface plasmon resonance [1]. Surface plasmons may be defined as the collective oscillations of electrons at the NPs’ surface. If the frequency of electron oscillation matches the frequency of incident light, this interaction (resonance) results in high extinction and scattering. Noble metal nanoparticles, such as gold or silver, possess an enhanced absorptivity in the ultraviolet–visible region, which favors transformation of photothermal energy during laser irradiation and provides a more effective ionization of analytes [6, 34]. Photothermal properties and heat generation at the NP surface are directly dependent of NP volume, size, and incident energy, and heat generation at a given point is related to the distance to the center of the NP [35, 36]. This way, ligands covalently bound to the NP surface will ionize easily as distance to the NP is minimal, but the desorption process is more difficult due to higher bonddissociation energy. Analytes interacting weakly with NP surface will ionize differently than those covalently bound, and so NPs ought to be tailored to optimize interaction to maximize ionization and desorption efficiency. Most reports of nanoparticles for SALDI-MS focus on spherical nanoparticles regardless of composition. Spherical nanoparticles seem to be the most effective for SALDI due to their high surface area, homogeneity of functionalization with ligands, and surface heating, and energy transfer from nanospheres to the vicinity occurs evenly. Of extreme relevance is the fact that the most commonly used laser for ionization in SALDI is the nitrogen laser with a fixed wavelength at 337 nm, and nanospheres often possess high absorption values in this region of the spectrum. Other shapes usually exhibit high absorptions in other regions of the spectrum (e.g., nanorods, 650–800 nm), which would require change of laser. Despite the advantages, a major limitation observed so far is the optimization of the adequate NP surface according to the analyte of interest, rendering some NPs very inefficient as surface for LDI of some analytes [15], whereas commonly used organic matrices are often directed to a particular class or type of molecules, e.g., 3-hydroxipicolinic acid (3-HPA) for long polymers and oligonucleotides and CHCA for peptides. The following section will discuss the use of nanoparticles for SALDI-TOF-MS analysis for a wide number of analytes, considering surface functionalization.

Nanoparticles for Laser Desorption/Ionization Mass Spectrometry Noble Metal Nanoparticles Noble metal NPs, functionalized or not, have been extensively used for SALDI-MS analysis of a multitude of biomolecules and elements. These NPs have been employed as affinity probes/preconcentrating agents and surface for LDI simultaneously (see Table 3). The following section considers

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AuNPs, PtNPs AgNPs

Antibody-modified AuNPs Au@SiO2 NPs CHCA-modified AuNPs Dopamine dithiocarbamate-modified AuNPs Nile red-adsorbed AuNPs AuNPs, AgNPs, PtNPs

Aptamer-modified AuNPs

Nanoparticle for ionization AuNPs

Glutathione, cysteine, homocysteine Surfactant, peptides

14, 32, 56 20, 10–30, 20 14, 37 160 20, 60 34 50–100

Biomolecules, peptides, proteins Peptides Olefins Estrogen Lactobacillus and Streptococcus individuals

Detected analyte Peptides Melamine, ammeline, ammelide Tumor biomarkers (TRP, 5-HTP, 5-HT, and 5-HIAA) Nucleotides, modified nucleotides Glutathione, cysteine, homocysteine Captopril Carbohydrates Carbohydrates, indolamines, peptides ATP, glutathione Thrombin Escherichia coli Polymers Peptides Phosphopeptides

Size (nm) 2–10 14 13 13 3.5 and 14 14 9–14 13.2 14 13.3 5.5 20–38 14 5–12

Table 3 Noble metal nanoparticles for SALDI-MS

[80] [46] [47] [48] [49]

[45] [9]

1–2 mM and 25–54 nM N.A.a 140 fmol, 23pmol N.A.a N.A.a 0.2–2.1 mM N.A.a

References [8] [37] [28] [38] [14] [39] [90] [40] [15] [87] [41] [42] [43] [44]

Detection limit 100 fmol 5, 10, and 300 nM 1.5 and 1.8 mM ~5 mM 2–44 nM 1 mM 82–151 nM 46.5–5,115 nM 0.48 mM 50 fM 1,000 CFU.mL 1 10 fmol 20 pmol 0.01–1.6 nM

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Page 8 of 23

N.A. non-available

50

IgG-modified PtNPs

a

N.A.a 10, 20 N.A.a 100–400 10 2–10

Monoisotopic AgNPs Functionalized AgNPs PtNPs

Alkaloids, saccharides, amino acids, nucleosides Glutathione, cysteine, homocysteine Peptides, insulin, phospholipids, proteins Peptides Amino acids, peptides, proteins Saccharomyces cerevisiae, Chlamydomonas reinhardtii Bacillus thuringiensis, B. subtilis

4.5 nmol, 49–112 pmol 7 nM 0.7 fmol 100 pmol N.A.a 3,200 cells/mL and 640 cells/ mL N.A.a [55]

[50] [51] [52] [53] [88] [54]

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Page 9 of 23

[ATP − H]−

b

1

0 1

c

470

520

350

400

[GSH + K]+

0 420 [GSH + Na]+

Signal Intensity (a. u.)

0 1

a

[ATP − Pt]

1

−

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

d

0 300

m/z

Fig. 3 Mass spectra of ATP and GSH in a cell lysate. (a, c) Apt–AuNPs and AuNPs were used both to capture ATP and GSH in deproteinized cell lysates and to assist in ionization; (b, d) DHB was used as the matrix. 1.0 mL of an ammonium citrate solution (15.0 mM, pH 6.0) containing 15.0 mM CTAB was used as additive. Spectra were acquired in both negative-ion mode (a, b) and positive-ion mode (c, d). The peaks at m/z 444.07, 460.07, and 481.07 in (a) are assigned to [Au + citrate + 2NH4 + Na – H] , [Au + citrate + 2NH4 + K – H] , and [Au + citrate + NH4 + 2 K – H] ions (Reprinted with permission from [15]. Copyright 2007 American Chemical Society)

gold, silver, and platinum NPs for SALDI-MS of different analytes, with an emphasis on functionalized NPs. For AuNP-based SALDI-MS analysis, the most utilized AuNPs are citrate-capped 14 nm ones, most favorable for ionization of biomolecules when compared to others with smaller and larger diameter [45]. These AuNPs can be easily synthesized with a relatively fair control of size dispersion and reproducibility via the method developed by Turkevich [56]. Moreover, citrate-capped AuNPs are rather simple to derivatize with molecules containing thiol or amino functional groups [2, 43]. Citrate-capped AuNPs have been reported for LDI detection of melamine, ammeline, and ammelide in infant formula and grain powder with detection limits in the nanomolar range [37]. These compounds interact weakly with AuNPs, through Au–N bonds, and allow easy and rapid separation through centrifugation, prior to analysis. On a different study, AuNP-based SALDI was employed toward quantification of four urinary biomarkers for carcinoid tumors in human urine samples [28], by using an internal standard. Recently, a nucleotide-fingerprint identification concept was proposed for the determination of modified and unmodified nucleotides using AuNPs for SALDI-TOF [38]. Aptamer–AuNP conjugates have also been used as capturing probes for ATP and glutathione molecules for SALDI analysis [15], but unmodified 14 nm AuNPs were used as surface for LDI because the aptamer–AuNP conjugates were not effective for biomolecular ionization (Fig. 3). Another consideration on efficiency of AuNPs toward ionization was recently presented by Kim and Lee [57], where a time-offlight secondary ion mass spectrometry (TOF-SIMS) signal amplification is promoted by enlarging AuNPs through the NH2OH/Au3+ seeding method. Due to an increased surface area and spherical structure of the Au, the mass signal intensity of the peptides became higher on the enlarged-AuNP Page 10 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

a 5 (a)

[Au1]+

[Au2]+

[Au3]+

Signal Intensity (a. u.)

0 5 (b) 0 5 (c) 0 5 (d) 0 5 (e) 0 5 (f) 0 100

200

300

400

500

600

700

800

900

1000

m/z 0.5

0.25

0

(IAu+ - IAu+)/IAu+

0

b

0 0

10−12

10−11

10−10

10−9

10−8

[Thrombin] (M)

Fig. 4 (a) Mass spectra recorded using TBA29 AuNP/NCM (10 pM) as a probe for the detection of (a) 0, (b) 1.0  10 13, (c) 1.0  10 12, (d) 1.0  10 11, (e) 1.0  10 10, (f) 1.0  10 9, and (g) 1.0  10 8 M spiked thrombin in a biological buffer containing BSA (100 mM). (b) Relative signal intensity of [Au1]+ ions [(IAu+0 IAu+)/IAu+0] plotted with respect to the concentration of thrombin (0–10 nM) (Reprinted with permission from [87]. Copyright 2012 American Chemical Society)

surface, when compared to bare gold surface or submonolayer of AuNPs. AuNPs functionalized with a thrombin-binding aptamer were employed for thrombin binding and deposition on a nitrocellulose membrane [87]. Upon pulsed laser irradiation, Au cluster signals decreased proportionally to the amount of bound thrombin, and by measuring the intensity of these decreasing mass signals, very sensitive (fM) quantification of thrombin was achieved (see Fig. 4). Antibody-modified AuNPs were used to actively interact with bacterial components, allowing for a rapid separation by centrifugation and subsequent deposition on a nitrocellulose membrane for SALDIMS identification of bacteria [41]. Upon deposition, samples were irradiated with a pulsed laser (LDI), and the Au cluster signals were analyzed. This method was validated by analyzing different samples (tap water, juice, milk, and urine), and if the surface modification is altered, it may be employed for several other analytes, such as biomarkers and viral epitopes. Gold–silica core–shell nanoparticles (Au@SiO2 CSNPs) for LDI-TOF-MS [42] with different core sizes and shell thickness have been combined to attain optimal enhanced ionization. The system was applied to a polymer (dPEG6), and results suggest that NPs with smaller core and ultrathin SiO2 shell Page 11 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

* 800

*

[E2-H]− [E3-H]−

Intensity (a. u.)

[E1-H]−

400

*

* *

*

*

*

0 265

270

275

280

285

290

m/z

Fig. 5 SALDI mass spectrum of a mixture of estrogens, using AgNPs as a surface: 100 mM of estrone (E1), 10 mM of estriol (E2), and 100 mM of estradiol (E3). Peaks from the background are marked as asterisks (Reprinted with permission from [48]. Copyright 2008 American Chemical Society)

(2–4 nm) exhibited the best efficiency, both in signal intensity and S/N ratio. Comparing to common MALDI-TOF-MS, this approach shows improved sensitivity for small molecules, but is not capable to match common organic matrices. AuNPs functionalized with dopamine dithiocarbamate were also used as a surface for SALDI-TOF-MS quantification of small molecules [44], allowing cleaner mass spectra than conventional MALDI-TOF using CHCA as a matrix and better sensitivity when analyzing and quantifying small molecules such as glutathione or the drugs desipramine and enrofloxacin. Besides this, dopamine dithiocarbamate-modified AuNPs served as efficient affinity probes and ionization surface for rapid and straightforward and determination of phosphopeptides from casein proteins. Silver nanoparticles (AgNPs) have also been employed in LDI processes. AgNPs exhibit higher scattering than AuNPs, which may be valuable when transferring absorbed energy to an analyte in the vicinity [46]. For example, unmodified AgNPs were used both as affinity probes and as a surface for SALDI for determination and quantification of three different estrogen-derived molecules [48] in the low micromolar range (Fig. 5). Estrogens in the urine were capable of establishing weak interactions with the AgNPs’ surface, allowing for separation and pre-concentration but without notable sensitivity (0.2 mM). Recently, Niziol et al. [50] applied monoisotopic cationic 109AgNPs as a surface for LDI analysis of different low molecular weight organic compounds, including alkaloids, saccharides, amino acids, nucleosides, and nucleic bases. These 109AgNPs were further characterized on cationization adducts for higher sensitivity, mass accuracy, and resolution. SALDI-TOF using AgNPs has also been employed toward bacterial analysis of dairy products [49]. By using AgNPs, bacterial identification was improved by sixfold in yogurt samples preventing interference from milk complex proteins. In the same study, an ionic solution of CrO42 was also used for SALDI-MS analysis and proved to be more effective than AgNPs as it improved bacteria determination by 40-fold. AgNPs functionalized with different functional groups were employed as both affinity probes and SALDI surface for analysis of biothiol molecules such as glutathione, cysteine, and homocysteine [51]. A comparison between 10 and 20 nm AgNPs for LDI revealed that smaller diameters correspond to better

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

efficiency, possibly due to a higher surface area. Unmodified AgNPs were also used as a surface for direct SALDI-MS analysis of sulfur drugs. Platinum nanoparticles (PtNPs) have been characterized in terms of SALDI efficiency, where the elevated melting point and low heat capacity of the Pt contributed to a more effective ionization than the one obtained with silver and copper NPs [9]. The use of PtNPs for SALDI analysis of amino acids, peptides, proteins, and microwave-digested proteins has also been reported (Shrivas et al. 2011). PtNPs played three main roles in this approach: affinity probe, surface for LDI, and acceleration of protein digestion by absorbing the microwave irradiation. Higher numbers of peptide sequences were obtained for PtNP-accelerated microwave digestion of the lysozyme protein, when compared to standard digestion of proteins for MALDI-MS. Besides being used as surface for SALDI, PtNPs with sizes between 2 and 10 nm (mainly 4 nm) were used as additives with an SA matrix to enhance sensitivity when analyzing cell populations of Saccharomyces cerevisiae and Chlamydomonas reinhardtii (an improvement of 125- and fivefold, respectively) [54]. An approach using modified PtNPs for both pre-concentration and as matrix additives for signal enhancement was described for bacterial proteomic analysis [55]. Adding immunoglobulin G-functionalized PtNP probes to samples from rhizospheric soil and carrot plant roots proved to be an effective enrichment strategy, as the PtNP probes interact and adsorb to the bacteria surface. Together with a signal enhancement from the combination of SA with the PtNP probes, Bacillus thuringiensis and B. subtilis isolates were directly detected with low concentrations.

Oxide Nanoparticles Iron oxide nanoparticles (mainly MNPs) have been used both as affinity probes but also as LDI surface. For instance, NPs with different metal compositions (chromium, manganese, iron, and cobalt) were used as surface for ionization toward SALDI-TOF characterization of nucleic acids [58], and iron oxide NPs with hydrogen citrate were considered the most effective for oligonucleotide ionization. DNA analysis using LDI methods is somewhat difficult, and due to its molecular weight and ionization mechanism, specific organic matrices such as 2,4,6-trihydroxyacetophenone (THAP) or 3-HPA are usually utilized. A considerable number of metal adduct signals were detected, which were directly related to the oligonucleotide length. Iron oxide MNPs functionalized with specific antibodies anti-hemagglutinin were employed for ionization of high molecular weight proteins (>30 kDa) and detection of influenza virus H5N2 [59]. As different surface modifications alter affinities and efficiency, MNPs were derivatized with DHB molecules to enhance ionization [60], allowing quantification of small molecules in urine with good precision. A key step was the seed-layer sample preparation on the plate after a liquid–liquid extraction. One of the fundamental aspects in MALDI or SALDI is the crystallization of the matrix/surface/analyte mixture and application of DHB-modified MNPs on the plate before adding the sample: MNP mixture improved homogeneity, thus better analyte quantification. Others have reported the comparison between MALDI- and MNP-based SALDI, while discussing the efficiency of MNPs modified with human serum albumin (HSA) as affinity probes for small drugs [61]. The performance of HSA-modified MNPs as affinity probe improved when using denatured HSA, probably because the open chains ensured the effectiveness of drug extraction, resulting in a tenfold increase in sensitivity. While MALDI showed to be a good approach for the identification solely of warfarin sodium in human urine, SALDI with magnetic NPs made possible identification of other drugs, such as ibuprofen, phenytoin, and camptothecin. More recently, polydopamine-coated MNPs were synthesized and applied as a surface for LDI analysis of eleven small-molecule pollutants (masses ranging from 251.6 to 499.3 Da), including benzo(a)pyrene, perfluorinated compounds, and antibiotics [20] in both positive and negative-ion modes. These MNPs possess higher affinity toward benzo(a)pyrene, which potentiated the development of a magnetic SPE Page 13 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Fig. 6 MALDI/SALDI-TOF mass spectrum of 1 pg/mL benzo(a)pyrene (BaP) in pure water solution without and with Fe3O4@PDA NPs enrichment (Reprinted with permission from [20]. Copyright 2013 American Chemical Society)

protocol for target enrichment that was applied to benzo(a)pyrene pre-concentration from environmental samples (lake water) – see Fig. 6. A SALDI-MS approach with direct application toward detection of platinum-containing antitumor drugs (e.g., cisplatin) was proposed by Radisavljević et al. [62]), where TiO2 NPs were utilized for LDI of transition metal complexes. Specific mass signals when using organic matrix were attained together with the specific signals of TiO2 NPs. However, when compared with MALDI, TiO2 NP-based SALDI did not constitute an improvement in the method sensitivity. Determination of steroid hormones in human urine has also been achieved through SALDI-MS using catechin-modified 5 nm TiO2 NPs for LDI analysis of cortisone, hydrocortisone, progesterone, and testosterone, with detection limits below 1 mM [82]. Silica nanoparticles (SiO2 NPs) with an average diameter of 199 nm prepared by sol–gel chemistry have been shown to improve peptide ionization [63]. SiO2 NP deposition on the plate prior to sample application improves sensitivity (in the fM range) and soft desorption/ionization when analyzing a variety of components on a peptide mixture, with masses comprised from 500 to 1,700 Da. MCM-41-type mesoporous SiO2 NPs have also been used as matrix additive for peptide analysis [64]. The presence of these SiO2 NPs provided mass signal suppression, thus reduced matrix interference when using DHB or CHCA. For the tested peptides however, the referred SiO2 NPs revealed ineffective for LDI analysis. An elegant concept using functionalized SiO2 NP probes for inductively coupled plasma mass spectrometry (ICP-MS) was presented by Yan et al. [65]. In this work, lanthanide (Ln)-coded proteasespecific peptide-functionalized SiO2 NP probes were employed for a multiplex protease assay, where the sample proteases will cleave the peptides and the Ln is released from the probes. Afterward, non-cleaved Ln-coded protease-specific peptide–NP probes were pelleted by centrifugation and discarded, while the protease-cleaved Ln in the supernatant was analyzed using ICP-MS. The high specificity of the synthesized probes for a determined protease was also assessed. There are not many reports on LDI approaches using magnesium oxide nanoparticles (MgO2 NPs). One report described these metal oxide NPs for SALDI analysis of polyester degradation products [66], showing that better resolution, cleaner background, and S/N ratios 20–100 times higher for MgO2 NPs when compared to organic matrices such as DHB, dithranol, and 2-(4-Hydroxyphenylazo)benzoic acid (HABA).

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Quantum Dots

Quantum dots are semiconductor nanocrystals with distinct electronic properties, firstly described by Ekimov and Onushchenko [67]. The use of quantum dots (QDs) for SALDI applications has thus far not been widely explored. Among the few existing reports, one describes the use of 3-mercaptopropionic acid (3-MPA)-modified zinc selenide QDs (ZnSe) for SALDI-MS analysis of peptides and proteins from a sodium salt solution [68]. The analytes adsorb to the surface of 3-MPA-modified QDs, resulting in improved ionization, and most peptides and proteins are detected as sodium adduct ions with mass signal intensities enhanced 25- to 95-fold. Another method using cadmium selenide (CdSe) QDs functionalized with 11-mercaptoundecanoic acid (MUA) was reported for SALDI analysis of amino acids and peptides [69]. The functional groups at the CdSe QD surface interact with low concentration biomolecules in the sample, thus improving ionization. This QD-based SALDI approach allowed selective ionization of insulin, lysozyme, and myoglobin with high resolution and increased sensitivity with quantification limit of 100 pM, which is not attained using conventional MALDI with SA as matrix. Moreover, CdSe QDs were successfully employed on a pre-concentration protocol, toward peptide analysis after microwaveassisted enzymatic digestion of lysozyme. One of the advantages of SALDI over MALDI is homogeneous crystallization on the plate, which avoids sweet spot formation and, in many cases, enables analyte quantification due to minimal shot-toshot variability. Therefore, most SALDI applications and developments focus on sweet spot prevention. An extremely curious approach uses quantum dots (QDs) to promote the formation of sweet spots visible to the naked eye [70]. In this study, the proportion of matrix/QDs for optimum crystallization and generation of visible sweet spots on a metallic plate was assessed, which originated higher mass signals for standard peptides and phosphopeptides (five and threefold, respectively) than those observed by conventional MALDI analysis. Moreover, QD-assisted LDI analysis resulted in greater number and more intense peaks leading to better detection of individual peptides in peptide mixtures (Fig. 7). These findings are in agreement with the ones reported for core–shell CdSe/ZnS QDs in conjunction with CHCA for MALDI analysis of peptides [71]. These nanocomposites when spotted together with CHCA improve S/N ratio, mass signal quality, and several specific signals allowing detection of a number of peptides otherwise undetected. Nevertheless, core–shell CdSe/ZnS QDs alone seem to be inefficient as surface for LDI of peptide samples as no mass signals were observed in the absence of an organic matrix.

Carbon-Containing Nanoparticles Graphene nanoparticles have already been used for SALDI-TOF characterization of diverse commercial polymers, such as polypropylene glycol, polystyrene, and polymethyl methacrylate in a wide range of molecular weights, comprised between 425 and 3,500 Da [72]. These polymer molecules have a particular affinity toward graphene NPs, adsorbing to its surface and providing an efficient ionization without organic matrix interference and sweet spot formation that greatly enhance shot-to-shot and spot-to-spot reproducibility. Co-crystallization on the plate was not verified, which indicates that this approach may be utilized for the analysis of both soluble and insoluble polymers. Sensitivity and effect of different graphene-based nanoparticles, e.g., graphene, graphene oxide, and reduced graphene oxide, for LDI of low molecular weight molecules and compounds, such as flavonoids and phenylpropanoids, have also been reported [86]. Flavonoids and phenylpropanoids, such as coumarin and its derivatives, are usually difficult to analyze by MALDI due to the absence of a suitable organic matrix, for optimal desorption. Graphene oxide NPs seemed to be a suitable matrix substituent for SALDI analysis of these analytes in negative-ion mode, despite some undesired fragmentation upon laser irradiation. Other NPs, such as graphitized carbon NPs, have been used for SALDI-TOF/TOF-MS quantification of citrulline [73] via a novel method of tandem MS-parallel fragmentation monitoring (PFM) using graphitized carbon NPs as a surface for LDI. This way, it was possible to quantify citrulline and an isotopic analog that is 1 mass unit Page 15 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

Fig. 7 MALDI mass spectra obtained from BSA digest on a microstructure chip. The matrices included (a) CHCA only and (b) CHCA combined with QDs. The open circle indicates the peaks that existed only in QD-assisted MALDI analysis. The open and solid stars indicate less than or more than a 1.5-fold improvement in signals, respectively (Reprinted with permission from [70]. Copyright 2011 American Chemical Society)

heavier ([ureido-13C] citrulline). Another approach used graphene-coated cobalt NPs functionalized with benzylamine groups for target enrichment and subsequent direct SALDI analysis of organic compounds [85]. These 30 nm modified NPs constitute a CoC–NH2 nanomagnet suitable for affinity SALDI-MS, capable of magnetic separation and direct on-plate analysis. A practical demonstration of this approach was demonstrated by extracting perfluorooctane sulfonate from a large volume of aqueous solution with high sensitivity (0.1 ng/L). Its applicability for the enrichment and SALDI-MS detection of small drugs, pentachlorophenol, bisphenol A, and polyfluorinated compounds (PFCs) with varying chain length was also evaluated. Benzylamine groups seem to increase the yield of peptide ions and decrease fragmentation of benzylpyridinium ions during SALDI analysis.

Nanoparticles for Mass Spectrometry Imaging In the last decade, the visualization of analytes being ionized in a tissue or surface at a given moment has been made possible – mass spectrometry imaging (MSI) [74, 75]. This strategy allows for two-dimensional spatial localization of metabolites or peptides in a specific tissue. Although many applications of the MSI technique have been reported, this section will focus on SALDI-MS imaging using NPs, namely, noble metal, TiO2, and SiO2 NPs. The main advantage over conventional MALDI imaging is that specific mass signals for NP-based desorption become visible, which allows localization of a vast number of biomolecules in a sample [76, 89]. AuNPs functionalized with unique ligands containing a thiol group, an alkane chain, an oligo(ethylene) glycol, and a variable ammonium group to provide distinct mass signatures are capable of acting as Page 16 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_32-1 # Springer International Publishing Switzerland 2015

exclusive mass barcodes as LDI agents for the analysis of ink-jet-printed patterns [77]. The patterns can only be visualized by mass constituting a system for potential anti-counterfeiting applications in industry. Also, vapor deposition of PtNPs for SALDI-MS analysis of ink-jet-printed surfaces allowed identification of low molecular weight pigments and other small molecules (e.g., sugars) on ink-jet-printed papers [84]. A comparison between PtNP and AuNP vapor deposition showed that PtNPs originated more intense mass signals than AuNPs for a given sample. Direct application of SALDI-MS imaging using AuNP to life sciences was demonstrated through the molecular histology analysis of mouse brain tissue by Tang et al. [76]. This approach relies on the coating of the target tissue with a layer of AuNPs with less than 10 nm by an ion sputtering technique suitable for ionization and subsequent identification of a wide range of metabolites, e.g., neurotransmitters, nucleobases, and fatty acids in different regions of mouse brain with great sensitivity, which enabled the distinction between tumor and unaffected brain areas. Another SALDI imaging for the analysis of low weight metabolites in mouse brain used TiO2 NPs for ionization [89]. The application of TiO2 NPs for MALDI imaging using DHB as matrix demonstrated that TiO2 NPs increase sensitivity allowing identification of a higher number of metabolites in distinct brain regions. The analyzed brain tissue showed 179 specific mass signals when analyzed with TiO2 NPs and only four specific mass signals when using DHB.

Conclusion Since the first experiments in the late 1980s, functionalized and unmodified NPs have proposed nanoparticles have shown to be suitable platforms for optimal ionization of molecules for SALDI-MS analysis. In most situations, NPs, alone or in combination with traditional organic matrices, showed remarkable capabilities for analyte characterization and quantification of biological, environmental, or industrial samples. The signal enhancement and background reduction provided by nanoparticle-based SALDI-MS in protein and peptide detection strategies have assisted the development of extremely sensitive platforms suitable for metabolite identification and localization in imaging approaches. Additionally, functionalized nanoparticles provide extremely rapid, simple, and inexpensive sample preparation methodologies for subsequent analysis by MS. The potential of nanoparticles with different compositions for ionization of biomolecules and the effects produced on the attained mass spectra are still the focus of great debate. Further investigation is still required to clearly evaluate the use of NPs as platforms for analyte enrichment or energy transfer during laser irradiation and the impact on assay efficiency of the nanoparticles’ size, composition, and functionalization. Nevertheless, thus far, nanoparticles have already proven that they can be suitable platforms for simple and rapid characterization of important molecules such as protein biomarkers with increased sensitivity and reproducibility by mass spectrometry-based techniques. With the widespread synthesis, characterization and application of nanoparticles in bioassays, one can predict that NPs will soon be part of the elementary selection of surfaces that will further potentiate the use of mass spectrometry as a key technique in molecule identification and quantitation.

Acknowledgments The authors acknowledge Fundação para a Ciência e Tecnologia (FCT/MEC) for funding CIGMH (PEstOE/SAU/UI0009/2011), REQUIMTE (PEst-C/EQB/LA0006/2011), UCIBIO (UID/Multi/04378/2013), and SFRH/BD/64026/2009 for M. Larguinho. Page 17 of 23

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54. M. Manikandan, H. Wu, N. Hasan, Cell population based mass spectrometry using platinum nanodots for algal and fungal studies. Biosens. Bioelectron. 35, 493–497 (2012) 55. F. Ahmad, M.A. Siddiqui, O.O. Babalola, H. Wu, Biofunctionalization of nanoparticle assisted mass spectrometry as biosensors for rapid detection of plant associated bacteria. Biosens. Bioelectron. 35, 235–242 (2012) 56. J. Turkevich, Colloidal Gold. Part I. Gold Bull. 18, 86–91 (1985) 57. Y. Kim, T.G. Lee, Secondary ions mass spectrometric signal enhancement of peptides on enlargedgold nanoparticle surfaces. Anal. Chem. 84, 4784–4788 (2012) 58. S. Taira, I. Osaka, S. Shimma, D. Kaneko, T. Hiroki, Y. Kawamura-Konishi, Y. Ichiyanagi, Oligonucleotide analysis by nanoparticle-assisted laser desorption/ionization mass spectrometry. Analyst 137, 2006–2010 (2012) 59. T. Chou, H. Wei, C. Wang, Y. Chen, J. Fang, Rapid and specific influenza virus detection by functionalized magnetic nanoparticles and mass spectrometry. J. Nanobiotechnol. 9, 52–64 (2011) 60. Y. Ho, M. Tseng, Y. Lu, C. Lin, Y. Chen, M. Fuh, Nanoparticle-assisted MALDI-TOF MS combined with seed-layer surface preparation for quantification of small molecules. Anal. Chim. Acta 697, 1–7 (2011) 61. Y. Iwaki, H. Kawasaki, R. Arakawa, Human serum albumin-modified Fe3O4 magnetic nanoparticles for affinity-SALDI-MS of small-molecule drugs in biological liquids. Anal. Sci. 28, 893–900 (2012) 62. M. Radisavljević, T. Kamčeva, I. Vukićević, M. Radoičić, Z. Šaponjić, M. Petković, Colloidal TiO2 nanoparticles as substrates for M(S)ALDI mass spectrometry of transition metal complexes. Rapid Commun. Mass Spectrom. 26, 2041–2050 (2012) 63. M. Dupré, S. Cantel, J. Durand, J. Martinez, C. Enjalbal, Silica nanoparticles pre-spotted onto target plate for laser desorption/ionization mass spectrometry analyses of peptides. Anal. Chim. Acta 741, 47–57 (2012) 64. C. Jun, H. Tianxi, F. Xuemei, A novel matrix additive, MCM-41-type mesoporous silica nanoparticles, used for analysis of peptides by MALDI-FT/ICRMS. Talanta 100, 419–424 (2012) 65. X. Yan, L. Yang, Q. Wang, Lanthanide-coded protease-specific peptide–nanoparticle probes for a label-free multiplex protease assay using element mass spectrometry: a proof-of-concept study. Angew. Chem. Int. Ed. 50, 5130–5133 (2011) 66. N. Aminlashgari, M. Hakkarainen, Surface assisted laser desorption/ionization mass spectrometry (SALDI-MS) for analysis of polyester degradation products. J. Am. Soc. Mass Spectrom. 23, 1071–1076 (2012) 67. A.I. Ekimov, A.A. Onushchenko, Quantum size effect in three-dimensional microscopic semiconductor crystals. J. Exp. Theor. Phys. 34, 345–349 (1981) 68. H. Wu, F. Chung, 3‐Mercaptopropionic acid modified ZnSe quantum dots as the matrix for direct surface‐assisted laser desorption/ionization mass spectrometric analysis of peptides/proteins from sodium salt solution. Rapid Commun. Mass Spectrom. 25, 1779–1786 (2011) 69. K. Shrivas, S.K. Kailasa, H. Wu, Quantum dots laser desorption/ionization MS: multifunctional CdSe quantum dots as the matrix, concentrating probes and acceleration for microwave enzymatic digestion for peptide analysis and high resolution detection of proteins in a linear MALDI-TOF MS. Proteomics 9, 2656–2667 (2009) 70. C. Liu, M. Chien, G. Chen, S. Chen, C. Yu, M. Liao, C. Lai, Quantum dot enhancement of peptide detection by matrix-assisted laser desorption/ionization mass spectrometry. Anal. Chem. 83, 6593–6600 (2011) 71. J. Bailes, L. Vidal, D.A. Ivanov, M. Soloviev, Quantum dots improve peptide detection in MALDI MS in a size dependent manner. J. Nanobiotechnol. 7, 10 (2009)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_33-1 # Springer International Publishing Switzerland 2015

Biomediated Atomic Metal Nanoclusters: Synthesis and Theory Mark H. Griepa*, Abby L. Westa, Michael S. P. Sellersa, Molleshree Karnaa, Edric Zhanb and Nabila Hoquea a Weapons and Materials Research Directorate, US Army Research Laboratory, Aberdeen Proving Grounds, MD, USA b United States Military Academy, West Point, NY, USA

Abstract Fluorescent metal nanoclusters are an emerging class of multifunctional materials engineered at the singleatom level, with dimensions approaching the Fermi wavelength of electrons that offer competitive functionalities of traditional semiconductor QDs including tunable emission, ease of conjugation, extended photostability, and high quantum yield. With the additional advantages of being composed of nontoxic/ biocompatible materials, function with a fraction of the metal content, greatly reduced size for enhanced cellular uptake, opportunity for two-photon absorption at biologically relevant wavelengths, and demonstrated renal evacuation efficacy for in vivo applications, metal nanoclusters hold substantial promise. More recently the development of hybrid atomic cluster synthesis routes has expanded the materials’ multifunctional capabilities. This chapter will summarize the current high-yield synthesis and functionalization strategies for producing monodisperse pure metal and hybrid nanocluster materials from both wet chemistry and newly developed biomediated nanocluster synthesis methodologies, involving protein and DNA hosts. The role of the bio-host and surface functional groups on the nanoclusters formation, stability, and physical properties will be detailed through recent experimental and theoretical simulation efforts.

Keywords Biomediated Nanocluster; Biomaterials; Bionano Hybrid; Multifunctional Materials; Protein-Nanoparticle Interface

Introduction Noble metal nanoclusters (NCs) are very attractive within the fields of biosensing, biodetection, and biomedicine as they offer the necessary functionalities of traditional semiconductor QDs, including tunable emission, ease of conjugation, extended photostability, and high quantum yield [1, 2]. In addition, NCs also surpass traditional quantum dots in several notable areas such as (i) being composed of nontoxic/ biocompatible materials, (ii) green synthesis routes, (iii) function with a fraction of the metal content, (iv) considerably reduced size for enhanced cellular uptake, and (v) exhibit demonstrated renal evacuation efficacy. These added unique properties make noble metal nanocluster research an area of tremendous interest with numerous applications in a variety of research fields ranging from biologics to optics and photovoltaics [2–11]. Nanoclusters are small clusters of metal atoms ranging from fewer than ten to several hundred atoms with a diameter of less than 2 nm [2]. Nanoclusters exhibit quantized energy fluorescence similar to QDs due to the small diameter as opposed to the plasmons associated with the continuous density of states in noble metal nanoparticles and the associated Mie theory [12, 13]. The discrete energy levels allow for tunable photonic emission in the visible and IR regions (Fig. 1), *Email: [email protected] Page 1 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_33-1 # Springer International Publishing Switzerland 2015

T

OU

Au5 Au13 Au25

Plasm onic AuNP

IN Fig. 1 Comparison of distinct fluorescence emissions exhibited by gold nanoclusters to the plasmonic transitions of gold nanoparticles

Electronic Energy Level Spacing (eV)

6

0.1

5

0.075

4 0.05

kbT = 0.2585 eV (RT)

3 0.025

2 0 0

25 50 75 100 125 150 175 200 225 250 275 300

1

0 0

25

50

75

100 125 150 175 200 225 250 275 300 # of Au Atoms (N)

Fig. 2 Electronic energy level spacing versus number of gold atoms composing a nanocluster

highly efficient two-photon absorption, and quantum yields comparable to semiconductor QDs, which however are composed of nontoxic materials with reduced metal content [14]. At the NC size scale, the band structure quantizes from continuous energy bands to discrete HOMO–LUMO energy levels. The critical size at which a nanoparticle transitions to the quantized states of a nanocluster and will exhibit quantum properties is determined by the average spacing of its electronic energy levels (d), following the Jellium model. d is roughly equal to Ef/N1/3 where Ef is the Fermi energy and N is the number of atoms. The precise, critical size where the nanocluster will exhibit quantum properties can be estimated using the inequality: d
KbT, where Kb is the Boltzmann constant and T is temperature in Kelvin. When d is greater than or equal to KbT, the nanoparticle is considered a nanocluster and will exhibit quantum characteristics. In the case of gold at room temperature, this translates to a maximum N value of about 214 or 215 gold atoms (Fig. 2), which estimates to about a 2 nm diameter [15, 16]. Thus, the NCs exhibit distinct electronic transitions within these conduction bands, which translate into a strong fluorescence emission upon UV photoexcitation [17, 18]. These distinct molecularlike characteristics allow NCs to serve as the link between noble metal atoms and nanoparticles [13]. Page 2 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_33-1 # Springer International Publishing Switzerland 2015

Research utilizing nanoclusters for bioimaging is currently underway to harness the clusters’ biocompatibility, strong photostability, large two-photon absorption cross section, and strong two-photon luminescence [2]. Previously, organic dyes have been used for photon imaging but are limited by their small two-photon absorption cross sections and susceptibility to photobleaching. The labeling of biological molecules like protein or DNA has been a large thrust in various clinical applications ranging from targeted drug delivery, cancer imaging, radiotherapy, and cardiovascular disease. Commercially available fluorophores are limited by several inherent deficiencies such as photobleaching, biotoxicity, native function perturbation of the labeled biomolecule, and toxic synthesis protocols. For example, organic dyes such as fluorescein isothiocyanate (FITC) green and diamidino-2-phenylindole (DAPI) blue are easily photobleached with FITC exhibiting 20 % fluorescence after just 2 min, while DAPI fluorescence is minimal after 5 min [19, 20]. Fluorescent proteins such as green fluorescent protein (GFP) and yellow fluorescent protein (YFP) are nicely biocompatible. However, the large size of the tag often disrupts the native function of the labeled protein including protein–protein interactions and cellular transport [21]. Semiconductor quantum dots (QDs) are very attractive label for biological processes as they have several advantageous qualities including photostability, high quantum yield, small size, and narrow emission profile. QDs are composed of a single crystal of a semiconductor material such as cadmium selenide (CdSe) and are roughly a few nanometers in diameter [22]. The diameter of the QD crystal can be explicitly controlled with temperature and duration variations in the synthesis protocol [22]. QDs are a few nanometers in diameter, thus smaller than the Bohr exciton radius. Therefore the energy levels within the crystal are quantized and directly proportional to the dimensionality of the formed QD core. Ultimately, QDs exhibit unique, size-dependant absorbance and emission profiles which allows for greater diversity in biological labeling applications [22]. However, QDs have several important drawbacks photoblinking due to imperfections on the crystal surface [23]. In addition, as materials like CdSe are inherently toxic, large capping molecules must be added to the QD exterior in order to ensure biocompatibility. Furthermore, this process leads to an increase of the QD diameter to 10–14 nm, which is quite large relative to the size of proteins leading to the disruption of normal protein function [24]. Recent advances in nanoclusters have proven them to have a plethora of more diverse applications in biolabelling and bioimaging where they interact with metal ions [25], proteins [3, 14, 26–30], nucleic acids [25, 29–31], and other small biomolecules [3]. Specific functionalities and material designs, such as engineered 2D/3D NC structures, in vivo physiological targeting/monitoring, chem biosensors, tunable emission wavelength/intensity, etc., are more readily achieved utilizing biomediated NC growth/encapsulation methodologies. Initial studies depict noble metal NCs as a new, favorable alternative to common fluorescence emitters and as a single-molecule detector in living cells [31]; however, protein encapsulation of non biomediated NCs has been shown to hinder material fluorescence in biological environments [32]. Recent efforts have shown the ability to achieve efficient NC growth via biomolecules, and the fundamental biomediated synthesis mechanisms are being explored to provide the foundation for future engineered biomediated NC hybrid material applications [14, 26–29, 31, 33–35]. An overview of current efforts toward nanocluster synthesis is outlined in Table 1.

Table 1 Overview of typical nanocluster synthesis methodologies Synthesis route Wet chemistry Template Template Template

Forming agent Capping agents Protein DNA Dendrimer

Nanocluster Mat’l Ag, Au, Pt, Cu Ag, Au, Pt, Cu Ag, Au, Cu Ag, Au, Cu

References [3, 5, 8, 10, 12, 36–45] [3, 12, 14, 18, 19, 26–30, 33, 46–49] [27, 28, 30, 31, 34, 35, 50–56] [12, 57–60]

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_33-1 # Springer International Publishing Switzerland 2015

Traditional Synthesis Routes Recent efforts have demonstrated efficient and high-yield protocols for the preparation of fluorescent NCs. To date the synthesis protocols are broken down into two basic themes, the bottom-up and top-down approaches. The more common bottom-up procedure reduces metal precursors and directly stabilizes nanoclusters with thiol stabilizing ligands or onto different biotemplates, including proteins, small molecules, nucleic acids, and small organisms [3, 14, 26–28, 61]. The second approach is the top-down procedure, where large, preprepared nanoparticles are etched down to the nanocluster regime utilizing various small molecule or macromolecule etchants [62–64]. Gold (Au) and silver (Ag) NCs have been at the forefront of the research on NCs because of their wide range of potential applications based on desirable properties such as size-dependent optical tunability, photostability, and high quantum yield [2, 12, 65]. One of the most common methods of synthesizing gold nanoclusters is a one-pot synthesis in which the metal ions are reduced in the presence of a selected thiol stabilizing ligands. The thiol ligand acts as a capping agent to hold the formed cluster stable in the desired solvent and provide subsequent linkage functionality. A typical synthesis generates gold nanoclusters by mixing an NaOH-stabilized reducing agent with an aqueous solution of HAuCl4 (gold salt) and desired thiol ligand [5], which have included L-cysteine, D-penicillamine (DPA), glutathione (GSH), dihydrolipoic acid (DHLA), and L-proline, among others [5, 10, 41–44]. Reactions are performed for 2 nm) with (111) and (100) facets lead to weaker and less selective adsorption. They also note that in these simulations, backbones of peptides on surfaces and particles are typically in b strand or coiled conformation (Fig. 14). With knowledge of amino acid energies on surfaces and large nanoparticles, Yu et al. once again used the CHARMM–METAL potential to investigate the stabilizing behavior of the A3 peptide to

Page 17 of 24

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_33-1 # Springer International Publishing Switzerland 2015

experimentally produce monodisperse ( 1,   rij < Rð1Þ
 2 2 R  R : rij > Rð2Þ 0

(2)

where bij is the many-particle parameter of bond order (3), specifying the creation of bonding energy (the attractive part of Vij) in the case of local atom distribution in the presence of other neighboring atoms (k-atoms). The potential energy is a many-particle function of positions of the atoms i, j, and k, and it is influenced by the parameters  1=ð2nÞ ; bij ¼ 1 þ xniji xij ¼



 h
3 i fC rij bi g yijk exp l33 rij  rik ;

X k6¼i, j

g ðyÞ ¼ 1 þ

c2 c2 h i;  d2 d 2 þ ðh  cos yÞ2

 1=ð2nÞ ; aij ¼ 1 þ gn
niji X


ij ¼

k6¼i, j


 h 3
3 i fC rij exp l3 rij  rik ;

(3) (4)

(5)

(6) (7)

 
1=
1= ðk Þ ðk Þ ðk Þ lij ¼ li þ lj =2; Aij ¼ Ai Aj 2 ; Bij ¼ Bi Bj 2 ; ð1Þ

Rij

Rð1Þ ¼ R  D; Rð2Þ ¼ R þ D;  1=  1= ð1Þ ð1Þ 2 ð2Þ ð2Þ ð2Þ 2 ¼ Ri Rj ; Rij ¼ Ri Rj :

(8)

where x is the effective coordination number; g(y) is the function of the angle between rij and rik that stabilizes the tetrahedral structure; l3 and g are set equal to zero. The potential defined by Eqs. 1, 2, 3, 4, 5, 6, and 7 is differentiated from the corresponding potential of the single-component system [38] by introducing one additional parameter w. This parameter amplifies or attenuates the heteropolar bonds with respect to the value obtained by simple interpolation. Thus, the “chemistry” is involved in this parameter or it is taken into account on choosing the interpolation formula. Page 3 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

Here, wii ¼ 1 and wij ¼ wji so only one independent parameter is required for a pair of two atom types. The parameter b in Eq. 4 is involved for getting additional flexibility, which is typical for the pair made up of the atoms of essentially different types. The parameters of the Tersoff potentials for silicon, oxygen, gallium, nitrogen, and arsenic can be found in Billeter et al. [5], Munetoh [26], and Nishidate and Nikishkov [27]. Here, the deficiently physically justified parameter wij is assumed equal to one. The procedure of adjusting parameters with using the original Tersoff potential is presented in Yasukawa [42]. The Tersoff potential is well transferable for the bond orbitals; the parameters fitted for sp3-hybridization can be used for the description of interaction in the materials with sp2-hybridization [2]. The initial configurations of nanoparticles were made by cutting the spheres and spherical layers out of the crystals of GaN or GaAs with the wurtzite crystal structure and the crystal of a-quartz. The previously built crystal of GaN (GaAs) was specified by the parameter of the cubic lattice: a = 0.5656 nm [29]. The packing of SiO4-tetrahedrons for obtaining the crystal of a-quartz with the parameters a, b = 0.5082 nm, c = 0.55278 nm [38] was generated by the program-generator of mineral crystal structures GRINSP [22]. The four-component particle was built by surrounding a sphere consisting of one type of base units by a layer of the other atomic units. In order to obtain the nanoparticles of the first type, a sphere of SiO2 was inserted into the spherical layer of GaN (GaAs), aligning their centers. Producing the nanoparticle of the second type included analogous attachment of the sphere of GaN (GaAs) to the spherical layer of SiO2. In both cases, in the region of interfacing the sphere and the layer surrounding it, the base units of the spherical layer, the atoms of which were closer to any atom of the sphere than a certain selected value rm, were removed. As a result, after assembling the nanoparticles, the minimal spacing between the atoms of different types ranged between 0.33 and 0.36 nm. The required quantity of base units of each type remained outside in the vicinity, while the atoms located farther than the others from the center of mass of the created nanoparticle were removed. Finally, depending on its composition, the nanoparticle contained 86 base units of SiO2, or 129 base units of GaN (GaAs), or 50 base units of SiO2 and 54 base units of GaN (GaAs). In other words, in every case the nanoparticle was generated from 258 atoms. The calculation of physical properties was performed by the classical molecular-dynamic ensemble representing the special case of a microcanonical ensemble. Integration of the equations of motion was performed by the Runge–Kutta method of the fourth order with the time step Dt = 1016 s. In the preliminary stage of calculation with duration of 100,000 Dt, the correction of the velocities of atoms was performed in order to balance the systems at a given temperature. The major calculation was made without any correction and lasted for 106 time steps. The molecular-dynamic (MD) calculations for every nanoparticle, I (SiO2)86, II (GaN)129, III (GaAs)129, (SiO2)50 (GaN)54 and (SiO2)50 (GaAs)54 with interior (IV, VI) and surface (V, VII) placement of SiO2, were performed at temperature 300 K. Besides spectral properties of nanoparticles I, III, VI, and VII were investigated at temperatures of 900 and 1,500 K. The configurations of the nanoparticles, produced at low temperatures, were used in the calculations at higher temperatures.

Dielectric Properties The calculation of the dielectric properties of two- and four-component particles based on them differs from the calculation of the corresponding characteristics of oxygen- and ozone-containing water clusters in the presence of the ions Cl, Br, and NO 3 [12–15]. The water or ozone (oxygen) molecule invariant in composition acts as a base unit for the water systems. Each molecule has its own electrical characteristics: permanent dipole moment dper, polarizability a(p), and calculated induced dipole moment dind. The compositionally stable molecules can be found neither in silicon dioxide nor in gallium nitride or gallium arsenide nor in the nanoparticle based on them. Consequently, in this case the exact characteristics of Page 4 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

molecules (dper, a(p), and dind) cannot be used for calculating the dielectric properties of nanoparticles. But the presence of covalent bonds in SiO2, GaN, and GaAs or their combinations makes it possible to isolate the local units from some atom, surrounded by any other atoms of a nanoparticle, at each instant of time. The number of neighbors of every atom is chosen according to the assumed parameters of the interaction potential and does not exceed four, as a rule. The experimental values of polarizability were taken as 3.75, 0.793, 8.1, 1.1, and 4.3 Å3 [23] for the atoms of Si, O, Ga, N, and As, respectively. The permanent dipole moments of these atoms were assumed equal to zero. Considering the individual characteristics of atoms ind (p) for the local groups of dper atom and aatom one can determine the effective values of these quantities and d atoms. Precisely these effective characteristics of the local groups of atoms were used for calculating the dielectric properties of the nanoparticles (SiO2)86, (GaX)129, and (SiO2)50 (GaX)54, where X = N or As. The dielectric permittivity e(o) as a frequency o function was presented by the complex value eðoÞ ¼ e0 ðoÞ  ie00 ðoÞ. For determining this value, the following equation was used [12, 13]: 1 1 ð ð eðoÞ  1 dF dt ¼ 1  io expðiot ÞF ðt Þdt; ¼  expðiot Þ e0  1 dt 0

(9)

0

where e0 is the static dielectric permittivity, F(t) is the normalized autocorrelation function of the total dipole moment of a nanoparticle: F ðt Þ ¼

hMðt Þ  Mð0Þi  2 ; M

(10)

where Mðt Þ ¼

N X

dj ð t Þ

(11)

j¼1 ind , for each is the sum of the total dipole moments of the atoms. Calculating the values dj ¼ dper j þ dj atom, only those neighbors that interacted with this atom according to the potentials in use were taken into account. The Raman and infrared (IR) spectra of nanoparticles were calculated by the autocorrelation functions of fluctuations of the polarizability and dipole moment, respectively. The dipole moment di and polarizability ai of i-th atom are formed due to the interaction with the surrounding atoms, and as a result, we get [14, 15] X Tij dj , di ¼ di, 0 þ ai, 0 j6X ¼i (12) ai ¼ ai, 0 þ ai, 0 Tij aj ; j6¼i

where di,0 and ai,0 are the dipole moment and polarizability gained by an atom i before interaction with the renewed (as a result of thermal motion) surroundings.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

Here, Tij is the tensor of dipole–dipole interaction  1
Tij ¼ 3 3^rij^rij  1 ;

rij

(13)

where rij is the unit vector having the direction ri  rj and ri и rj are the positions of the centers of atoms i and j, and 1 is the unit tensor of rank 3  3. The system of equations 12 was solved by the iteration method. The scattering cross section of infrared emission was defined by the equation [6]  sðoÞ ¼

 1 ð 2 ħo Re dteiot hMðt Þ  Mð0Þi; o tanh ev cħ
2kT

(14)

0

where
is the refractive index independent of frequency, ev is the dielectric permittivity of a vacuum, and c is the speed of light. The light being depolarized, the Raman spectrum is defined by the following equation [6]: J ðoÞ ¼



o ðoL  oÞ

4

1e



ħo=kT



1 ð

Re dteiot hPxz ðt ÞPxz ð0Þi;

(15)

0

where PðtÞ

N X

  aj ð t Þ  aj ;

(16)

j¼1

oL is the exciting laser frequency, Pxz is the xz-component of P(t), and the axis x is directed along the dipole of the group of directly interacting atoms (atom j and the neighbors interacting with it). The refraction index
and the absorption coefficient x are defined by the equations [21] sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 2 0 0 00 e þ e þe e0 þ e0 2 þ e00 2 , x¼ :
¼ 2 2

(17)

The coefficient x determines the rate of wave attenuation as it propagates in the medium. The total number of electrons nel interacting with the external electromagnetic field in a unit volume of the nanoparticle is defined by the following equation [21]: m nel ¼ 2 2 2p e

1 ð

oe00 ðoÞdo;

(18)

0

where e and m are the electron charge and mass.

Page 6 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

Fig. 1 Configurations of (GaN)54 (SiO2)50 nanoparticles corresponding to time 100 ps; nanoparticle nucleus is (a) GaN and (b) SiO2

The Particles Containing SiO2 and GaN Bond energies in (SiO2)86 and (GaN)129 particles calculated in this work were –9.6 and –4.7 eV/atom, respectively. The corresponding experimental values for a-quartz and gallium nitride with the wurtzite structure are –9.058 [36] and –4.529 [33]. The configurations of nanoparticles containing both SiO2 and GaN and obtained at time 100 ps are shown in Fig. 1. Packing of SiO2, especially when these structural units are arranged externally in a nanoparticle, is closer to the amorphous state rather than a-quartz. In both cases, separate oxygen atoms become detached from Si atoms and closely approach Ga atoms. If GaN is situated in the central part of a nanoparticle, the surface layer consisting of SiO2 is strongly inhomogeneous and contains breaks. The GaN nucleus remains sphereshaped during whole calculations. The N and Ga atoms are strongly bound with each other. During calculations, these bonds remain intact, but N atoms shift inside the GaN nucleus, and Ga atoms outside it. If GaN is situated on the surface of a cluster, N atoms closely approach Ga atoms and do not penetrate inside the cluster. Ga atoms can be in contact with both Si and O atoms. Except loss of separate O atoms, the framework of SiO2 is retained. The inside SiO2 nucleus has dense and loose regions. Ga atoms fairly closely approach this nucleus. The totality of microcrystalline quartz kinds are traditionally divided into two types on the basis of crystalline habitus determined using optical microscopy [18]. Granular diversities include chert and finegrained sandstone, whereas fibrous varieties of fine-crystalline quartz are combined under a name of chalcedonies. The axis in chalcedonies is most often perpendicular to the long fiber axis. Although the majority of chalcedonies grow with just this orientation, special chalcedonies with the axis parallel to fibers or directed at an angle of 30 to them are also numerous [11]. The Raman spectra of the (SiO2)86 (a-quartz) nanoparticle, natural chalcedony from Arizona [17], and a SiO2 film [3] grown on sapphire are shown in Fig. 2. The spectra of crystalline quartz were measured at 297  3 K. The low-frequency region with o < 50 cm1 was not considered in Berezhinsky et al. [3] because, according to the authors, strong spurious scattering was observed at these frequencies. The strongest bands of crystalline SiO2 were situated at 128, 206, and 464 cm1. In addition, two bands at 696 and 808 cm1 were observed. The strongest band situated at 400–530 cm1 corresponds to O ‐ Si ‐ O symmetrical stretching-bending modes. The bands at 128 and 206 cm1 correspond to torsional and O ‐ Si ‐ O bending modes. Recent measurements of Raman scattering from a silicon dioxide cell showed the presence of bands at 495.8 and 748.5 cm1 [32]. The bands at 128 and 206 cm1 are strongest in the Raman spectrum of chalcedony. Weak peaks of the same origin were observed in the J spectrum of chalcedony at 262 and 355 cm1. The SiO2 film at T = 293 K consisted of the amorphous phase, but crystalline fragments were also Page 7 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

1 3

2

J, arb. units

4

0

200

400 , cm

600

1

Fig. 2 Raman spectra of (1) (SiO2)86 nanoparticle, (2) a-quartz, (3) natural chalcedony from Arizona (Reproduced with permission from reference Kingma and Hemley [17]; Copyright 1994 Mineralogical Society of America), and (4) SiO2 film grown on sapphire (Reproduced with permission from reference [3]; Copyright 2005 Institute of Semiconductor Physics, NAS of Ukraine)

present. The structure of SiO2 glass is an amorphous network of Si atoms tetrahedrally surrounded by O atoms. Tetrahedra are linked with each other through oxygen atoms, and Si ‐ O ‐ Si bridges with interbond angles close to 150 are formed. In other words, each Si atom in the amorphous network is surrounded by four O atoms, and, in turn, each oxygen atom is linked with two silicon atoms. The Raman spectrum of a SiO2 film grown on a sapphire substrate is shown in Fig. 2, curve 4. A broad band at about 400 cm1 corresponds to Si ‐ O tetrahedron rocking vibrations. A peak at 800 cm1 was also observed. This peak was related to periodic bends of chemical bonds in Si ‐ O ‐ Si bridges. According to [8], an intense narrow peak at 378 cm1 corresponds to plasma radiation in an Ar-laser gas discharge tube. The stoichiometry of SiO2 is disturbed at elevated temperatures. Nonstoichiometric SiO2 films were obtained after annealing at 773 K for 15 min. The Raman spectrum of such a film had a broad band centered at approximately 490 cm1 which corresponded to Si ‐ Si bond vibrations. This means that amorphous silicon clusters formed in the film. The first peak in the J spectrum of a low-temperature film situated at ~50 cm1 was a wing of the Raleigh line. A well-defined low-frequency peak at 34 cm1 was also observed in the Raman spectrum of the (SiO2)86 nanoparticle. Its appearance can also be related to the presence of Raleigh scattering. The most intense broad band appears in the vicinity of a 248 cm1 frequency. This band is caused by torsional vibrations and O ‐ Si ‐ O bending modes. As distinct from crystalline SiO2, a large number of vibrations close in energy is observed in the (SiO2)86 nanoparticle in the vicinity of the 248 cm1 band. Their superposition forms a broad intense Raman spectrum band. A weak burst in the J spectrum of the nanoparticle is also observed close to the 620 cm1 frequency. This burst is an overtone of modes responsible for the intense Raman spectrum band at 248 cm1. The positions of the main Raman spectrum bands of the (SiO2)86 nanoparticle, a-quartz, and SiO2 film are limited by the frequency range 0
o
500 cm1. Two new Raman lines at 295 and 380 cm1 and a weak mode at 605 cm1 were recently observed in the Raman spectrum of amorphous silicon dioxide [8]. The authors relate the origin of the new branches to vibrations in five- and more-membered SiO2 rings. Because of thermal instability of gallium nitride crystals, GaN semiconductors are mainly produced and used in the form of thin films. The Raman spectrum of the GaN film grown on sapphire substrate and on GaAs is shown in Fig. 3 as well as the calculated J spectrum of the (GaN)129 nanoparticle. The spectrum of the GaN film grown on sapphire has a noticeable peak at 247 cm1 [40]. In [35], the origin of this peak was related to As impurities in GaN films. Page 8 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

1

J, arb. units

3 2

0

200

400

600

800

, cm 1

Fig. 3 Raman spectra of (1) (GaN)129 nanoparticle, (2) GaN film grown on a sapphire substrate, and the GaAs substrate (Reproduced with permission from reference [40]; Copyright 2006 Division of Natural Science Academic Publishing, Higher Education Press, China)

This mode is present at 293 K and does not disappear up to 500 K. This is the temperature at which the beginning of the electronic transition with an increase in the number of donors is expected. The peak at 558 cm1, which appears in the Raman spectrum, corresponds to the existence of stresses in GaN films with the wurtzite structure. The E2 additional active Raman mode is responsible for the appearance of this peak. When stresses appear, the peak shifts toward higher frequencies; its localization at 566 cm1 was mentioned. The longitudinal asymmetric vibration mode is observed at 733 cm1. This mode has an obvious “tail” extended toward high frequencies. It is present in the form of a prominent signal at low temperatures. The coalescing lines at 410 and 420 cm1 are acoustic overtones [40]. The lines at 417 and 750 cm1 related to sapphire were excluded from the spectrum. The most striking observation in [34] was that the additional peaks were present only in spectra taken from samples grown on GaAs. Samples grown on sapphire did not exhibit these features. For example, quite pronounced mode at 95 cm1 as well as modes at 60, 102.5, 125, and 250 cm1 were found in the Raman spectrum of a GaN layer grown on GaAs. The theory cannot explain all additional Raman peaks observed at low energies in GaN grown on GaAs. Either N impurities in GaAs or As defects in GaN are likely to be their origin. The Raman spectrum of the (GaN)129 nanoparticle is continuous and contains several bands localized at 0
o
650 cm1. The calculated Raman spectrum of the (GaN)129 nanoparticle has a noticeable peak of bosons (at 131 cm1) and two accompanying subpeaks at 98 and 164 cm1 (Fig. 3). The boson peak is a universal special feature of the Raman spectra of most of glasses. This peak is equally strong in many glasses and weakly changes as glass connectedness decreases. This observation was used in [25] to draw the conclusion that the boson peak appeared because of vibrations local in character. These vibrations can be represented by a harmonic oscillator. On the whole, the form of the spectrum of the nanoparticle corresponds to the form of the spectrum of a GaN film over the frequency range 100
o
650 cm1. The Raman spectrum of the film has a smoother relief. The mean frequency value of nanoparticle spectrum peaks at 210, 260, and 283 cm1 is 251 cm1, which closely agrees with the position of the Raman peak observed in a GaN film (247 cm1). The most intense band in the J spectrum of the nanoparticle at 408 cm1 can be treated as an acoustic overtone. Taking anharmonicity into account, the peaks at 464, 510, 599, and 635 cm1 can be assigned to overtones of modes with a 251 cm1 mean frequency. The continuous spectrum of the (GaN)129 nanoparticle extends to ~694 cm1, whereas the J spectrum of the (SiO2)86 nanoparticle extends to a 415 cm1 frequency only; at 415 cm1, a break of the spectrum is observed. A large number of active frequencies in the Raman spectrum of the (GaN)129 nanoparticle is caused by its small size and a small time interval during which observations were made.

Page 9 of 20

J, arb. units

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

1

3

2

0

200

400 , cm

600

1

Fig. 4 Raman spectra of (GaN)54 (SiO2)50 nanoparticles with (1) GaN and (2) SiO2 nuclei and (3) Raman spectrum of GaN/SiO2/Si nanocrystals with a mean size of h = 50 nm, (Reproduced with permission from reference [19]; Copyright 2003 American Institute of Physics)

The (GaN)54 (SiO2)50 nanoparticle with a GaN nucleus has a fairly smooth continuous Raman spectrum over the frequency range 0
o
600 cm1 (Fig. 4). The band in the vicinity of a 400 cm1 frequency is not most intense, as with the (GaN)129 nanoparticle. The band situated close to a 254 cm1 frequency is most intense. The intensity of the J spectrum linearly decreases as the frequency increases from 425 to 600 cm1. The Raman spectrum of the (GaN)54 (SiO2)50 nanoparticle with a SiO2 nucleus is characterized by a substantially cut relief. This spectrum has a somewhat higher extension compared with the J spectrum of the (GaN)54 (SiO2)50 particle with a GaN nucleus. At o > 559 cm1, the Raman spectrum of the particle with a SiO2 nucleus is not continuous. Over the frequency range 0
o
700 cm1, the J spectrum of this particle has 11 bands. Some of these peaks (3–5) are split. The fourth peak has two subpeaks, and the third and fifth peaks have subpeaks and shoulders on the right. The first two peaks at 47 and 79 cm1 should be treated as boson peaks. The position of a broad peak at 139 cm1 is in agreement with the low-frequency additional active Raman mode E2 = 144 cm1 experimentally observed in GaN films [35]. The bands at 212, 241, and 291 cm1, which have the mean frequency value 248 cm1, on the one hand, correspond to the main mode (248 cm1) of the Raman spectrum of the (SiO2)86 nanoparticle and, on the other hand, are close to modes with the mean frequency 251 cm1 observed in the J spectrum of the (GaN)129 nanoparticle. The band at 291 cm1 is also close to a 295 cm1 frequency mode in amorphous silicon [8]. In exactly the same way, the bands at 452 and 516 cm1 correspond to 464 and 510 cm1 modes in the spectrum of the (GaN)129 nanoparticle. In addition, the position of the band at 516 cm1 coincides with the localization of the Raman spectrum band for a GaN nanocrystal with size 50 nm grown on a SiO2 substrate [19]. The Raman spectrum of this nanocrystal contains only one peak (516 cm1) caused by Si atom vibrations. The position of a well-defined peak at 372 cm1 is close to that of a sharp Raman spectrum peak of a SiO2 film (378 cm1) [3] and amorphous SiO2 (380 cm1) [8]. The other peaks at 615 and 664 cm1 appear because of splitting of the peak at 620 cm1 in the Raman spectrum of the (SiO2)86 nanoparticle. A peak close in its position (605 cm1) is also observed in amorphous SiO2 [8]. It follows that the positions of peaks in the J spectrum of the (GaN)54 (SiO2)50 nanoparticle with a SiO2 nucleus are caused not only by collective vibrations in the GaN subsystem but also by group vibrations in the SiO2 subsystem.

Page 10 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

Fig. 5 Configurations of nanoparticles: (a) (SiO2)86; (b) (GaAs)129; (c), (d) (SiO2)50 (GaAs)54, (c) SiO2 inside, (d) SiO2 outside the nanoparticle. Instant of time 100 ps, T =1,500 K. The coordinates of atoms are given in Å

The Particles Containing SiO2 and GaAs The configurations of four nanoparticles obtained at Т = 1,500 K after 106 time steps are presented in Fig. 5. The island of oxygen atoms appeared in the top piece of nanoparticle (SiO2)86 at the surface. The surface of nanoparticle (GaAs)129 is slightly disordered. The four-component nanoparticle with the core of SiO2 still remains sufficiently compact, but the delamination of atoms Ga and As is observed at the surface. The nanoparticle with inverted arrangement of the SiO2-component at the surface is characterized by the most loose, heterogeneous structure. In the dense central part of this nanoparticle, the bigger atoms of As dominate at the surface. The partially delaminated shell of SiO2 is unequal in thickness and does not cover the GaAs core completely. The base units of SiO2 do not all persist. In the surface region there are single atoms of Si and O and the base units, which are not connected to the frame: SiO, SiO2, and SiO4. Let us consider the general properties of the nanoparticles at the temperature of 300 K, at which the spectral characteristics of GaAs and SiO2 films and crystals are usually obtained. In most of the frequency range, the functions e0 (o) and e00 (o) are increasing; i.e., the dielectric response is enhanced with the increase in the outer radiation frequency (Fig. 6). For the nanoparticles (SiO2)50 (GaAs)54 of like composition but with different component placement (1, VI; 2, VII), the behavior of the frequency dependence of the real e0 and imaginary e00 components of the dielectric permittivity at Т = 300 K is rather identical. The values of function e0 (o) for nanoparticles VI and VII are enclosed by the experimentally obtained values of the corresponding functions for amorphous SiO2 (curve 3) [37] and the crystal of GaAs with the structure of zinc blende (curve 4) [41]. At high frequencies the smoothing of oscillations of function for particle VI is observed. The infrared absorption spectra of nanoparticles VI and VII essentially differ in their intensity (1, VI, 2, VII, Fig. 7). The intensity of the infrared spectra of the nanoparticles under consideration is mostly caused

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

a 20 10

4 2

5 Re( )

1

3

0

b 10

Im( )

2 5

1

0 0

500

1000 , cm

1500

1

Fig. 6 The frequency dependence of real (a) and imaginary (b) components of dielectric permittivity for nanoparticles (SiO2)50 (GaAs)54: 1, VI; 2, VII; 3, amorphous SiO2 (Experiment from [37], Copyright by John Wiley and Sons (JWS) reproduced by permission of JWS); 4, crystal GaAs (Experiment from [41], Copyright by Elsevier reproduced by permission of Elsevier)

4

( ), arb. units

3

1

2

0

500

1000 , cm

1500

1

Fig. 7 The infrared absorption spectra for various systems: 1, nanoparticle VI; 2, nanoparticle VII; 3, amorphous gallium arsenide (Experiment from Ref. [31], Copyright by John Wiley and Sons (JWS) reproduced by permission of JWS); 4, a-quartz, (Experiment from Ref. [28], Copyright by Springer reproduced by permission of Springer)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

a

1 2

, arb. units

3

b

2

1 3

0

500

1000 , cm

1500

1

Fig. 8 The smoothed infrared absorption spectra for nanoparticles (SiO2)50 (GaAs)54 with SiO2-core (a) GaAs-core (b) at temperatures of 1, 300 K; 2, 900 K; 3, 1500 K

by oscillations of atoms along the ion-covalent Si ‐ O bonds. The locations of the peaks, which can be recognized for particle VII in the second, more high-frequency half of the spectrum s(o), coincide with the ones for particle VI. The experimental infrared spectrum of the GaAs film [31] has fundamental peaks in the low-frequency half of the range under consideration (0
o
1,600 cm1), and the major peak of the infrared spectrum of a-quartz [28] is located in the second (more high-frequency) half of this spectrum. In Fig. 8 are shown the infrared absorption spectra of nanoparticles VI and VII, smoothed by the polynomial of the ninth degree and calculated for three temperatures. For nanoparticle VI with the SiO2core, the intensity Itot of s(o) spectra decreases as the temperature rises (Fig. 8a). The relationship between the values of Itot for temperatures 300, 900, and 1,500 K is 1:0.85:0.49. Temperature variation does not lead to shifting of the fundamental peak (on 1,380 cm1) of the s(o)-spectra. The decrease in the infrared spectrum intensity with increasing temperature is caused by intensification of attenuation of the autocorrelation function of the total dipole moment. The faster attenuation of this function at high temperature is provided both by decreasing the value of |M| and faster change of the vector M direction. But the continuity of decreasing the s(o)-spectrum intensity with increasing temperature is broken in the case of nanoparticle VII with external placement of the SiO2 component. This is due to the weak impact of the GaAs-core on the outer shell of SiO2 at T = 300 K. At 900 K the loose structure of SiO2 consolidates because the atoms of Si and O approach the GaAs core consisting of heavier atoms. As this takes place, the distance between Si and O atoms reduces. This amplifies the Si- and O-atom oscillations. As a result, the s(o)-spectrum intensity significantly increases. As temperature further rises (up to 1,500 K), the nanoparticle with a more homogenous structure behaves naturally: the infrared spectrum intensity decreases due to reducing the correlation time of the total dipole moment. The

Page 13 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

4

J( ), arb. units

3 1 5 2

0

500

1000 , cm

1500

1

Fig. 9 The Raman spectra for various systems: 1, nanoparticle VI; 2, nanoparticle VII; 3, amorphous gallium arsenide (Experiment from Ref. [31], Copyright by John Wiley and Sons (JWS) reproduced by permission of JWS); 4, a-quartz (Experiment from Ref. [28], Copyright by Springer reproduced by permission of Springer); 5, molten quartz (Experiment from Ref. [7], Copyright by Elsevier reproduced by permission of Elsevier)

relationship between the Itot values for nanoparticle VII when passing from 300 K to 900 and 1,500 K is 1:1.80:0.76. The anti-Stokes Raman spectra J(o) for nanoparticles VI and VII essentially differ from each other not in intensity but in the number and location of peaks. In the frequency range being studied, there are observed five Raman shifts (peaks at o > 0) for nanoparticle VII and four distinguished frequency shifts for particle VI (Fig. 9). The experimental Raman spectrum of GaAs film at Т = 300 K (curve 3) was obtained up to o < 700 cm1 and had two fundamental bands on the frequencies of ~60 and 230 cm1 [31]. These bands characterize the acoustic and optical vibrational modes of amorphous GaAs, respectively. One should note that the band 245 cm1, which is likely to be caused by the optical mode of crystal GaAs, is present in the Raman spectrum of nanoparticle VII. The Raman spectrum of nanoparticle VII differs significantly from the corresponding spectrum of nanoparticle VI. Recall that in this case GaAs in the nanoparticle is a compact nanocrystal. The peak with weak intensity on o ¼ 1,450 cm1 in the J(o)spectrum of nanoparticle VI can be considered as an overtone of the second mode (422 cm1) to a precision of 13 %. The fundamental peaks of the Raman spectrum of a-quartz (curve 4) [28] and molten quartz (curve 5) [7] are located at the frequencies of 437 and 463 cm1, respectively, which is in good agreement with the location of the Raman shift on 422 cm1 for nanoparticle VI with the center of the monolithic nanoparticle of SiO2. The temperature distinctions of the anti-Stokes Raman spectra of nanoparticles VI and VII are obvious from Fig. 10. For both nanoparticles, the Raman spectrum intensity considerably increases as the temperature rises. This is due to retarding the attenuation of the autocorrelation function of fluctuations of atomic polarizability. As the temperature rises, the polarizability deviation from the mean and the correlation time of these functions increase. The first peak of the J(o)-spectrum of nanoparticles VI and VII at T = 300 K is located in the range of 30
o
600 cm1. At T = 1,500 K the first peak of nanoparticle VII keeps its location, while for nanoparticle VI this peak has a blue shift by ~60 cm1. In Berg et al. [4] the Raman peak at the frequency of 47 cm1 was generated due to the buffer layer of GaAs, obtained by the low-temperature molecular beam epitaxy. Such a low oscillation frequency was assigned to the presence of point defects (vacancies and interstitial atoms). Such defects can be generated, for example, as a result of excess of arsenic atoms and deficiency of gallium atoms. The intensity ratio (2) (J (2) 1,500K/J 300K) of the second peaks of J(o)-spectrum is 134.78 for nanoparticle VI and 11.44 for nanoparticle VII. The location of the second peak (422 cm1) of J(o)-spectrum of nanoparticle VI

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

a 2

J, arb. units

1

b

2

1

0

500

1000 , cm

1500

1

Fig. 10 The anti-Stokes spectra of Raman scattering for nanoparticles (SiO2)50 (GaAs)54 with SiO2-core (a) and GaAs-core (b) at temperatures of 1, 300 K; 2, 1500 K

does not change as the temperature rises (Fig. 10a). However, the third peak has a red shift by 18 cm1 at 1,500 K. Peaks 2–5 of the J(o)-spectrum of particle VII do not shift under heating from 300 to 1,500 K (Fig. 10b). The more dense SiO2-structure of nanoparticle VI as compared with the structure of nanoparticle VII leads to shifting of the Raman spectrum peaks towards higher frequencies. Not all the distinct peaks in the J(o)-spectra, obtained at 1,500 K for nanoparticles VI and VII, can reflect the fundamental frequencies of normal oscillations of atoms. For example, in the Raman spectrum of nanoparticle VI, the third and fourth peaks can reflect the overtones of the representative frequency, defined by the second peak, to a locating accuracy of 4.3 % and 0.3 %, respectively. In the J(o)-spectrum of nanoparticle VII, the fifth peak can be determined accurate to 6.9 % as an overtone of the third peak frequency. The frequency dependences of the refraction index
and the absorption coefficient k of nanoparticles VI and VII are of the same type (Fig. 11). But the oscillations of the
(o) and k(o) functions are usually phase-shifted. The experimental values of the refraction index
of crystal GaAs [43] (line 3) and amorphous silicon dioxide SiO2 [24] (line 4) in the frequency range of 700 to 1,500 cm1 form a band where the index
values for nanoparticles VI and VII lie. The high-frequency oscillation of the k(o) function for nanoparticle VI has a lower amplitude but longer duration than the analogous feature for nanoparticle VII. The number nel of electrons involved in creating optical effects decreases as the nanoparticles heat (Fig. 12). Nanoparticle VI (curve 1) has higher values of nel than nanoparticle VII. This is due to the location of Ga atoms near the nanoparticle surface. However, as the temperature rises, the difference in nel values for nanoparticles VI and VII smoothes and at Т = 1,500 K it almost disappears. The number of optically active electrons is distinctly higher for Page 15 of 20

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

a 4 3

3 1 2

2

4 1

0

b 1,5 2 1,0 , 103

1

0,5

0,0 0

500

1000 , cm

1500

1

Fig. 11 The frequency dependence of refraction index (a) and absorption coefficient (b) for various systems: 1, nanoparticle VI; 2, nanoparticle VII; 3, crystal GaAs, (Experiment from [43], Copyright by authors reproduced by permission of L. Yu and D. Li); 4, amorphous SiO2, experiment from [24], Copyright by Optical Society of America (OSA) reproduced by permission of OSA)

nel, 1017 1/cm3

10

4 1 2

5 3

500

1000

1500

T, K

Fig. 12 The number of optically active electrons in nanoparticles: 1, VI; 2, VII; 3, I; 4, III

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

the GaAs nanoparticle and lower for SiO2 particle than for four-component nanoparticles. Nanoparticle III has a descending convex plot nel(T) and nanoparticle I has a concave plot like four-component nanoparticles.

Conclusions Progress in the synthesis of high-quality nanomaterials makes it possible to investigate one of the most fundamental issues concerning the influence of the size, structure, and surface of nanoparticles on their dynamic properties including the infrared and Raman spectra. Such investigations are necessary to gain better understanding of the basic physics of controlling the parameters of nanoparticles in order to get the required dynamic properties, including the cases of thermal and mechanical load of nanoobjects. The calculation results show that, over the larger part of the 0
o
700 cm1 frequency range, the Raman spectra of nanoparticles consisting of SiO2 and GaN are continuous. The form of the Raman spectrum of the (GaN)54 (SiO2)50 nanoparticle depends to a substantial extent on the arrangement of components in the volume of this nanoparticle. If GaN forms its nucleus, the J spectrum has a smooth shape, and if SiO2 occupies its center, the Raman spectrum has a large number of bands. These bands correspond to vibration of groups of atoms of different kinds and atoms of the same kind. The Raman spectrum of the nanoparticle with a SiO2 nucleus has a larger extension, but its “tail” is not a continuous spectrum continuation. In this chapter, the basic optical properties of two- and four-component nanoparticles of silicon dioxide and gallium arsenide at temperatures of 300–1,500 K were studied. The integral intensity of the infrared absorption spectra of four-component nanoparticles decreases as temperature rises. But the structural relaxation of the SiO2-coating of the GaAs-core can result in increasing the intensity of this part of the infrared spectrum despite the temperature rise. The shape of Raman spectra for these particles also depends strongly on the way the GaAs- and SiO2-components are located in the nanoparticle. Increasing the temperature of (SiO2)50 (GaAs)54-nanoparticles causes a significant rise in the intensity of the antiStokes part of the Raman spectrum. Heating the nanoparticles to 1,500 K does not lead to the shift of J(o)spectrum peaks for the nanoparticle with SiO2-coating, while the odd J(o)-spectrum peaks for the nanoparticle with the SiO2-core shift in opposite directions. The refractive index and absorption coefficient depend weakly on the arrangement of the conductor (GaAs) and isolator (SiO2) in the nanoparticle. The number of optically active electrons is also barely sensitive to the spatial inversion of a semiconductor and isolator in the nanoparticle formed from gallium arsenide and silicon dioxide. Thus, using molecular-dynamic modeling, one can predict the significant optical properties of semiconductor particles having widespread application.

References 1. A.P. Alivisatos, Perspectives on the physical chemistry of semiconductor nanocrystals. J. Phys. Chem. 100, 13226–13239 (1996). doi:10.1021/jp9535506 2. F. Benkabou, M. Certier, H. Aourag, Elastic properties of zinc-blende GaN, AlN and InN from molecular dynamics. Mol. Simul. 29, 201–209 (2003). doi:10.1080/0892702021000049673 3. L.I. Berezhinsky, V.P. Maslov, V.V. Tetyorkin, V.A. Yukhymchuk, Investigation of Al-ZERODUR interface by Raman and secondary ion mass-spectroscopy. Semicond. Phys. Quantum Electron. Optoelectron. 8, 37–40 (2005)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_34-1 # Springer International Publishing Switzerland 2015

4. R.S. Berg, N. Mavalvala, T. Steinberg, F.W. Smith, Raman study of defects in a GaAs buffer layer grown by low-temperature molecular beam epitaxy. J. Electron. Mater. 19, 1323–1330 (1990). doi:10.1007/BF02673349 5. S.R. Billeter, A. Curioni, D. Fischer, W. Andreoni, Ab initio derived augmented Tersoff potential for silicon oxynitride compounds and their interfaces with silicon. Phys. Rev. B 73(1–15), 155329 (2006). doi:10.1103/PhysRevB.73.155329 6. W.B. Bosma, L.E. Fried, S. Mukamel, Simulation of the intermolecular vibrational spectra of liquid water and water clusters. J. Chem. Phys. 98, 4413–4421 (1993). doi:10.1063/1.465001 7. R. Bruckner, Properties and structure of vitreous silica. J. Non Cryst. Solids 5, 123–175 (1970). doi:10.1016/0022-3093(70)90190-0 8. M. Chligui, G. Guimbretiere, A. Canizares, G. Matzen, Y. Vaills, P. Simon, New features in the Raman spectrum of Silica: key-points in the improvement on structure knowledge. Phys. Rev. B (2010). http://hal.archives-ouvertes.fr/docs/00/52/08/23/PDF/chliguiSiO2.pdf. Accessed 15 May 2013 9. P. Colomban, C. Truong, Non-destructive Raman study of the glazing technique in Lustre Potteries and faience (9-14th centuries): silver ions, nanoclusters, microstructure and processing. J. Raman Spectrosc. 35, 195–207 (2004). doi:10.1002/jrs.1128 10. M.G. Deceglie, V.E. Ferry, A.P. Alivisatos, H.A. Atwater, Design of nanostructured solar cells using coupled optical and electrical modeling. Nano Lett. 12, 2894–2900 (2012). doi:10.1021/nl300483y 11. R.L. Folk, J.S. Pittman, Length-slow chalcedony: a new testament for vanished evaporates. J. Sediment. Petrol. 41, 1045–1058 (1971). doi:10.1306/74D723F1-2B21-11D78648000102C1865D 12. A.Y. Galashev, Computer study of of absorption of oxygen and ozone molecules by water clusters with Cl and Br. Can. J. Chem. 89, 524–533 (2011). doi:10.1139/V10-174 13. A.Y. Galashev, Molecular dynamics simulation of adsorption of ozone and nitrate ions by water clusters. High Temp. 50, 204–213 (2012). doi:10.1134/S0018151X12010051 14. A.Y. Galashev, O.R. Rakhmanova, O.A. Novruzova, Molecular-dynamic modeling of the spectral characteristics of the ozone–water cluster system. High Temp. 49, 193–198 (2011). doi:10.1134/ S0018151X11010056 15. A.Y. Galashev, O.R. Rakhmanova, O.A. Novruzova, Computational study of interaction of bromine ions with clusters (O2)6(H2O)50 and (O3)6(H2O)50. High Temp. 49, 528–538 (2011). doi:10.1134/ S0018151X11040080 16. J. Kao, P. Bai, J.M. Lucas, A.P. Alivisatos, T. Xu, Size-dependent assemblies of nanoparticle mixtures in thin films. J. Am. Chem. Soc. 135, 1680–1683 (2013). doi:10.1021/ja3107912 17. K.J. Kingma, R.J. Hemley, Raman spectroscopic study of microcrystalline silica. Am. Mineral. 79, 269–273 (1994). INIST-CNRS, Cote INIST : 503, 35400004574316.0070 18. C. Klein, C.S. Hurlbut Jr., Manual of Mineralogy, 20th edn. (Wiley, New York, 1985) 19. E.V. Konenkova, Y.V. Zhilyaev, V.A. Fedirko, D.R.T. Zahn, Raman spectroscopy of GaN nucleation and free-standing layers grown by hydride vapor phase epitaxy on oxidized silicon. Appl. Phys. Lett. 83, 629–631 (2003). doi:10.1063/1.1592623 20. T. Kozawa, T. Kachi, H. Kano, Y. Taga, M. Hashimoto, N. Koide, K. Manabe, Raman scattering from LO phonon-plasmon coupled modes in gallium nitride. J. Appl. Phys. 75(1–4), 1098 (1994). doi:10.1063/1.356492 21. L.D. Landau, E.M. Lifshitz, Course of Theoretical Physics: volume 8. Electrodynamics of Continuous Media (Butterworth–Heinemann, Oxford, 1984) 22. A. Le Bail, Inorganic structure prediction with GRINSP. J. Appl. Crystallogr. 38, 389–395 (2005). doi:10.1107/S0021889805002384 Page 18 of 20

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23. D.R. Lide (ed.), CRC Handbook of chemistry and physics, 77th edn. (CRC Press, Boca Raton, 1996) 24. I.H. Malitson, Interspecimen comparison of the refractive index of fused silica. J. Opt. Soc. Am. 55, 1205–1208 (1965). doi:10.1364/JOSA.55.001205 25. C. McIntosh, J. Toulouse, P. Tick, The Boson peak in alkali silicate glasses. J. Non Cryst. Solids 222, 335–341 (1997). doi:10.1016/S0022-3093(97)90133-2 26. S. Munetoh, T. Motooka, K. Moriguchi, A. Shintani, Interatomic potential for Si–O systems using Tersoff parameterization. Comput. Mater. Sci. 39, 334–339 (2007). doi:10.1016/j. commatsci.2006.06.010 27. Y. Nishidate, G.P. Nikishkov, Atomic-scale modeling of self-positioning nanostructures. Comput. Model. Eng. Sci. 26, 91–106 (2008). doi:10.3970/cmes.2008.026.091 28. M. Ocana, V. Fornes, J.V. Garcia-Ramos, C.J. Serna, Polarization effects in the infrared spectra of a-quartz and a-cristobalite. Phys. Chem. Miner. 14, 527–532 (1987). doi:10.1007/BF00308288 29. H. Ohno, A. Shen, F. Matsukara, A. Oiwa, A. Endo, S. Katsumoto, Y. Iye, (Ga, Mn)As: a new diluted magnetic semiconductor based on GaAs. Appl. Phys. Lett. 69, 363–365 (1996). doi:10.1063/ 1.118061 30. J. Pérez-Arantegui, J. Molera, A. Larrea, T. Pradell, M. Vendrell-Saz, I. Borgia, B.G. Brunetti, F. Cariati, P. Fermo, M. Mellini, A. Sgamellotti, C. Viti, Luster pottery from the thirteenth century to the sixteenth century: a nanostructured thin metallic film. J. Am. Ceram. Soc. 84, 442–446 (2001). doi:10.1111/j.1151-2916.2001.tb00674.x 31. W. Prettln, N.J. Shevchik, M. Cardona, Far-infrared absorption in amorphous III-V compound semiconductors. Phys. Status Solidi B 59, 241–249 (1973). doi:10.1002/pssb.2220590122 32. N. Schonbachler, W. Luthy, Measurements of Raman Lines in Silica, Dimethyl-Methylphosphonate and Methyl Salicylate (University of Bern Press, Bern, 2010) 33. J. Serrano, A. Rubio, E. Hernandez, A. Muñoz, A. Mujica, Theoretical study of the relative stability of structural phases in group-III nitrides at high pressures. Phys. Rev. B 62, 16612–16623 (2000). doi:10.1103/PhysRevB.62.16612 34. H. Siegle, I. Loa, P. Thurian, L. Eckey, A. Hoffmann, I. Broser, C. Thomsen, Comment on “shallow donors in GaN studied by electronic Raman scattering in resonance with yellow luminescence transitions”. Appl. Phys. Lett. 70, 909 (1997). doi:10.1063/1.119072. Appl. Phys. Lett. 69,1276 (1996) 35. H. Siegle, A. Kaschner, A. Hoffmann, I. Broser, C. Thomsen, S. Einfeldt, D. Hommel, Raman scattering from defects in GaN: the question of vibrational or electronic scattering mechanism. Phys. Rev. B 58, 13619–13626 (1998). doi:10.1103/PhysRevB.58.13619 36. C. Stampfl, C.G. van de Walle, Density-functional calculations for III–V nitrides using the localdensity approximation and the generalized gradient approximation. Phys. Rev. B 59, 5521–5535 (1999). doi:10.1103/PhysRevB.59.5521 37. G.-L. Tan, M.F. Lemon, R.H. French, Optical properties and London dispersion forces of amorphous silica determined by vacuum ultraviolet spectroscopy and spectroscopic ellipsometry. J. Am. Ceram. Soc. 86, 1885–1892 (2003). doi:10.1111/j.1151-2916.2003.tb03577.x 38. J. Tersoff, New empirical model for the structural properties of silicon. Phys. Rev. Lett. 56, 632–635 (1986). doi:10.1103/PhysRevLett.56.632 39. J. Tersoff, Modeling solid-state chemistry: interatomic potentials for multicomponent systems. Phys. Rev. B 39, 5566–5568 (1989). doi:10.1103/physrevb.39.5566 40. R.-M. Wang, G.-D. Chen, J.-Y. Lin, H.-X. Jiang, Comparative analysis of temperature-dependent Raman spectra of GaN and GaN/Mg films. Front. Phys. China 1, 112–116 (2006). doi:10.1007/ s11467-005-0007-3

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41. D. Weaire, D. Hobbs, G.J. Morgan, J.M. Holender, F. Wooten, New applications of the equation-ofmotion method: optical properties. J. Non Cryst. Solids 164–166, 877–880 (1993). doi:10.1016/ 0022-3093(93)91137-R 42. A. Yasukawa, Using an extended Tersoff interatomic potential to analyze the static–fatigue strength of SiO2 under atmospheric influence. Jpn. Soc. Mech. Eng. Int. J. A 39, 313–320 (1996). NII Article ID (NAID) : 110002964467 43. L. Yu, D. Li, S. Zhao, G. Li, K. Yang, First principles study on electronic structure and optical properties of ternary GaAs:Bi alloy. Materials 5, 2486–2497 (2012). doi:10.3390/ma5122486

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

Nanoparticle-Assisted Organic Transformations Sonal I. Thakore* and Puran Singh Rathore Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India

Abstract Designing an efficient and cost-effective catalyst is a subject of extensive research. This chapter describes a new fast-growing area of catalysis, viz., metal nanocatalysis. In the nanosize regime, metals show perceptible change in their electrical, optical, and catalytic properties which allows them to act as catalysts in various electron transfer processes as well as organic transformations. Metal nanoparticle (NP) catalysts exhibit superior reactivity and selectivity compared to their bulk counterparts. Additional advantages include easy synthesis and separation, tunable size and shape, as well as improved efficiency under mild and environmentally benign conditions in the context of green chemistry. These systems offer efficient protocols for sustainable and environmentally friendly future, leading to the development of active and selective materials for a wide variety of applications.

Keywords Nanocatalysis; catalyst; organic transformations; Nanoparticles; Nanomaterials; Magnetic Nanoparticles; C-C coupling

Introduction Heterogeneous catalysis has received great attention from a scientific as well as industrial perspective. The 2007 Nobel Prize in Chemistry was awarded to Prof. Ertl, who introduced surface science techniques to the field of heterogeneous catalysis. This leads to in-depth understanding of chemical reactions taking place at the surfaces [1, 2]. There is a need to develop catalysts for industrial and pharmaceutically important chemical reactions (like organic transformation reactions) in environmentally friendly manner. On the other hand, nanomaterials (NPs) find application in every field such as electronics, medicine, and cosmetics. They are now evolving in the field of catalysis because their optical, electrical, mechanical, and chemical properties are a function of their size, composition, and structural order. This leads to new improved catalytic properties. Nanocatalysis has attained the form of a strategic field of science because it represents a new way to meet the challenges of energy and sustainability. Nanomaterials can be designed to control their size, shape, chemical composition, and nature of the microenvironment surrounding the NPs and assembly structure for advanced applications [3–5]. These materials can be a new class above the classical homogeneous and heterogeneous catalysts. Nanocatalysts are often considered as quasihomogeneous systems. More than 90,000 scientific publications appear on SciFinder with the keyword “nanocatalysis” in past years which suggests an exponential growth in this field. NPs have a large surface area which makes possible new quantum mechanical effects [6]. A higher surface area-to-volume ratios and active binding sites increased catalytic activity of NPs because more catalytic reactions can occur at the same time. The *Email: [email protected] Page 1 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015 Nanomaterials Synthesis

Physical methods

Mechanical

Chemical methods

Hybrid methods

Biological methods

1) Inverse micelles, 2) L-B films 1) Electrochemical 1) DNA, 2) enzymes, 2) Microemulsion 3) colloids, and 4) sol-gel 3) using biomembranes 3) Chemical vapour deposition and 4) micro organisms and 4) Particle arresting in glass or zeolites or polymer, microemulsion Vapour

1) High energy ball milling, 1) Laser ablation 2) Sputter deposition and 2) melt mixing 3) Electric arc depostion 4) Physical vapour deposition and 5) ion implantation

Fig. 1 Various methods of synthesis of nanomaterials

ultimate goal of nanocatalysis is to design catalysts with excellent activity, selectivity, and stability which operate under environmentally benign conditions [7]. These characteristics can easily be achieved by tailoring the size, shape, composition, morphology, electronic structure, and chemical and thermal stability of the particular nanomaterial. There are quite a few excellent reviews on nanoparticle catalysis [8–10]. In this chapter, we will focus on some fundamental issues which affect the properties of a nanocatalyst. With a mention of synthesis and characterization of NPs, we discuss the key focus of this chapter, that is, a variety of reactions and organic transformations using nanocatalysts such as hydrogenation, oxidation, and synthetically important carbon–carbon coupling reactions, such as Suzuki, Stille, Sonogashira, and Heck reactions. We then discuss the use of nanomaterials as organocatalysts and their application in other important reactions. Finally, the recently emerging area of using nanomaterials for environmental applications, particularly photo- and nanobiocatalysis, is summarized. Finally, we recapitulate the advantages of nanocatalysts, over conventional catalysis, and offer perspectives for further development.

Synthesis of Nanoparticles A number of techniques are available to synthesize NPs of different size and shape for catalytic application. These include various physical, chemical, biological, and hybrid techniques as presented in Fig. 1. Unlike classic heterogeneous catalysts, NPs are typically synthesized in a bottom-up approach from precursors such as a metal salt, a stabilizer, and a reducing agent [11]. The most interesting fact is that nanomaterial can be designed to have different forms like clusters, powders, tubes, rods, wire, thin films, etc.

Strategies for Controlling Size and Shape of Nanoparticles The size and shape of nanoparticles for catalytic studies can be controlled by colloidal solution-based methods. One of the approaches to synthesize NPs with various shapes like cubic and tetrahedral or octahedral is to employ surface-directing agents along with surface-capping agent. Surface-directing agents such as alkali and organic salts of halides [12, 13], transition metal crystals, cations, and complexes such as Ag+ [14], Fe3+ [15], Co+ [16], W(CO)6 [17], etc., are employed for this purpose. Some gas molecules such as H2, O2, CO, NO, etc., are also well-known surface-directing agents [18].

Page 2 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

1)TTABr 2)NaBH4

1)PVP 2)NaBH4 3)H2

1)TTABr 2)NaBH4 3)H2

Fig. 2 Schematics illustrate a generic synthetic procedure for preparing Pt nanoparticles with cube, octahedron and cuboctahedron shapes

For fcc crystals, {111} surfaces have the lowest surface free energies and thus are thermodynamically the most stable followed by {100} and then {110} surfaces. In the case of Pt group metal NPs, bromide ions present in the reaction solution produce cubic shapes by stabilizing {100} surfaces, whereas molecular hydrogen favors tetrahedral shapes with dominantly {111} surfaces. As shown in Fig. 2, NaBH4 reduction of aqueous solution of H2PtCl6 in the presence of tetradecylammonium bromide (TTABr) salt produced Pt cubes. Here TTABr acts as both a surfactant and a surface-directing agent. Similarly, Ag+ ions are known to favor cubic shapes when present in high concentrations and exclusively cuboctahedral shapes when present in trace amounts [14].

Mesoporous Materials and 2-D and 3-D Nanocatalyst A mesoporous material contains pores with diameters between 2 and 50 nm. Because of its high surface area, ordered pore structure, and large pore volume, mesoporous materials have been utilized widely as excellent catalyst and support in the field of heterogeneous catalysts [19]. Colloidal metal NPs can be applied to two types of catalysts: two-dimensional (2-D) and threedimensional (3-D) catalysts [20]. Langmuir–Blodgett technique is employed for 2-D catalysts wherein the self assembled NPs get deposited on a substrate (Fig. 3). The colloidal metal and alloy NPs are incorporated into the pores of mesoporous supports by methods such as [20] capillary-induced inclusion method (involving simple sonication in solution) (Fig. 3) and encapsulation [21].

Characterization of Nanocatalyst Some techniques that can be used to characterize nanomaterial catalysts are given in Table 1.

Unique Properties of Nanoparticles and Catalysis Nanocatalysts with good activity, stability, and selectivity can be designed by simple manipulation of their sizes, shapes, and morphologies [22–25]. Tuning material properties is easy at the nanoscale, compared to macroscopic counterparts. The nanocatalytic systems are active for several such reasons.

Page 3 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015 Colloidal Nanoparticles

Mesoporous Support Assembly of NPs by Langmuir Blodgett film

2D NP Catalyst

3D NP Catalyst

Fig. 3 Schematic illustrations for preparation of colloidal nanopartcle-based 2D and 3D catalysts

Table 1 Commonly used characterization techniques for nanomaterials Techniques X-ray diffraction (XRD) Transmission electron microscopy (TEM) UV–vis–NIR spectroscopy X-ray photoelectron spectroscopy (XPS) Photoluminescence spectroscopy (PL) Chemisorption, physisorption Scanning electron microscopy (SEM) Scanning tunneling microscopy (STM) Atomic force microscopy (AFM) Ultraviolet photoelectron spectroscopy (UPS) X-ray emission spectroscopy (XES) Near-edge X-ray absorption fine structure (NEXAFS) Extended X-ray absorption fine structure (EXAFS) Small-angle X-ray scattering (SAXS) Energy-dispersive X-ray analysis (EDXA) Fourier transform infrared spectroscopy (FTIR)/attenuated total reflection infrared (ATR-IR) spectroscopy

Property characterization Crystal structure Size, shape, and crystallinity Light absorption and scattering Chemical composition Light emission Surface area Shape and assembly structure Shape, size, and surface structure Shape, size, and work function Electron valence band Electron band gap Chemical composition Chemical composition and bonding environment Characteristic distances of partially ordered nanomaterials Chemical composition Surface functionalization, composition, and conjugates

High Surface Area-to-Volume Ratio Main advantage of the nanosize which favors the nanocataysts is the surface area-to-volume ratio. The available surface area of the active component of a nanocatalyst increases contact with the reactant molecules significantly. This enhanced interaction facilitates the heterogeneous catalytic system and helps to achieve a better reaction rate that mimics the homogeneous counterpart. Larger surface area increases the relative contribution of the surface energy so that the thermodynamic stability decreases with decreasing particle size. Page 4 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015 o

a

dihydrofuran (DHF) o o

tetrahydrofuran (THF) OH

butanol

propylene

b 60 % Selectivity

50 40 30 20 10 0 0

2

4

6

8

Size (nm)

Fig. 4 Reaction scheme of furan hydrogenation showing successive hydrogenation steps (a). % Selectivity for different reaction products, color coded as in (a) as a function Pt particle size (b)

Nanosize

Nanoparticles are not simply finely divided metals. In bulk metals, the large density of states at the Fermi level forms a conduction band of continuous energy levels. But as the particle size decreases, due to quantum confinement, discrete energy levels are formed. It is a gradual change that occurs over a range of sizes. This phenomenon is called the size-induced metal–insulator transition. For instance, it is reported that clusters of 13 atoms are nonmetallic, while clusters of 309 atoms and larger show distinct bulk metal properties [26]. The consequences of metal–insulator transition are reflected as changes in electronic, optical, and catalytic properties of NPs [27]. The fraction of surface atoms increases drastically with decreasing particle size. A nanoparticle of 1 nm would have ~76 % of the atoms on the surface, while a 3 nm nanoparticle will have only ~45 % [28]. According to literature, hydrogenation of small molecules such as pyrrole, crotonaldehyde [29, 30], furan [31, 32], and methylcyclopentane (MCP) [33] was reported to be of structure-sensitive nature as seen in Fig. 4. Dihydrofuran was produced by incomplete hydrogenation of the aromatic ring in presence of small NPs, while butanol resulted from hydrogenative ring opening of furan over larger NPs [31].

Shape and Morphology

Shape-dependent nanocatalysis has been extensively explored in the past two decades [34–37]. It was first suggested in 1996 [38]. It has been reported that higher efficiency was found for NPs having more and sharper edges and corners [35, 36, 39]. The exposed crystallographic facets also affect the catalytic property of the NP. The arrangement of atoms on the surface strongly influences the adsorption/activation of the reacting molecules and the desorption of the products [40]. Thus, the morphology of the catalyst particle determined by the exposed crystal planes could substantially alter the catalytic property as well. This is termed as morphology-dependent nanocatalysis: an NP having an anisotropic shape can modify the performance of reaction by selectively exposing specific crystal facets [41–43]. Single-crystal studies

Page 5 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

a Dehydrogenation / Ring Enlargement

Hydrogenation / Ring Opening

Isomerizaiton

CH3 H 3C

Dehydrogenation

H 3C

CH3

H3C

H 3C

CH3 CH3

g Crackin

CH3

H3C

CH3 H3C H3C

C1-C5

CH3 CH3

240°C

b 100 % Selectivity

CH3 CH3

80 60 40 20 0 Oh

%Hexane

TOh

%Benzene

Spherical

%2-methylpentane

Cube

%C1-C5

Fig. 5 Reaction scheme of methylcyclopentane hydrogenation showing different reaction pathways and products (a). % Selectivity for different reaction products as a function of Pt nanoparticles shapes, (110) octahedron (Oh), truncated octahedron (TOh), sphere and (100) cube (b). Representative model atom clusters are also given

have revealed that the exposed crystallographic plane has great influence on catalytic pathways and activities. El-Sayed and co-workers used PtNPs with different shapes (tetrahedral, cubic, and spherical) [44] as catalysts for electron transfer reactions [45]. The results of activation energy showed that the tetrahedral PtNPs were the most catalytically active, while cubic PtNPs were the least catalytically active. The spherical PtNPs had a moderate catalytic activity. Such a shape dependency was also observed in the case of the Suzuki reaction. Narayanan and El-Sayed found that when they moved from nearly spherical PtNPs to tetrahedral PtNPs, catalytic activity improved [45]. Tetrahedral PtNPs with (111) facets (as well as edges and corners) contain more active surface atoms than nearly spherical PtNPs with (100) and (111) facets. Similarly, shape dependence was observed for methylcyclopentane/H2 reaction over PtNPs (Fig. 5) [46]. Hydrogenation of methylcyclopentane results in ring opening, and a subsequent isomerization leads to various C6 isomers. Due to different surface crystallographic orientations, both activity and selectivity exhibited strong shape dependence. Similar shape dependence of surface reactivity was observed for benzene hydrogenation over Pt cubes and cuboctahedra [42].

Page 6 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

Advantages of Nanoparticles as a Catalyst In general, these properties of nanoparticles and their advantages as catalysts can be summarized as follows: 1. Heterogeneous nature, improved efficiency under mild and environmentally friendly conditions (green chemistry) 2. Higher surface area 3. Easy separation and recycling efficiency 4. Less fouling: less by-product, easy work-up 5. Possibility of surface modification 6. Stability in organic solvents 7. Enhanced reactivity and selectivity 8. Higher efficiency of NP catalysts under mild conditions probably due to their good dispersion in solvent and three-dimensional rotational freedom

Fundamental Challenge for Nanoparticle Catalysis Since NPs possess a large fraction of their atoms on the external surface, their surfaces are less stable compared to their bulk counterparts; under catalysis, their surface structures are dynamic due to the changing adsorbate–surface interactions. This can alter the reactivity of the nanocatalyst [47, 48]. To overcome this challenge, it is necessary to terminate the particle growth and to stabilize the surface which can be done in various ways such as immobilization or grafting onto inorganic supports and use of porous materials as matrix for particle growth [49, 50].

Nanocatalytic Approaches: The Role of Stabilizers and Ligands A nanoparticle-based catalytic system generally involves three components, i.e., metal core, stabilizer, and solvent. The metal core is the catalytic material with an activity and selectivity. The stabilizer protects the metal core against aggregation and controls its solubility. The role of the solvent is to offer dispersion medium for both metal core and stabilizer. It serves as a carrier for transfer of reactant(s) to the metal core and product(s) away from the active site. The solubilities of both the stabilizer and the reactant(s) in the solvent are therefore related to the final activity of the system. The symbiotic relation between metal core, stabilizer, and solvent together constitutes an effective catalytic system [8]. Some general approaches based on role offered by the metal, role of ligand, and location of the ligand in catalytic applications of NPs are represented in Fig. 6 [51].

Magnetically Recoverable Nanocatalysts Conventional techniques such as filtration are not efficient for the isolation and recovery of nanocatalysts because of their nanosize. Magnetic NPs have emerged as a viable solution to this limitation. The insoluble and paramagnetic nature of magnetic NPs easily facilitates efficient separation of the catalysts from the reaction mixture with an external magnet. This makes the nanocatalysis protocol practical and

Page 7 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

b A+B

a A+B

C C

d

A+B C:

c

A+B

L L L

L

L C

L

M L

L L

L L

L

Fig. 6 Catalysis with a) metal nanoparticles, b) metal nanoparticles capped with a protective shell, c) metal nanoparticles capped with ligands contributing to the catalytic activity, and d) metal nanoparticles with catalysts supported on the protective shell. Only in the last case the core material does not promote the reaction

Table 2 C–C coupling reactions catalyzed by magnetic nanosupports Reaction studied Suzuki Heck Suzuki, Heck Suzuki, Heck, Sonogashira Sonogashira

Particle composition NHC–Pd/polymer-coated g-Fe2O3 Pd/NH2–Fe3O4, Pd/polypyrrole nanotubes Pd/DA–NiFe3O4 Pd/DA–a-Fe3O4, Pd/Fe3O4, Pd/N-MCNPs Pd/Sio2–Fe3O4

Ref. [117] [118, 119] [120] [121–123] [124]

sustainable. Several magnetic materials have been used as supports for NPs, thus forming magnetically recoverable nanocatalysts [10].

Applications of Nanocatalysis Nanocatalyst has been used in a wide range of catalytic reactions such as hydrogenations, oxidations, C–C bond formation, and photocatalysis (Table 2) as well as in novel applications in asymmetric synthesis and other reactions [9, 52, 53]. Furthermore, high turnover numbers (TONs) and turnover frequencies (TOFs) make nanocatalysis very cost-efficient. In this section, we provide an overview of the applications of various metallic, nonmetallic, supported, and unsupported nanomaterials used in a wide range of catalytic processes.

Hydrogenation Reactions Hydrogenation is an important chemical reaction used in hydrogenation of carbon–carbon double and multiple bonds, carbonyls, and nitrogen-containing bonds. Therefore, research has focused on Page 8 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

a C

20 mol% NiNPs

C

C

i-PrOH, 76 °C

C

H*

b

(50%) H

R H*

R

O

H +

- acetone

H (50%)

[H-Ni-H*] R

H*

Fig. 7 Proposed dihydride-type mechanism for the transfer hydrorenation of olefins with isopropanol catalysed by NiNPs

heterogeneous catalysis systems for hydrogenation reactions. Most of the transition metal NPs are showing hydrogenation ability, for example, Ti, Zr, Nb, and MnNPs [54]. Colloidal TiNPs are very efficient catalysts for the hydrogenation of titanium, zirconium sponges, and nickel hydride battery alloy [55]. Other transition metal NPs such as Pd, Cu, Ag, Rh, Pt, Au, Ru, and Ni [56] showed higher catalytic activity than conventional-supported metal catalysts in simple hydrogenation [57] as well as for the hydrogenation of C–C bonds. The activity trend of some metal NPs is Rh > Ru > Pt > Ir, which is similar to that observed in traditional heterogeneous catalysis [58]. Hydrogenation of the benzene ring has increased attention recently because it is a challenging task. Januszkiewicz et al. reported the first example of benzene hydrogenation by RuNP [59]. Research focus is on the development of more stable and active NPs with high turnover numbers (TON) on benzene hydrogenation [60]. The Ir, Pt, and Ru metals exhibit excellent activity for the hydrogenation of C–O bonds. Özkar and Finke prepared IrNPs for the hydrogenation of acetones [61]. The reaction carried out under ambient temperatures. However, the temperature applied for this reaction under traditional supported catalyst is between 100  C and 300  C. The selectivity of reaction is about 95 % for 2-hydroxyl propanol and a TON is 16,400. Nickel NPs have been found to efficiently catalyze the hydrogen-transfer reactions of a variety of functionalized and non-functionalized olefins using 2-propanol as the hydrogen donor [62]. The NPs have been shown to be highly chemoselective with high yields. The optimized reaction conditions (Fig. 7a) were applied to a variety of olefins. The reaction involved dihydride species, where the two hydrogen atoms of the donor become equivalent after being transferred to the metal to give the dihydride (Fig. 7b) [63]. Magnetically Recoverable Nanocatalyst in Hydrogenation Magnetically recoverable platinum (Pt)- [65], rhodium (Rh)- [64], gold (Au)- [65–67], ruthenium (Ru)[68], and palladium (Pd)-based catalysts are used for various hydrogenation processes. Pd metal has been paid much attention as catalyst for hydrogenation reaction. Palladium on carbon (Pd/C) is a form of palladium that is commonly used for hydrogenation reactions in organic synthesis. Interestingly, this type of catalyst can be a designer to a magnetically separable catalyst [69]. Ying et al. also reported the preparation of magnetically separable PdNPs supported on silica-coated Fe2O3NPs and catalyst employed in the hydrogenation of nitrobenzene (Fig. 8) [70]. Silica-coated Fe2O3NPs exhibited higher activities relative to those obtained with commercial Pd/C catalysts. Asymmetric Hydrogenation Some of the homogeneous chiral Ru complexes are very active in asymmetric hydrogenations (Fig. 9) [71]. A magnetically recoverable chiral Ru complex was designed for the hydrogenation of a wide range

Page 9 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015 SH SH

HS HS

e) 3

OM

i( H 2)S

SH SH

HS

C

HS(

SH

HS HS

NO2

SH

SH

HS-SiO2/Fe2O3

Pd(OAc)2

room temperature and 1 atm of H2

MW.toluene HN 2 (C H

2 )NH

SiO2/Fe2O3

(CH

2 )3 S

i(O

Me

)3

H2N NH2 NH2 H2N NH2 H2N NH2 H 2N

Pd/HS-SiO2/Fe2O3 or Pd/H2N-SiO2/Fe2O3

NH2

H2N

NH2

NH2 (Yield = 99%)

NH2

H2N-SiO2/Fe2O3

Fig. 8 Synthesis of Pd/SiO2/Fe2O3 magnetic nanocomposites

PPh2 PPh2

HO

P

Ph Ph Cl P Ru P Cl Ph Ph

(R, R)–DPEN [Ru(benzene)Cl2]2

OH

HO

O

H2 N N H2

Ph2

Ph Ph Fe3O4

Ph2

P OH

+ Ar

R

OH

Cat. H2

KO’Bu, IPA

(conv. >99%, ee=70.6-98%) Ar

Cl

H2 N

Ph2

N H2

Ph2

Ru

Ph Ph Cl P O O

O O

P P

O

Fe3O

R

Fig. 9 Magnetite chiral Ru catalyst for asymmetric hydrogenation of aromatic ketones

of aromatic ketones to their corresponding secondary alcohols with high reactivity and enantioselectivity. Phosphonic acid was used to link the complex to the magnetite NPs. The enantiomeric excess (ee) values significantly higher than those of the parent homogeneous catalyst. Conventional supported gold nanocatalysts have been capable of selective hydrogenation of a,b-unsaturated ketones to produce a,b-unsaturated alcohols, with side products of saturated ketones from C–C hydrogenation and saturated alcohols from further hydrogenation [72, 73]. Instead [74] welldefined Au25(SR)18 nanoclusters have been used to attain chemoselective hydrogenation of the C–O bond in a,b-unsaturated ketones (or aldehydes) with 100 % selectivity for a,b-unsaturated alcohols at room temperature or 0  C [75]. The low-coordinate Au atoms of Au25(SR)18 nanoclusters were expected to provide a favorable environment for the adsorption and dissociation of H2 (Fig. 10).. Surprisingly, a complete stereoselectivity could be achieved although the nanoclusters are non-chiral. The spatial environment of Au25(SR)18 seems to have a strong impact on the direction that this H atom attacks; the catalytic results indicate that the preferred direction is along the axial direction rather than the equatorial direction (Fig. 11). Consequently, the diastereoselective hydrogenation is a result of the three-dimensional restriction imposed by the Au25(SR)18 nanoclusters and of the activated geometry of the ketone as well [74].

Oxidation Reactions Oxidation reactions are important to the chemical industry because of their potential for producing a variety of chemicals. However, most of the known oxidation reactions are unacceptable with regard to waste generation and selectivity. Traditional methods using stoichiometric quantities of inorganic oxidants such as permanganates, chromium (VI) reagents, or N-chlorosuccinimide are not environmentally Page 10 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

H C

C

H

H C

C

CH3

C

H

H O

H CH3

C

C

C

CH

H

H O

OH

H

H

CH3

Fig. 10 The proposed mechanisum of Au25(SR)18 nanocatalysts for the chemoselective hydrogenation of a,b-unsatureted alcohol (for clarity,only Au25 was shown; magenta: Au atom of the core, blue: Au atom of the shell. Thiolate ligands are omitted)

O

O N O

Ph O

H

H

O N

Ph

N O

H

Ph

H

H

H

Fig. 11 The proposed mechanism of sterioselective hydrogenation of bicyclic krtone on the Au25(SR)18 catalyst: the activation of C=O bond and H2; H-atome addition to the activated C-O group in a particular direction, and the formation of theexo-alcohol isomer. Color labels: magenta for Au13 core atomes, blue for Au12 shell atome, yellow for S grey for –CH2CH2Ph

Fe nanoparticles

O +

OH

OOt-Bu

+

Fig. 12 Oxidation of cyclooctane catalysed by Fe nanoparticles in reverse microemulsion (26)

benign [76]. Because of growing environmental concerns, continuous efforts have been made to the development of easily reusable and recoverable heterogeneous catalysts. In light of these concerns, the use of nanomaterials as a solid support for heterogeneously catalyzed oxidation reactions has been highly effective. Transition metals like Fe-, Co-, Ni-, Cu-, Ag-, and Au-based catalysts are widely used in oxidation reactions in industry. For example, FeNPs can catalyze the oxidation of cyclooctane with acceptable activity under mild conditions (Fig. 12) [77]. Vukojevic et al. found that CuNPs (3–5 nm) were as reactive as commercialized Cu/ZnO catalyst in methanol synthesis [78, 79]. The author claimed that the traditional catalyst requires a second component, like zinc, to be active. It was recently discovered that 3 nm CuNPs also catalyzed synthesis of methyl formate (MF) from methanol by carbonylation reaction in the absence of any base [80] with 100 % selectivity (Fig. 13). Commercially, this reaction is catalyzed by a CH3ONa which is highly efficient but leads to inevitable

Page 11 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

CO + CH3OH

Cu nanoparticles

HCOOCH3

353-443 K, 0.3-3 MPa

Fig. 13 Production of methyl formate from methanol carbonylation catalyzed by Cunanoparticles (29)

O H2C

CH2

Ag nanoparticles 363-403 K, 0.1 MPa O2

H2C

CH2

Fig. 14 Epoxidation reaction of ethylene catalysed by Ag nanoparticles (30)

problems such as by-product formation, corrosion, and the possible deactivation of catalyst by H2O and CO2 impurities. Epoxidation reaction catalyzed by AgNPs is well known and widely applied in ethylene oxide production. AgNPs are superior catalysts relative to a conventional bulk Ag catalyst (Fig. 14) [81]. Now AuNPs are also used on oxidation reactions of carbon monoxide into carbon dioxide and glucose into gluconic acid [81]. Au and AgNPs can also effectively decompose NaBH4 into H2 and NaBO2 [82, 83]. Haruta discovered that AuNPs catalyzed the CO oxidation [84]. The Pt/PdNP catalysts that are currently used in cars for CO oxidation work only at temperatures above 200  C. Hence most of CO pollution occurs in the initial minutes after starting the engine [85]. Clearly, the low-temperature oxidation of CO by supported Au catalyst could solve this problem. The gas-phase hexaauride clusters (Au6 ) of AuNP particles are reported to catalyze the oxidation of CO to CO2 in the presence of O2 [86]. The mechanism is shown Fig. 15. The well-defined Aun(SR)m nanoclusters offer a unique opportunity for oxidation of styrene also, in particular regarding how the electronic properties and the core–shell structure of Aun(SR)m nanoclusters influence their catalytic performance. Tsukuda and co-workers [87] immobilized Au25(SR)18 nanoclusters on a hydroxyapatite support for the selective oxidation of styrene in toluene (solvent). They achieved 100 % conversion of styrene and 92 % selectivity for the epoxide product [88]. The use of magnetic nanomaterials as a solid support for heterogeneously catalyzed oxidation reactions has proven to be highly effective. Mizuno and colleagues developed a heterogeneous magnetic retrievable ruthenium hydroxide (Ru(OH)x) catalyst [89]. This catalyst system was used in the catalysis of the aerobic oxidation of alcohols and amines, as well as in the reduction of carbonyl compounds to alcohols (Fig. 16). These systems are able to catalyze these reactions for a range of substrates in good yields and without requiring any additives. Another example is a Pd catalyst supported on dopamine-functionalized nanoferrite developed by Polshettiwar and Varma (Fig. 17) [90]. Dopamine was chosen as a linker on the basis of its ability to make octahedral geometry for oxygen-coordinated iron. These functionalized materials coated with Pd displayed high catalytic activity in the oxidation of olefins and alcohols.

C–C Coupling Reactions Metal-catalyzed coupling reactions such as Heck, Negishi, Suzuki, Stille, and Sonogashira are of paramount importance in synthetic organic chemistry. This fact was recognized by the award of the 2010 Nobel Prize for Chemistry for C–C coupling reactions [91]. The C–C couplings offer an extremely convenient route to join large fragments of molecules in a controlled manner for designing convergent overall synthetic schemes. The resulting products have found numerous applications in the synthesis of natural products and drug compounds.

Page 12 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

(I) (–)

(II) O2

CO2

(VI)

(–)

(–)

CO

CO (V)

(III)

(–)

(–)

CO2 (–)

(IV)

Fig. 15 Proposed schematic mechanism of CO oxidation by Au6- cluster (I) ; the bare Au6- adsorbs molecular oxygen in the superoxo form (II); subsequent co-adsorption of CO may initially yield an Au6CO3- species (III), which rearranges to produce the very stable CO3- adsorbate (IV). Elimination of CO2 yields the Au6O-form (V). Adsorption of a second CO yields the Au6CO2- (VI). Reprinted with permission from [19]

HO R

8 examples Yield = 53-99%

H R' O

2-Propanol R

R'

Ru(OH)x/Fe3O4 HO

H2N

H

R

R'

O2

O2

R

H N

O R

H

R R'

10 examples Yield = 80-99%

9 examples Yield = 89-99%

Fig. 16 Ruthenium hydroxide (Ru(OH)x) catalyst supported on magnetic ferrites

Palladium is probably the most versatile metal in promoting C–C bond formation, compared to other transition metal catalysts [92]. The difficulties in recycling of soluble palladium-based catalysts were widely overcome in the past by heterogenization of homogeneous palladium NPs on various solid

Page 13 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

H2N H2N H2 N HO +

Fe 3O4

NH2

HO

Sonication

H2N

RT. H 2O

H2N

NH2 NH2 NH2

Fe3O4

NH2

H2N H2N

Magnetic Nano Particle

NH2

H2N

NH2

NH2 NH2 NH2

O = O

Na2PdCl4 NH2NH2

Pd H R

O

Nano-Ferrite-Pd OH

R

75 °C, H2O2

H2N H2 N

H Pd

R=alkyl, aryl

H2N H2N Pd

Pd H2N NH2 NH 2 NH2 Pd Fe3O4

NH2 H N 2

NH2 NH2

NH2 NH2

Pd

Pd

Fig. 17 Pd Catalyst supported on dopamine-functionalized nanoferrite

R′

R

Heck R′ Sonogashira

[Pd]

R′

R′

H R

R

Suzuki

R Ar

X ArB(OH)2 X= Cl, Br, I

Negishi

R R′

R′ZnX Stille

R

R′SnBu3

R′

Fig. 18 Selected C-C coupling reaction catalysed by supported Pd metal nanoparticles

supports (Fig. 18) [92–95]. Here, these systems and other salient evidences are explored concerning the heterogeneity of NP-catalyzed C–C coupling reactions (Tables 2 and 3). PdNP-catalyzed C–C coupling reactions act truly heterogeneously, even though this may be a result of a less extensive number of studies. El-Sayed and co-workers identified the importance of surface sites in the reaction [96] and the effect of Ostwald ripening on activity [97]. Both these factors specify the role of

Page 14 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

Table 3 Some of metal nanoparticle-catalyzed reactions Hydrogenations Reaction Alkynes

Ref. [128, 129]

Oxidation reactions Reaction Cyclooctane

Ref. [148]

Coupling reactions Reaction Heck coupling

[130–135]

Dihydrogen

[149]

Suzuki coupling

Ref. [97, 162, 163] [164–167]

[136]

Aromatic amines

[150]

Sonogashira coupling

[168, 169]

[137–140] [142]

1-Phenylethanol Alkyl amines

[151] [152]

Stille coupling Negishi coupling

[170] [171]

[142] [132, 143]

CH3OH CO

[153] [154–156]

[172, 173] [174]

Acrolein

[144]

Cyclohexane

[157]

N-Isopropylacrylamide

[143]

[158]

Asymmetric hydrogenation Cinnamaldehyde

[145]

Ethene and propene epoxidation Glucose

Kumada coupling Dehydrohalogenation of aryl halides Amination of aryl halides and sulfonates Hydrosilylation

[159]

Coupling of silanes

[176]

[160]

[3 + 2] Cycloaddition

[177]

Ketones, benzonitrile

[147]

[161]

McMurry coupling

[178]

Simple olefins and dienes Aromatic nitro compounds Arene rings Arene rings of dibenzo18crown-6 Methacrylate Allylic alcohols

[146]

Diol, glycerol, ethylene glycol Oxalate

[152] [175]

the PdNPs surface in C–C coupling reactions. A study using ionic liquids showed again that NPs play important role in the catalysis [98]. Cao and co-workers used Pd and Pd/Au alloy NPs for Suzuki coupling reactions under microwave (MW) irradiation (Fig. 19a) [61]. They found that Pd/Au alloy NPs showed superior performance and recyclability in the coupling of aryl boronic acids with aryl bromides as well as aryl chlorides. The proposed mechanism is shown in (Fig. 19b). The Suzuki–Miyaura reaction involves the coupling of aryl halides with aryl boronic acids. Metallic PdNPs supported on alumina- and silica-based oxides [99–101], commercial magnetic NPs [102, 103], and polymers including polyaniline nanofibers have been reported as highly active and reusable catalysts for this reaction. Budarin et al. prepared highly active and reusable PdNPs on biopolymers for the crosscoupled product of bromobenzene within a few minutes of reaction (Fig. 20) [104]. Amitabha Sarkar et al. reported aqueous nanosized Pd as a highly efficient catalyst for Suzuki, Heck, Sonogashira, Stille, and Hiyama coupling [105–107]. Brindaban C. Ranu et al. [108] reported a PdNP-catalyzed C–H functionalization of aliphatic aldehyde by aryl halides leading to an easy route to alkyl–aryl ketone (Fig. 21a). Alkyl–aryl ketones are of much importance as useful intermediates in industries [109]. The reaction follows a similar reaction pathway as proposed by Xiao and co-workers [110], as outlined in Fig. 21b. In situ-generated PdNPs undergo oxidative addition followed by Heck coupling to provide an intermediate A with the insertion of aryl group at the a-position of the heteroatom. The intermediate A on b-hydride elimination followed by hydrolysis furnished the product alkyl–aryl ketone.

Page 15 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

a R

+

Cl

0.5 mol % catalyst

B(OH)2

H2O/EtOH (3:2), MW K3PO4, 100°C, 30 min R Me MeO

b Ar-Ar′ + “Pd(0)”

reductive elimination

discrete Pd(0) species

Pd(II)

yield (%) 55 43

Ar-X

or Ar-Ar′ + Pd(0) nanoparticle

Ar Ar′

R

oxidative insertion Ar

L

L

X Ar

XB(OH)2 L

Pd(ll)

chemical etching

X

Ar′-B(OH)2

L

transmetalation

discrete Pd(II) species

Fig. 19 (a) Suzuki cross-coupling reactions catalysed by Pd/AuNPs. (b) Proposed mechanism of the Suzuki cross-coupling catalytic cycle

B(OH)2

Br

+

Fig. 20 Suzuki coupling of bromobenzne and phenylboronic acid using Pd metal nanoparticles on expanded starch

Magnetic Nanocatalysis for C–C Coupling Reaction Gao and colleagues reported the preparation of a Pd/N-heterocyclic carbene that could be immobilized onto maghemite NPs to improve the solubility of nanocatalyst in organic solvents (Fig. 22a) [111, 112]. By using Na2CO3 as the base in the presence of DMF, this catalyst provided nearly quantitative yields for electron-rich and electron-poor aryl iodides and bromides (Fig. 22b). This catalytic system was shown to be faster than an analogous polystyrene solid-phase system. This Pd/N-heterocyclic carbene complex could also be applied to the Heck and Sonogashira cross-coupling reaction [112]. The Stille reaction has widespread use in organic synthesis [112–115]. The first example of Stille reaction, catalyzed by heterogeneous Pd–SiO2/Fe3O4, was provided by Jin and colleagues [116]. Some of the examples of magnetic nanosupported C–C coupling reactions are given in Table 2.

Organocatalysis Metal-free catalysts for the synthesis of organic molecules have recently attracted great attention [125]. Polshettiwar et al. reported Paal–Knorr reaction catalyzed by glutathione-functionalized

Page 16 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015 O

a

X +

O H

R1 n

Pd(OAc)2, TBAB

R1 n

Pyrrolidine, 4A° MS DMF, 100°C

R

R O

b

Ar-X

Base.HX

R

Oxidative H addition

Pd(0)

Enamine formation with pyrrolidine

Base Ar

Reductive eimination H

(II)Pd X

N

Ar

N

H

Pd(II) X

R

R

Ar

H Pd(II)

R

(II)Pd

H2O

Ar

N

β-Hydride elimination

A X

O

N

X Insertion

R π-Complex

R

Ar

Fig. 21 (a) Direct acylation of aryl halides with aldehydes. (b) Probable mechanism of acylation reaction

a

O γ−Fe2O3

O O

N

Si

PS

N

CH2

Cl

b R

N Me

Cl

Pd 2

X +

N

Me

B(OH)2

Pd 2

Iron Oxide-Pd DMF, 12h Na2CO3, 50°C R

R X

Yield%

2-Me

I

87

2-Me

Br

84

3-OMe

I

91

3-OMe

Br

90

4-OAc

I

93

Fig. 22 (a) Pd-N-Heterocyclic carbene immobilized on magnetic nanoparticles and on polystyrene resins. (b) Maghemite nanoparticle-supported Suzuki cross-coupling reaction

MNPs [126]. The glutathione molecules were attached on MNPs through thiol groups. The catalyst displayed high activity for a wide variety of amines like aryl, alkyl, and heterocyclic (Fig. 23). Remarkably, functionalized amines were selectively converted into the corresponding pyrroles, while preserving their functional groups (C–C bonds, esters, alcohols, ketones, etc.). Another nano-organocatalyst was prepared with a magnetic cobalt core using “click” chemistry (Fig. 24) [127]. The CoNP-TEMPO showed high catalytic activity in the chemoselective oxidation of Page 17 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

R NH2 +

MeO

O

OMe

nano-FGT H2O, MW, 140°C

R

R = C6H5, CH2C6H5, CH2C5H4N, C(O)C6H5, NHC(O)C6H5, (CH2)3NH2

N

72−92%

O O OH

N H nano−FGT =

S

N H O O H2N

OH

Fig. 23 Nano-FGT-catalyzed Paal–Knorr reactions

Co

OH 1. NaNO 2/HCl, RT, H 2O

+ H2N

N3

Co

2. HN 3, PPh3, DEAD RT, Toluene

n CuVNEt3 RT. Toluene

O N

O

Co N N N N

O

O CoNP-TEMPO Catalyst

Fig. 24 Synthesis of the magnetic CoNP-TEMPO catalyst system

primary and secondary alcohols. The catalyst could be reused without any considerable loss in activity. Magnetic nature of the catalyst provides facile isolation and recycling.

Nanocatalysts in Miscellaneous Reactions Nanoparticles have been reported to catalyze a wide range of related reactions with significant catalytic performance. The NPs can be modified with various functional groups to generate different types of catalytically active sites that can be employed in various reactions (Table 4).

Environmental Applications In this section, an outline of the applications of various NPs in environmental challenges, including photodegradation of pollutants, biocatalysis, and photocatalysis for clean energy applications, is provided. Page 18 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

Table 4 Miscellaneous reactions catalyzed by different NPs Reaction type Hydroformylation of 1-dodecene Acylation Transesterification Dehalogenation Phenyl-selenylation Aza-Michael reaction Monoalkylation 1,4-Addition of boronic acids Polymerization Selective H–D exchange Phenylborylation Ullmann C–C coupling Carba–Michael addition reaction Cyanation reactions Mannich reaction Deoxygenation Cycloaddition of terminal alkynes and azides C–N bond-forming reaction Aldol reaction/hydrogenation Oxidative cyclization of Schiff’s bases Synthesis of polyhydroquinoline derivatives via Hantzsch condensation Cyclization of 2-(1-hydroxy-3-arylprop-2-ynyl) phenols Azide–alkyne click reaction in water Wittig-type olefination of alcohols Homocoupling of aryl iodides Knoevenagel reaction Bis-Michael addition Anti-Markovnikov addition One-step synthesis of “privileged medicinal scaffolds,” 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines N-Alkylation Hydrochlorination of ethyne

NPs/supported nanoparticles Rh(0)(rhodium NPs) Fe3O4-nanoparticle-supported 4-N, N-dialkylaminopyridine catalyst Immobilization of amine on Nickel NPs Fe–Pd(2.4  0.5 nm), Pd (2.7 nm), Pd/Au (4 nm Au, Pd surface coverage 71.2 %), Pd (2.4 nm) Cu (4.3  0.6 nm) SiO2@Cu (57 nm) Pt (5–8 nm) Rh–Fe2O3(10 nm) Ag (10–20 nm) Pd (3.4  0.5 nm) Ir (3.5 nm) Pd and Cu nanoparticle Cu (50–60 nm) Pd(0) Cu nanoparticle(18  2 nm) Ag NPs CuNPs Fe (0) Pd/hydrotalcites CuNPs NH4OAc/Ni-NPs

Ref. [179] [180]

AgNPs

[205]

Cu@Fe NP Nickel NPs Nickel(0) NPs CoFe2O4NPs Silica nanoparticle Silica nanoparticle Silica NPs

[206] [207] [208] [209] [210] [211] [212]

Fe3O4 NPs Activated carbon impregnation AuNPs

[213] [214]

[181] [182–185] [186] [187] [188] [189] [190] [191] [192] [193–195] [196] [197] [198] [199] [200] [201] [202] [203] [204]

Photocatalysis The treatment of industrial waste waters for removing organic pollutants by heterogeneous photocatalysis has developed as an advanced technique [215]. Recently, metal NPs were reported as effective photocatalysts under ambient temperature with visible light illumination [216]. This can be attained by increasing the optical path of photons leading to a higher absorption rate of NPs in the presence of a local electrical field [217, 218]. Hence, the interest for the photocatalytic degradation of dyes by using NPs has developed. The widespread use of nanomaterial like semiconductor metal oxides increases the possibility Page 19 of 28

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

NH2

NH2

O +

NHAc +

O

Fig. 25 Racemic resolution of 2-Pentylamine using a biocatalyst based on candicaantartica entrapped on magnetite containing a methyl-/ propyltrimethoxyorthosilane gel

H O P M N

OEt OH

+

EtO Si

NH2

H O P M N

−EtOH

OEt

O NH2

Si O

Glutaraidehyde

H O P M N

O Si O

N

N

Lipase-NH2

Lipase

H O P M N

O Si

N

CHO

O

Fig. 26 Immobilization of Lipase on the Novel Hierarchically Ordered Porous Magnetic Nanocomposites

due to their excellent properties such as ferroelectricity, high-temperature stability, superconductivity, semiconductivity, ferromagnetism, piezoelectricity, and catalytic activity [219]. NPs such as WS2, CdS, ZnO, SnO2, TiO2, AgS, ZrO2, MOS2, ZnS, WO3, and SrTiO3 have been identified as photocatalysts for the degradation of numerous synthetic dyes and organic contaminants. Although some pure metal and its alloy NPs are also used as photocatalyst like Ag [220], Fe–Ni [221], etc., the photocatalytic activity of TiO2 NPs is well recognized. Again, the combination with MNPs allows a simple recovery of such welldispersed TiO2 particles [222–225]. TiO2 NPs immobilized on various magnetic supports such as ferrites, magnetite, and Fe3O4–SiO2 have been used for photodegradation of various dyes like [226] methylene blue [227], rhodamine B [228], and methyl orange (MO) [229].

Nanobiocatalyst Nanobiocatalysis, in which enzymes are incorporated into nanostructured materials, has developed as a fast-growing area. Enzymes are versatile macromolecular biocatalysts [230]. However, their widespread application is hampered by inherent disadvantages, including cost, availability, and recycling. To improve the reusability of enzymatic systems, a wide range of inorganic materials are used as a support. Nanostructures, including NPs, nanofibers, carbon nanotubes, and nanoporous media, have showed great efficiency in the manipulation of the nanoscale environment of the enzyme, and magnetic NPs have the additional advantage of stability and separation [231]. In literature, the first reports of the entrapment of enzymes in magnetic materials for heterogeneous nanobiocatalysis were described by Reetz et al. in 1998 [231, 232]. The activity of the biocatalyst was investigated for the esterification and also tested as an enantioselective catalyst in the kinetic resolution of racemic 2-pentylamine (Fig. 25). The ee obtained in the resolution was 97–99 % [233, 234]. Another such example is magnetically immobilized lipase which was used to produce biodiesel fuels from soybean oil [235]. Magnetic Fe3O4 NPs treated with (3-aminopropyl) triethoxysilane were used as immobilization material. Lipase was covalently bound to the amino-functionalized MNPs by using glutaraldehyde as a coupling reagent with the activity recovery up to 70 % and the enzyme binding efficiency of 84 %. Similar immobilization of lipase on magnetic nanocomposites (hierarchically ordered porous-functionalized magnetic nanocomposites) is demonstrated in Fig. 26. The resulting nanobiocatalysis has been utilized for hydrolysis reaction [236]. Similarly horseradish peroxidase entrapped on magnetite-containing

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

spherical silica NPs [237] was reported by a reverse-micelle technique. The present progress of nanobiocatalysis has demonstrated the advantages of nanobiocatalytic approaches and their bright future as a fusion of nanotechnology and biocatalysis.

Nanocatalysts for Clean Energy Applications Today the world is on the verge of an energy crisis. Hence alternative technologies that can provide replacement to existing fossil fuel-based energy system are highly required. The concept of green chemistry is also involved in the progress of sustainable energy technologies such as H2 and fuel cells [238]. These technologies that depend mostly on catalysis for energy harvesting and nanocatalysis have been extensively used for the H2 storage, H2 generation, and energy conversion [239]. When hydrogen reacts with oxygen to form water the stored chemical potential is released. Water is considered as the ideal source for H2 production; however, this process is a highly energyintensive process. Water splitting in the presence of a photocatalyst (e.g., TaON, TiO2, and LaTiO2N) has been studied extensively as a potential method to supply renewable H2 [240]. The two challenging problems in TiO2 photocatalysis are (i) the necessity of near-UV light because of its relatively high band gap and (ii) the relatively low quantum efficiencies because of quick electron–hole pair combination. The issues that affect the photocatalytic efficiencies of TiO2 include the surface area, size, morphology, and phase of the particles [241]. For example, the nanotubular architecture allows for more efficient absorption of incident photons as well as decreased bulk recombination.

Conclusions and Perspectives Catalysis is of vital significance for the development of the world by providing a sustainable way to transform raw materials into valuable chemicals in an efficient, cost-effective, and environmentally benign manner. While nanotechnology has several applications, the use of nanomaterials as catalysts has attracted great attention. Advances in the synthesis and characterization of nanostructured materials could lead to their manipulation at the atomic level to attain desired catalytic properties. This chapter provides an extensive overview on the applications of nanocatalysts in a wide range of catalytic processes and numerous synthetically significant reactions including oxidation, hydrogenation, and carbon–carbon coupling reactions. It also discusses the use of nanomaterials in some emerging areas such as environmental applications for removal of pollutants from water and air and generation of hydrogen for clean energy applications. From the various examples, it can be concluded that the performance of any nanocatalyst for a particular reaction strongly depends on the particle composition, shape, size, and interaction with the support. There has been an increasing recent trend of the use of magnetically separable nanomaterial for the reason of their facile separation, high selectivity, stability, and activity. Nanomaterials show great potential as chiral catalysts, which are used extensively for the synthesis of drugs, medicines, and other bioactive molecules. By using chiral ligands, a series of surfacefunctionalized chiral nanocatalysts can be designed, which are economic catalyst systems. The detailed mechanistic aspects of these catalytic processes are essential to develop new catalyst. Atomically resolved knowledge of the active site will provide a platform for designing new and improved catalyst materials.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_35-1 # Springer International Publishing Switzerland 2015

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Bio-Functionalized Metallic Nanoparticles with Applications in Medicine Stela Pruneanu*, Maria Coroş and Florina Pogacean National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania

Abstract Due to their special physicochemical, optical, and biological properties, noble metal nanoparticles have huge potential for application in many different biological and medical areas, such as highly sensitive diagnostic assay, thermal ablation, radiotherapy, or carriers for drugs and gene delivery. This chapter selectively reviews the bio-functionalization of metallic nanoparticles and their recent applications in medicine. The chapter is divided into four sections: Introduction, Bioconjugation of Metallic Nanoparticles, Cancer Therapy, and Gene Delivery. After a short introduction, we present few general strategies for bioconjugation of metallic nanoparticles: physisorption, physisorption using mediator molecules, covalent binding of biomolecules to cross-linkers, covalent binding of biomolecules to nanoparticles, and linking of biotinylated biomolecules to streptavidin-functionalized nanoparticles. The third section presents the recent advances in cancer therapy based on two strategies: passive targeting and antibody targeting, using functionalized gold nanoparticles. The fourth section describes the gene delivery process, by which foreign DNA is introduced into the host cells. The process typically involves the formation of transient pores or “holes” into the cell membrane, which allows the uptake of foreign material. The main aspects that are discussed about the gene delivery process are the stealth character and the targeted recognition of tissues.

Keywords Bio-functionalization; Cancer therapy; Gene delivery; Metallic nanoparticles

Introduction Therapeutic applications of nanoparticles are ranging from antimicrobial action gene, drug, and vaccine delivery to cancer therapy. Cancer, a complex disease that involves unregulated cell growth, is one of the leading causes of mortality in the modern world. Finding an efficient tool for treating cancer is a constant challenge for researchers. Effective treatments include surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy. Chemotherapy – treatment with cytotoxic chemicals – is an efficient tool for cancer therapy, but the therapeutic efficacy of many drugs is seriously compromised by the low bioavailability and intrinsic toxicity, since most chemotherapeutics also kill the healthy cells. The synthesis of drugs that may differentiate the normal cells from the cancer ones is very difficult. Nanoparticles can be designed to overcome some of the disadvantages of the conventional therapies. The small dimensions of the nanoparticles allow them to pass through the weak membrane of the blood vessels, which supply the tumors, without the penetration of the healthy tissues. Therefore, by loading the particles with chemotherapy drugs, the tumor cells can be reached without damaging the healthy ones [1].

*Email: [email protected] Page 1 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Noble metal nanoparticles (Au, Ag, or combination of both) have the potential to be used in many different biological and medical applications including highly sensitive diagnostic assay, thermal ablation, and radiotherapy enhancement [2] as well as carriers for drug and gene delivery [3]. Researchers are interested to study the intracellular traffic of nanoparticles and to determine the critical parameters for their efficient cellular uptake and retention. Silver nanoparticles can be incorporated in several consumer products such as footwear, paints, cosmetics, and plastics due to their antibacterial properties. Since the size, shape, and composition of silver nanoparticles can significantly affect their efficacy, extensive research has been devoted to this field [4]. Gold nanoparticles have high chemical stability, good oxidation resistance, and biocompatibility and therefore can be used for diagnosis, therapeutic purposes, or as drug carriers. As in the case of silver nanoparticles, the properties of gold nanoparticles strongly depend on their size and shape. Therefore, there is an increased interest into the fabrication of gold nanostructures with specific shapes, through various methods [5, 6]. Although metal nanoparticles are innovative in therapy, imaging, and early diagnosis of several diseases, a special attention should be paid to their toxicity, due to their tendency to accumulate in the liver. For this reason, their removal from the body needs to be properly addressed. A recent number of papers have dealt with the application of metal nanoparticles in medicine. Murthy reported about the role of nanoparticles in modern medicine and the environmental and social impact of their usage [7]. Tiwari et al. reviewed the recent advances in the field of functionalization of gold nanoparticles and their potential applications in medicine and biology [8]. Dykman and Khlebtsov wrote a critical review about the application of gold nanoparticles in biomedical diagnosis, photothermal and photodynamic therapies, as well as the delivery of target molecules [9]. Ravindran et al. reported about the synthesis of silver nanoparticles along with their antimicrobial and anti-inflammatory properties. In addition, they discussed the possibility to link various functionalities like protein- or nucleic acid-based recognition elements for bioconjugation of silver nanoparticles and for the application in the field of biomedicine [10]. Labouta and Schneider highlighted in a recent review the current applications of inorganic nanoparticles and discussed about the status of their skin penetration. They reported the results generated from experiments on human skin and include some recommendations for future research [11]. In this paper, we provide an overview on the bio-functionalization of metallic nanoparticles with potential applications in cancer therapy and gene delivery (see Table 1).

Bioconjugation of Metallic Nanoparticles Bioconjugation is a procedure that links biomolecules to nanoparticles under mild (physiological) conditions [12]. Sometimes, nanoparticles cannot be directly attached to biomolecules, because their surface-chemical properties are not appropriate. In this case, they must be chemically changed so the bioconjugation reactions can successfully proceed. Murcia and Naumann have presented few strategies to bioconjugate nanoparticles [13]. The main requirements, which must be fulfilled during bioconjugation, are as follows: (i) the biomoleculenanoparticle link is stable in time; (ii) the biomolecular activity is preserved. In addition, it is of great interest to control the number of binding sites on the nanoparticle surface. The easiest approach is via physisorption or noncovalent coupling, as shown in Fig. 1a. In this case, the biomolecular activity might be affected, and in addition, it is difficult to control the amount of bound molecules. A more complex approach is based on noncovalent coupling between biomolecules and

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Table 1 Bio-functionalized metal nanoparticles and their potential applications Type of nanoparticles Bioconjugation of Au and Ag nanoparticles Au nanoparticles Au nanospheres and nanorods linked with thiolfunctionalized PEG Colloidal Au functionalized with PEG-SH molecules and recombinant human TNF-a Au nanorods conjugated with anti-EGFR antibody or TNF-a protein Calsequestrin-functionalized Au nanoparticles

PEG-modified Au nanoparticles Amine-functionalized Au nanoparticles Au nanoparticles coated with lysine-based headgroups Dendrimer-entrapped Au nanoparticles Au nanoparticles modified with 2aminoethanethiol, 8-amino-1-octanethiol, and 11-amino-1-undecanethiol Poly-L-lysine with citrate-capped gold nanoparticles Au nanoparticles functionalized with singlestranded DNA Au nanoparticles functionalized with cysteamine Au nanoparticles functionalized with covalently attached oligonucleotides

Potential applications Drug delivery, diagnostics, therapy, biosensors Radiofrequency thermal destruction of human gastrointestinal cancer cells In vivo/in vitro investigation of cancer therapy

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[42]

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Detection of Ca2+, useful in detecting and monitoring several diseases associated with hypercalcemia, such as malignant tumors Hepatocyte gene delivery and enhanced gene expression Intracellular delivery of small interfering RNAs Transfection vectors

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Gene delivery Gene transfection

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Gene delivery

[66]

Deliver highly structured RNA aptamers into the nucleus of human cells Deliver unmodified microRNAs into living cells Development of therapeutic and gene delivery systems

[67]

[52]

[68] [69]

nanoparticles, previously covered by a mediator, Fig. 1b. The presence of the mediator may help the binding of biomolecules in a proper orientation, which preserves the biomolecular activity. A stronger coupling can be obtained for biomolecules with reactive groups like thiols or primary amines, which can be covalently bound with cross-linker molecules, as shown in Fig. 1c. In this case, the bond is more stable, but the multiple active sites on the target biomolecules might prevent a coupling with high specificity. A facile approach is the chemical coupling of biomolecules directly to nanoparticles (Fig. 1d). This method is intensively used for attaching chemically modified oligonucleotides to nanoparticles, e.g., via thiol groups [14–16]. Finally, nanoparticles can be functionalized with streptavidin (or avidin) and then coupled with high specificity with biotinylated ligands or target biomolecules, like represented in Fig. 1e [17, 18]. The bioconjugation of metallic nanoparticles (gold, silver) is of high interest due to their multiple applications in medicine (drug delivery, diagnostics, and therapy) [19, 20] and biosensors [21, 22]. In particular, gold is extremely attractive due to its excellent biocompatibility. In addition, it does not require chemical modification prior the bioconjugation. The nanoparticles of both metals can be prepared with very narrow size distribution, which is greatly advantageous for controlling the number of bound biomolecules. The biomolecules can be attached to these nanoparticles either by physisorption or by chemisorption.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Fig. 1 Few strategies to bioconjugate nanoparticles: physisorption (a); physisorption using mediator molecules (b); covalent binding of biomolecules to cross-linkers (c); covalent binding of biomolecules to nanoparticles (d); high specificity binding of biotinylated biomolecules to nanoparticles functionalized with streptavidin (e) (Reproduced with kind permission from reference [13]. Copyright (2013) Wiley-VCH Verlag GmbH & Co. KGaA)

Cancer Therapy The recent advances in nanoscience and nanotechnology have evidenced the suitability of noble metal nanostructures in cancer therapy. This is due to their strong visible and near-infrared light absorption bands (surface plasmon resonance band, SPR) [23–28] which are more intense than those observed for the common laser phototherapy agents. As shown by Jain et al. [29], the absorption cross section of gold nanoparticles is up to five orders of magnitude stronger than that of rhodamine 6G dye molecule [30]. Based on these optical properties, a selective and efficient cancer therapy was developed, named plasmonic photothermal therapy (PPTT) [31]. In another study Gannon et al., [32] have reported that intracellular gold nanoparticles (GNP) favor the radiofrequency thermal destruction of human gastrointestinal cancer cells. Hep3B and Panc-1 cells were treated with 67 mM
L 1 GNPs and then exposed to external 13.56 MHz RF radiation. Both cell lines had markedly higher rates of cell death than the control samples not treated with GNPs at all time points, as measured by PI-FACS (p < 0.01). In addition, they reported that cells treated with RF after a GNP dose of 1 mM
L 1 had no increased cytotoxicity compared with control cells grown only with media (no GNPs). Cells receiving 10 mM
L 1 GNPs had slightly, but not significantly, greater cytotoxicity compared to cells treated without GNPs. Gold nanoparticles can be easily functionalized with tumor-targeting molecules. Two strategies are generally employed: the passive targeting and the antibody targeting. The passive targeting approach uses thiolated poly(ethylene)glycol (PEG) for functionalization of nanoparticles in order to increase their biostability and biocompatibility. This approach is also called stealth technology [33], and its main advantage consists in considerably reducing the interaction between nanoparticles and the immune system. In order to obtain functionalized metallic nanoparticles with stealth property in a cellular environment, it is necessary to understand the interaction between protein and various surfaces. Generally, such interactions are noncovalent and include electrostatic, hydrophobic, and hydrogen bonding. Protein

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

adsorption is most efficiently suppressed if the nanoparticle surface is neutral, hydrophilic, and highly dynamic. The functionalization of metallic nanoparticles with PEG chains strongly diminishes their interaction with proteins within the cellular environment. This is due to PEG molecules which are hydrophilic and electrically neutral (therefore hydrophobic and electrostatic interactions are minimized) and also highly dynamic in aqueous environment. Consequently, the formation of hydrogen bonding between the protein and polymer is completely suppressed. However, if the nanoparticles are so well coated that they become invisible to the immune system, they also lose their ability to bind to specific receptors. This is a common disadvantage of other drug-based therapies, where the drug is not delivered to a specific site but is widely dispersed in the body. Gold nanospheres and nanorods were linked with thiol-functionalized PEG and used for in vivo/in vitro investigation of cancer therapy [34, 35]. Experimental results (in vivo) have shown that PEG-linked nanoparticles are preferentially accumulated into tumor tissues due to the larger permeability of their blood vessels, compared with normal tissues. In addition, the tumor tissues have a longer retention time for large molecules, while normal tissues quickly expel them out. O’Neal et al. [36] have used PEG-linked gold nanoshells for treating tumor-bearing mice. They reported that after NIR laser irradiation, all tumors were ablated and the mice were tumor-free for several months. The same treatment applied to mice which were not injected with nanoshells was less efficient, and consequently they were affected by tumor growth. Stern et al. [37] have reported that high dose of PEG nanoshells (8.5 mL/g) injected in mice that were subsequently irradiated with NIR laser leads to tumor necrosis and regression (93 %). Surprisingly, when a slightly lower dose was used (7 mL/g), the results showed only a tumor growth arrest at 21 days but no tumor ablation. Such differences may be explained by the fact that this method is a passive targeting one, based on the nonspecific accumulation of nanoshells in tumor. As mentioned before, tumor tissues are characterized by an “enhanced permeability and retention (EPR) effect” [38] which favors the accumulation process. The second approach named the antibody targeting tries to overcome the nonspecific adsorption, by modifying the surface of the nanoparticles with an antibody which is specific to biomarkers on the diseased cells [39–43]. This method is highly specific, due to the fact that the nanoparticles are targeted to assemble on the surface of a certain type of cancer cell. The anti-epidermal growth factor receptor (antiEGFR) antibody is generally employed to detect cancerous cells that overexpress EGFR. Numerous papers have reported such studies for oral cancer cells [44, 45] and cervical cancer cells [46, 47]. Huang et al. [48] have used the antibody-targeting strategy for photothermal cancer therapy. Gold nanorods were conjugated with anti-EGFR antibody and then incubated with two cancerous oral epithelial cell lines: HOC313 clone8 and HSC3. The control experiment employed the noncancerous epithelial cell line (HaCat) that was also incubated with anti-EGFR–gold nanorods. They reported that lower laser fluence (about half) was necessary to kill the cancerous cells compared with normal cells. Such efficient ablation was due to the selective attachment of anti-EGFR–gold nanorods conjugates to the surface of the malignant cell that has overexpressed EGFR. Although this approach is without doubt more efficient than the passive targeting one, it also has its own limitations due to the potential activation of the normal host immune response. Besides anti-EGFR antibodies, another tumor necrosis factor-alpha (TNF-a) protein has been successfully linked with gold nanoparticles and used for the therapy of cancer cells. Like EGFR, TNF-a is overexpressed in solid tumors and induces hemorrhagic necrosis in tumor tissues [49, 50]. The main advantage of TNF–AuNPs conjugates relates with the selective penetration of cancerous cells by the protein component, through receptor-mediated endocytosis (RME). RME is a process by which cells internalize molecules or viruses. The process depends on the interaction of that molecule with a specific binding protein in the cell membrane, called receptor.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Previous reports have shown that native TNF-a has low therapeutic effect and acute toxicity. After linking with gold nanoparticles, TNF-a exhibited a reduced toxicity and more importantly the conjugates were able to selectively accumulate in tumor vasculature [51]. Paciotti et al. [42] have used functionalized colloidal gold as a therapeutic for the treatment of cancer as well as an indicator for immunodiagnostics. The optimal combination consists of PEG–SH molecules and recombinant human TNF-a that are directly bound onto the surface of the gold nanoparticles (designated PT-cAu-TNF). In vivo experiments have shown that after intravenous administration in tumor-bearing mice, PT-cAu-TNF rapidly accumulates in MC-38 colon carcinoma tumors. Little or no accumulation was detected in other healthy organs of the animals (livers, spleens). The marked color change of the tumor tissues indicates the accumulation of colloidal gold solution and was coincident with the active and tumorspecific sequestration of TNF-a. The results have shown that PT-cAu-TNF was extremely efficient to reduce the tumor effects compared with native TNF-a. A maximal antitumor response was obtained at lower doses of PT-cAu-TNF drug. Kim and Jon reviewed the diagnostic and therapeutic use of gold nanoparticles based on their research, emphasizing the applications in cancer therapy. Besides their unique physical and chemical properties, biocompatibility, ease of synthesis, and surface modification, gold nanoparticles have a higher X-ray absorption coefficient than iodine, being used as in vivo computed tomography (CT) contrast agent. A simple and rapid colorimetric method for the detection of Ca2+ with high specificity using calsequestrin-functionalized gold nanoparticles was developed. The technique is simple, rapid, and accurate, does not require specialized equipment, and may be useful in detecting and monitoring several diseases associated with hypercalcemia, such as malignant tumors [52].

Gene Delivery Gene delivery is the process by which foreign DNA is introduced into host cells. Gene delivery is, for example, one of the steps necessary for gene therapy and the genetic modification of crops. The process typically involves the formation of transient pores or “holes” in the cell membrane, to allow the uptake of material. In the last years, methods like electroporation, sonoporation, and hydrodynamic injections were used for gene delivery [53–55]. In vivo electroporation has been used as a method to increase gene expression after DNA injection into various tissues: the skin, muscles, liver, and tumors [56, 57]. The most important aspects that have to be considered during gene delivery process are the stealth character and the targeted recognition of tissues. The stealth character prevents the interaction of DNA complexes with plasma proteins. In addition, it favors a prolonged circulation period of DNA in blood, which is essential for in vivo gene delivery. Kawano et al. [58] have combined the use of PEG-modified gold nanoparticles with electroporation for hepatocyte gene delivery and enhanced gene expression. PEG–gold nanoparticles were functionalized with plasmid DNA (8.4 w/w ratio) and then intravenously injected into mice. About 20 % of gold nanoparticles were detected in blood at 120 min after injection, and 5 % of DNA strands were observed in blood after 5 min. By applying electroporation to a lobe of the liver following injection, significant gene expression was specifically observed in the pulsed lobe. The authors concluded that PEG–gold nanoparticles have weaker binding abilities for DNA than other cationic molecules, and therefore DNA can be easily released from complexes. In addition, the electrical pulses used in electroporation trigger the release of DNA. Such method can have clinical use, after optimization of electroporation parameters (e.g., number of pulses, strength, and frequency of current) in order to avoid tissue damage.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015 Nanosized complexes stabilized by PEG

100nm

PEGylated siRNA ––– ––– +

+

Cytoplasm

+ +

+

+ + Amine functionalized gold NPs +

––– ––– Naked siRNA Endocytosis Aggregation

Fig. 2 Schematic illustration for polyelectrolyte complexes formed from amine-functionalized gold nanoparticles (AF–AuNPs) with siRNA and siRNA–PEG conjugate (Reprinted with kind permission from reference [59]. Copyright (2013) Elsevier)

Lee et al. [59] have demonstrated the applicability of amine-functionalized gold nanoparticles for intracellular delivery of small interfering RNAs (siRNAs). The emerged interest for this method is based on the superior ability of siRNA to induce catalytic destruction of its complementary mRNA target. Additionally, the method might have a variety of potential therapeutic applications for diseases that cannot be cured by conventional treatments. The most challenging goal that must be fulfilled is the safe and effective intracellular delivery of siRNA. In their study, Lee et al. have reported that amine-functionalized gold nanoparticles form stable polyelectrolyte complexes (hydrodynamic diameter of 96.3  25.9 nm) through electrostatic interactions with PEG-conjugated siRNA (Fig. 2). The complexes have a disulfide link, which can be broken under reduced cytosol condition. By using confocal laser scanning microscopy, they have demonstrated that the complexes were efficiently internalized in human prostate carcinoma cells, favoring the intracellular uptake of siRNA. Additionally, they reported that siRNA/gold complexes significantly inhibited the expression of a target gene within the cells, without showing severe cytotoxicity. Pissuwan et al. reported in a recent review about the advantages of using gold nanoparticles for drug and gene delivery. They also discuss the topics of surface modification and site specificity [60]. Knipe et al. gave a general review on some of the most widely used types of inorganic nanoparticles in theranostic applications, including magnetic nanoparticles, gold nanoparticles, and quantum dots [61]. Ghosh et al. demonstrated that by coating gold nanoparticles with lysine-based headgroups, effective transfection vectors can be produced (Fig. 3). The efficiency of DNA delivery strongly depended on the ability of headgroups to condense DNA and on the structure of these groups. The lysine dendronfunctionalized gold nanoparticles were more effective by about 28 times than polylysine. They also reported that amino acid-functionalized gold nanoparticles showed no cytotoxicity, when used as transfection agents [62]. The layer-by-layer technique was also employed to deliver small interfering RNA (siRNA) and plasmid DNA into cancer cells with charge-reversal polyelectrolyte-deposited gold nanoparticles, as carriers. The occurrence of the charge-reversal property of functional gold nanoparticles was confirmed by polyacrylamide gel electrophoresis measurements of siRNA. The charge reversal under acidic environment facilitates the escape of gold nanoparticle/nucleic acid complexes from endosome/lysosome

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

Fig. 3 Schematic illustration of the monolayer-protected gold nanoparticles used as transfection vectors (a); chemical structures of headgroups presented on the surface of the nanoparticles (b) (Reprinted with kind permission from reference [62]. Copyright (2013) American Chemical Society)

and the release of functional nucleic acids into the cytoplasm, making the nanoparticles a promising material for in vivo therapeutic applications [63]. Shan et al. reported a new gene delivery vector based on dendrimer-entrapped gold nanoparticles. In order to synthesize gold nanoparticles with various Au atom/dendrimer molar ratios (25:1, 50:1, 75:1, and 100:1), they used as templates amine-terminated generation five poly(amidoamine) dendrimers. Gel retardation assay, light scattering, zeta potential measurements, and atomic force microscopic imaging were used to characterize the formed dendrimer-entrapped gold nanoparticles. Their results showed that the appropriate composition of dendrimer-entrapped gold nanoparticles (25:1 M ratio) enabled enhanced gene delivery with efficiency of 100 times higher than that of the dendrimers without nanoparticles. They suggested that the entrapment of gold nanoparticles within the dendrimer templates helped to preserve the 3D spherical shape of dendrimers, enabling high compaction of DNA. An important observation was that dendrimer-entrapped gold nanoparticles had lower cytotoxicity compared with the dendrimers without nanoparticles [64]. Chen et al. prepared gold nanoparticles modified with 2-aminoethanethiol, 8-amino-1-octanethiol, and 11-amino-1-undecanethiol, by the reduction of HAuCl4 with NaBH4 in water or water/ethanol solvents, in the presence of the respective thiols. The surface charge of gold nanoparticles was changed from negative

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_36-1 # Springer International Publishing Switzerland 2015

to positive, following the modification with thiol molecules. The cationic gold nanoparticles interacted with plasmid DNA, and their complex was used for gene transfection [65]. The interaction of poly-L-lysine with citrate-capped gold nanoparticles was also investigated for possible application of the functionalized gold nanoparticles, in gene delivery. Strong electrostatic interaction between polycationic chains of poly-L-lysine and citrate-capped gold nanoparticles was observed in weakly acidic to weakly alkaline solutions (pH 5–9). This interaction was evidenced by the bathochromic shift of the surface resonance plasmon band and by the strong increase of the resonance elastic light scattering intensity [66]. Ryou et al. have demonstrated that single-stranded DNA-functionalized Au nanoparticles can be used to deliver highly structured RNA aptamers into the nucleus of human cells, where they exert physiological effects by interacting with target molecules. Fluorescence microscopy analysis showed that the labeled aptamers were efficiently delivered into the cells [67]. Ghosh et al. developed cysteamine-functionalized gold nanoparticles to deliver unmodified microRNAs into living cells. Compared to the conventional liposome-mediated transfection, these cysteamine-functionalized gold nanoparticles are capable of delivering up to a 10–20-fold overexpression of mature microRNAs. The gold nanoparticle platform was able to release functional miRNAs that efficiently downregulate target genes and modulate the rate of proliferation, as it was showed by in vitro studies. The best formulation has the highest payload, lowest toxicity (98 % of cell viability following treatment), efficient uptake (96 % of cells took it), fastest endosomal escape, and increased half-lives (at least 5 days) [68]. Kim et al. reported that gold nanoparticles functionalized with covalently attached oligonucleotides activate the immune-related genes and pathways in human peripheral blood mononuclear cells. These oligonucleotide-modified gold nanoparticles can be applied in the development of therapeutic and gene delivery systems. Their results highlighted the need to study the potential harmful interactions between the engineered nanoparticle structures and the relevant biological system [69].

Conclusions In this review we selectively presented few strategies for bioconjugation of noble metal nanoparticles along with the advantages of their usage in cancer therapy and gene delivery. Although there are many advances in these fields, the requirements for new technologies that will allow the earlier treatment of cancer or other diseases are still needed. Among the most interesting studies, we have outlined the development of a colloidal gold nanoparticle vector (thiol-derivatized PEG and recombinant human TNF, directly bound to the surface of gold nanoparticles) that targets the delivery of TNF to a solid tumor growing in mice (in vivo experiments). The proposed vector was very efficient in reducing the tumor burden compared with native TNF. Other studies have shown that the efficiency of both cancer therapy and gene delivery can be considerably enhanced by exploiting the active targeting strategy, which offer greater specificity and are also cost-effective.

Acknowledgment This work was supported by grants of the Romanian National Authority for Scientific Research, CNCSUEFISCDI, Project Number PN-II-ID-PCE-2011-3-0125 and PN-II-PT-PCCA-2013-4-1282 (230/2014).

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62. P.S. Ghosh, C.-K. Kim, G. Han, N.S. Forbes, V.M. Rotello, Efficient gene delivery vectors by tuning the surface charge density of amino acid-functionalized gold nanoparticles. ACS Nano 2(11), 2213–2218 (2008) 63. S. Guo, Y. Huang, Q. Jiang, Y. Sun, L. Deng, Z. Liang, Q. Du, J. Xing, Y. Zhao, P.C. Wang, A. Dong, X.-J. Liang, Enhanced gene delivery and siRNA silencing by gold nanoparticles coated with chargereversal polyelectrolyte. ACS Nano 4(9), 5505–5511 (2010) 64. Y. Shan, T. Luo, C. Peng, R. Sheng, A. Cao, X. Cao, M. Shen, R. Guo, H. Tomás, X. Shi, Gene delivery using dendrimer-entrapped gold nanoparticles as nonviral vectors. Biomaterials 33, 3025–3035 (2012) 65. G. Chen, M. Takezawa, N. Kawazoe, T. Tateishi, Preparation of cationic gold nanoparticles for gene delivery. Open Biotechnol. J. 2, 152–156 (2008) 66. M. Stobiecka, M. Hepel, Double-shell gold nanoparticle-based DNA-carriers with poly-L-lysine binding surface. Biomaterials 32, 3312–3321 (2011) 67. S.-M. Ryou, J.-M. Kim, J.-H. Yeom, S. Hyun, S. Kim, M.S. Han, S.W. Kim, J. Bae, S. Rhee, K. Lee, Gold nanoparticle-assisted delivery of small, highly structured RNA into the nuclei of human cells. Biochem. Biophys. Res. Commun. 416, 178–183 (2011) 68. R. Ghosh, L.C. Singh, J.M. Shohet, P.H. Gunaratne, A gold nanoparticle platform for the delivery of functional microRNAs into cancer cells. Biomaterials 34, 807–816 (2013) 69. E.-Y. Kim, R. Schulz, P. Swantek, K. Kunstman, M.H. Malim, S.M. Wolinsky, Gold nanoparticlemediated gene delivery induces widespread changes in the expression of innate immunity genes. Gene Ther. 19, 347–353 (2012)

Page 13 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Thermo-optical Properties of Spherical Homogeneous and Core–Shell Nanoparticles and Their Applications Victor K. Pustovalov* Belarusian National Technical University, Minsk, Belarus

Abstract This review presents the results of the investigation of the interaction of optical (laser) radiation with spherical homogeneous and core–shell nanoparticles, absorption of optical radiation by nanoparticles, conversion of absorbed energy into nanoparticle thermal energy, the efficacy of nanoparticle heating itself, and heat transfer to ambient medium. Different homogeneous metallic (gold, silver, platinum, zinc, etc.) and core–shell (silica–gold, silver–gold, etc.) nanoparticles are considered. The models and results of computer and analytical calculations of nanoparticle heating by radiation pulse have been presented. The nonlinear dependences and comparative analysis of the thermo-optical properties of homogeneous and core–shell nanoparticles on parameters of radiation and nanoparticles are investigated. The results present the platform for the applications of thermo-optical properties of nanoparticles in photothermal nanotechnology, including light-to-thermal energy conversion and solar energy harvesting, laser nanomedicine, nonlinear optical diagnostics, laser processing of nanoparticles, etc.

Keywords Nanoparticles; Thermo-optical; Properties; Homogeneous; Core-shell; Applications

Introduction The advances in photothermal (PT) nanotechnology that are based on the thermal and plasmon effects induced by optical radiation–nanoparticle (NP) interaction have demonstrated their great potential [1–32]. In recent years, absorption and scattering of radiation energy by NPs, heating of NPs, heat dissipation and exchange with an ambience, and following thermal and accompanied phenomena have become an increasing important topic in nanotechnology [1–38]. There are many reasons for this interest, including PT applications in different nanotechnologies. Keeping in mind the huge data volume on PT nanotechnologies, one can restrict attention to a few ones presented in Table 1. Most of these technologies rely on the position and strength of the surface plasmon resonance on the nanosphere and absorption of radiation energy. The plasmonic properties of different NPs have been investigated in [30–32]. The processes of chemical synthesis and the properties of homogeneous and two-layered NPs have been presented in [33–36]. During past years, many research efforts have been focused on the investigation of homogeneous NPs from different materials (metals, alloys, semiconductors, etc). Among them, the metallic NPs demonstrate their unique size-dependent physical and chemical properties. The plasmonic properties of nanoscale metal particles depend on different parameters, such as their dimensions, shapes, optical properties of

*Email: [email protected] Page 1 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Table 1 Photothermal applications of NPs PT applications of NPs Light-to-thermal energy conversion and nanoenergy, solar cells Laser nanomedicine Laser processing of NPs Thermal catalysis Thermal diagnostics and imaging of the media containing NPs

References [1–8] [9–16] [17–23] [24–26] [27–29]

metal, and surrounding medium [30–32]. Gold and silver NPs are known for their interesting optical properties and applications caused by the plasmonic resonances with significant absorption and scattering at the wavelengths of
530 nm and
400 nm, respectively [10, 30–32, 36]. It is very interesting to use spherical two-layered core–shell NPs with different materials of NP core and shell and optical properties. Silica–gold NPs have unique plasmonic properties in the range of wavelengths 500–1200 nm and more [11]. Gold–silver and silver–gold NPs have the plasmon resonance wavelength in the range of 400–540 nm [29, 35, 37, 38]. By varying the materials and the sizes of the core and shell, the peak resonance of a core–shell NP can be adjusted across a broad range of the optical spectrum. This tunability is an interesting property of core–shell NPs and makes them ideal nanostructures for incorporation into different systems. Homogeneous and two-layered NPs can be used for conversion of absorbed energy into thermal energies of NP and ambience and following PT phenomena in nanotechnology. Optical radiation from CW and pulsed laser sources, solar radiation, and optical radiation from power lamps and devices can be used for these purposes. The prospects of NP applications in PT nanotechnology are strongly connected with modern achievements in laser physics, nonlinear optics, chemistry, and material sciences. Different parameters of optical (laser) radiation, spherical homogeneous and core–shell two-layered NPs, and the ambiences can influence on the thermo-optical properties of absorbing NPs and determine the achievement of maximal efficacy of conversion of absorbed energy into PT phenomena. Among these parameters, one can note the next ones: 1. Radiation – (a) pulse duration tP, (b) wavelength l, and (c) energy exposure (density E0, intensity I0) 2. Nanoparticle – (a) the materials of homogeneous NPs and the materials of core and shell of the two-layered NPs with own values of density, heat capacity, etc., (b) optical properties, (c) size, (d) concentration N0 of NPs in medium, and (e) composition and structure (core–shell NPs) 3. Ambient medium – (a) coefficient of thermal conductivity, density, and heat capacity and (b) coefficient of absorption, scattering, and extinction Different liquids (water, blood, bioliquids, etc.) and dielectrics (glasses, polymers, etc.) were used as ambient media under radiation–NP interaction [1–29]. The gases as ambient media are not investigated because this topic is out of the authors’ interest. The pressure in medium, containing NPs, is supposed constant during radiation–NP interaction.

Optical Properties of Homogeneous Nanoparticles Investigation of the optical properties of NPs in media is a prerequisite for PT nanotechnologies.

Page 2 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

a

b Kabs

Kabs

100

100

3

−1

10

2

10−1

3

10−2

2

10−3

1 −2

1 300

10

600

c

900

λ, nm

300

Kabs

600

900

λ, nm

3

100 2 1 10−1

300

600

900

λ, nm

Fig. 1 Efficiency factors of absorption Kabs of radiation with wavelengths in the range 250–1100 nm for homogeneous metallic NPs with the radii r0 = 10 (1), 25 (2), and 50 (3) nm: Au (solid), Ag (short dash dot), Cu (short dot) (a), Al(solid), Co (short dash dot), Zn (short dot) (b), Ni (solid), Pt (short dash), and Ti (short dot) (c), placed in water

Optical Confinement of Nanoparticles The parameters of radiation, NPs, and ambience should meet several requirements referred to as conditions or “confinements” for successful PT applications of NPs. Absorption of optical radiation by NPs should be greater than the absorption of radiation by ambient medium to enhance optical contrast of NPs. Radiation absorption by NP should be greater than the radiation scattering by NP, because of possible undesired action of scattered radiation on medium. Radiation extinction by NPs should be smaller than the extinction by an ambience for effective use of NPs for PT technology. These differences between the coefficients of absorption άabs, scattering άsca, and extinction άext of radiation by monodisperse NPs and the coefficients of absorption babs and extinction bext of radiation by an ambience should provide “optical NP confinement” [15]: άabs ¼ pN 0 r0 2 K abs > babs ;

(1)

άabs ¼ pN 0 r0 2 K abs > άsca ¼ pN 0 r0 2 K sca , K abs > K sca ;

(2)

άext ¼ pN 0 r0 2 K ext < bext

(3)

r0 is the radius of a spherical NP, and Kabs, Ksca, and Kext are efficiency factors of absorption, scattering, and extinction of radiation by NP, respectively [39].

Optical Properties of Metallic Nanoparticles Metallic NPs are most interesting among other NPs and can be used for possible PT applications (see Table 1). The analysis of the optical absorptive properties of metallic NPs for the radiation wavelengths in the spectral interval l = 250–1100 nm and for NP radii r0 = 10, 25, and 50 nm on the base of the results of computer modeling is presented. Nine metals were used as materials for NPs – Au, Ag, Cu, Pt, Co, Zn, Al, Ni, and Ti. Metallic NPs were placed in water for calculations. Water is the main component of the

Page 3 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Table 2 Maximal values of Kabs for NPs and for corresponding values of l and range of r0 Metals Au Ag Zn Cu

l, nm 532 400 350 532

r0, nm 31.834.7 16.617.5 14.716 41.443.8

Kmax abs ~4.0 ~10.6 ~5.5 ~2.64

Fig. 2 Dependences of the parameter P1 on l for metallic NPs: Ag (1), Al (2), Au (3) (solid), Cu (4) (dash dot), and Zn (5) (solid), with the radii r0 = 10 (a) and 25 (b) nm. Horizontal line (Fig. 2b) denotes the value of P1 = 1

solutions for the synthesis and processing of NPs, soft tissues, and blood. The optical constants were taken from [40, 41]. Figure 1a–c presents the efficiency factors of absorption Kabs of radiation for metallic Au, Ag, and Cu noble NPs (a); Al, Co, and Zn NPs (b); and Ni, Pt, and Ti NPs (c) placed in water. The increase of r0 to 25 and 50 nm leads to a significant increase of the values of Kabs. The dependences of Kabs (l) for Au and Cu NPs (Fig. 1a) and for Co and Zn NPs (Fig. 1b) are close to each other. Maximal values of Kabs allow to realize more effective PT regimes of laser–NP action with minimal values of radiation energy (intensity). Maximal values of Kmax abs for Au, Ag, Zn, and Cu NPs for corresponding values of l and ranges of r0 are presented in Table 2. Maximal values of Kmax abs for silver NPs are greater in comparison with other metal NPs. This fact means that different thermal processes, initiated by silver NPs under the achievement of the definite values of NP temperature, will be realized under a lower level of radiation exposure. Maximal values of Kmax abs lie near the wavelengths l  380–400 and l  520–540 nm for silver and gold NPs accordingly, and they are determined by their plasmon resonances. Maximal values of Kmax abs for Al, Ni, and for NPs presented in Table 2. Ti NPs are smaller than maximal values of Kmax abs The predominant role of radiation absorption by NP can be used for the heating and PT applications of NPs, and such NPs can be used as the absorbers of radiation. The predominant role of scattering by NPs can be used for the purposes of optical diagnostics and biomedical imaging, and NPs can be used as the scatterers of radiation. Scattered radiation can result in an undesired damage of ambient medium in some cases. The parameter P1 = Kabs/Ksca determines the predominant influence of absorption or scattering in the processes of radiation interaction with NP. The factor of absorption Kabs should be greater or smaller than Ksca in the cases of predominant role of absorption or scattering: K abs > K sca , P1 ¼ K abs =K sca > 1

(4a)

K abs < K sca , P1 ¼ K abs =K sca < 1

(4b)

Page 4 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

The condition (4a) is equal to the condition of optical NP confinement (2). Figure 2 presents the dependences of the parameter P1 on l for metallic NPs Ag, Al, Au, Cu, and Zn with the radii r0 = 10 and 25 nm. The dependences of P1 on l have a complicated behavior for different metallic NPs and values of r0. All presented metallic NPs appear to have high absorbance and the parameter P1 > 1 for r0 = 10 nm. Maximal values of P1 for Au and Cu NPs achieve the values P1  100 for 550 > l > 400 nm and for Zn and Al NPs maximal P1  500 and 60 accordingly for 950 > l > 800 nm for r0 = 10 nm (Fig. 2a). The increasing of r0 leads to the decreasing of absorbance and increasing of scattering for all presented metallic NPs. At r0 = 25 nm, the parameter P1 achieves maximal value P1  10 for Au and Cu NPs and P1  40 and 6 for Zn and Al NPs (Fig. 2b). Zinc NPs are the best absorbers with P1  10010 for l > 600 nm and for r0 = 10 and 25 nm among other NPs. Larger NPs are more suitable for lightscattering applications. All values of P1 are smaller or much smaller than 1, P1  1, at r0 = 50 nm instead of spectral interval 550 > l > 300 nm for Al and Au NPs. The analysis and selection of the optical properties and the sizes of NPs can give appropriate types of NPs for PT applications.

Computer and Analytical Modeling of Homogeneous Nanoparticle Heating by Radiation Free electrons are the first agents to interact with electromagnetic radiation (laser pulses) acting on NPs. In the case of the action of femtosecond laser pulses with characteristic durations of about tP
10–100 fs, the electron gas will undergo oscillations under the action of an electric field and electron–electron and electron–particle surface collisions that will lead to the quasiequilibration of a hot electron system. After the establishment of a thermal electronic system for time t > 1  1013 s, the hot electrons cool down by transferring their energy to the lattice by electron–phonon coupling. Absorption of short laser pulses by electrons in metallic NPs, electron–phonon coupling, and lattice heating are determined by nonlinear dependences of electronic heat capacity and electron–phonon coupling factor on temperature [42] and other parameters. The solutions of the two-temperature model [43, 19] determine the temporal behavior of electron and lattice temperatures and the characteristic time of electron–phonon relaxation
1  1012 s. The processes of radiation–NP interaction will be considered under the condition of the equality of electron and lattice temperatures for the pulse duration tP  1  1012 s.

Computer Modeling The processes of radiation–NP interaction include the absorption of radiation energy by NP and the heating of NP, heat transfer into ambience, and NP cooling after the termination of action. The length of mean free path of a water molecule in ambient water is about
0.1 nm, and this one is much smaller than the characteristic NP radii of r0
10–100 nm. It means that the model of heat conduction equation can be used [1, 13, 44]:
 @T 1 @ 2 @T ¼ 2 r ki þ qi ci ri (5) @t r @r @r T is the temperature, r is the radius of a spherical coordinate system with the origin fixed at the NP center, t is time, and ci, ri, and ki are heat capacity, density, and thermal conductivity, respectively. The NP parameters are determined for r r0 (i = 0) and ambient medium parameters are determined for r > r0

Page 5 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Fig. 3 Computer (solid) and analytical (dashed) dependences of the temperature T along the radius r for the time instants t/tp (left column) and temporal dependences of Tmax on t/tP (right column). For tP = 1  102 s, In = 2.9 MW/cm2, t/tp = 1  107 (1), 1  104 (2), 0.1 (3), 0.5 (4), 1 (5), and 1.000001 (6) (a); for tP = 1  10– 6 s, In = 3.0 MW/cm2, t/tp = 1  102 (1), 0.5 (2), 1 (3), 1.005 (4), and 1.1 (5) (b); for tP = 1  108 s, In = 4.3 MW/cm2, t/tp = 0.1 (1), 0.5 (2), 1 (3), 5 (4), and 20 (5) (c); and for tP = 1  10– 12 s, In = 2.5 GW/cm2, t/tp = 0.1 (1), 0.5 (2), 1 (3), 5 (4), 100 (5), and 300 (6) (d). Vertical lines in left column present the boundaries of NPs

(i = m), qi is the power density of heat sources (r r0 q0 ¼ I 0 K abs pr0 2 =V 0 , I0 is intensity of radiation, qm = 0 for r > r0), and V0 = 4/3pr03 is the volume of NP, with the initial condition: T ðr, t ¼ 0Þ ¼ T 1

(6)

Page 6 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

T1 is the initial temperature of NP and medium. Figure 3 (left column) presents the temporal-spatial distributions of the temperature T(r) for different time instants inside and around NP for spherical gold NP with r0 = 25 nm and the pulse durations tP = 1  102, 1  106, 1  108, and 1  1012 s and values of normalized radiation intensity In = I0Kabs on the basis of computer calculations of (5, 6). The radiation pulses cause an intensive heating of NP. The temperature inside NP is being virtually independent of the coordinate r, T(r r0)  const, for different instants of time. Temperature drop is being observed in the adjacent layer of the surrounding medium. The specific feature for the range of tP = 1  1021  108 s is the presence of developed NP heat transfer with the surrounding medium during the pulse action. A nonstationary character of NP heat exchange with the ambience for short pulses tP
1  1081  1012 s is confirmed by computer simulation. Figure 3 (right column) presents the temporal dependences of the NP maximal temperature Tmax(t) at r = 0 on t/tP for different pulse durations.

Analytical Modeling

The computer distributions show approximate uniform temperature T  T0  const inside NP during radiation action and cooling for wide interval values of tP (see Fig. 3, left column). This fact is used for the construction of an analytical model. The equation with uniform temperature T0 over the particle volume that describes the heating and cooling of an NP has the form [1, 13]: r0 c0 V 0

dT 0 1 ¼ I 0 K abs S 0  J C S 0 4 dt

(7)

T 0 ð t ¼ 0Þ ¼ T 1

(8)

with the initial condition

rð0

q0 4pr2 dr ¼ 14 I 0 K abs S 0 , where S0 = 4pr02 is the surface area of a spherical NP of radius r0, r0 and c0 0

are density and heat capacity of NP material, respectively, and JC is the energy flux density from NP by mechanism of heat conduction. Convective and hydrodynamical heat transfer from NP is negligible for  4 4 tP 1 s. Radiation cooling of NP  sðT 0  T 1 tT, the approximation of the quasi-stationary temperature distribution and heat exchange between a particle and its environment is justified. The quasi-stationary temperature distribution for r  r0 around the particle under condition t > tT was obtained in [1, 13] from (5) under @T @t ¼ 0 taking into account (10a) " r > r0

a 6¼ 1,

T ðrÞ ¼ T 1

r0 1þ r




T0 T1

1 !#aþ1

aþ1

1


,

a ¼ 1, T ðrÞ ¼ T 1

T0 T1

rr0 (11)

It is interesting to note that for tP = 1  102 and 1  106 s, computer and analytical distributions of T(r) practically coincide with each other for t/tP = 0.5, 1 (Fig. 3a, b); for example, indicators 1–5 denote analytical distributions, and indicators 1, 2, and 3–5 denote computer distributions of T(r) in Fig. 3a. This fact confirms the quasi-stationary character of temperature distributions for r > r0 and heat transfer from NP for tP > 1  107 s and for r0 25 nm. For tP = 1  10–8 s, the analytical distributions differ from the computer ones by up to 10–25 % inside and outside of NP volume. This behavior is explained by the nonstationary character of computer distributions of T(r  r0) for tP = 1  10– 8 s. Internal computer and analytical distributions of T(r) during pulse duration are close with each other for tP = 1  1012 s, because the heat exchange with ambience is practically absent in this case (Fig. 3d). But temperature distributions T(r) differ significantly outside of NP r > r0 because of the nonstationary character for computer distributions and quasi-stationary analytical dependences T(r  r0). The dependences of Kabs on temperature T0 for NPs from different materials can be presented in the forms:
K abs ¼ K 1

T0 T1

b

K abs ¼ K 1 exp½e0 ðT 0  T 1 Þ

(12a) (12b)

K1 = Kabs (T0 = T1) and parameters b = const and e0 = const. For constant Kabs = K1  const, b = 0 (12a), and temperature dependence k = k1(T/T1)a (10a), one can have analytical solutions for temporal dependence T0(t) from (7, 8, 9, 11) for the period of time 0 t tP [1, 13]:

Page 8 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015


 I 0 K abs r0 t a ¼ 0, T 0 ¼ T 1 þ 1  exp  t0 4k 1

(13)

A þ 1  ðA  1Þexpðt=t1 Þ ; A þ 1 þ ðA  1Þexpðt=t1 Þ

(14)

a ¼ 1, T 0 ¼ T 1 A c0 r0 r0 2 , A¼ t0 ¼ 3k 1




I 0 K abs r0 þ1 2k 1 T 1

1=2

1=

, t1 ¼

c0 r0 r0 2 ð2T 1 Þ 2 1=

3k 1 1=2 ðI 0 K abs r0 þ 2k 1 T 1 Þ 2

(15)

The cooling of NP can be described by expression, which can be derived from (7) with the use of (9, 11) under I0 = 0, T (t = tP) = Tmax and t > tP: a ¼ 0 T 0 ¼ T 1 þ ðT max  T 1 Þexpððt  tP Þ=t0 Þ a ¼ 1 T0 ¼ T1

T max þ T 1 þ ðT max  T 1 Þexpððt  tP Þ=t0 Þ T max þ T 1  ðT max  T 1 Þexpððt  tP Þ=t0 Þ

(16)

Tmax is the maximal value of temperature at the end of laser pulse t = tp in (16). Analytical temporal dependences of Tmax (see Fig. 3, right column) describe the computer ones with appropriate quantitative accuracy for tP < 107 s and with qualitative accuracy for tP
1081012 s. Analytical solutions of T0(t) and T(r  r0) for different dependences of km and Kabs on temperature (10,12) were investigated in [19]. Computer simulation confirms the possibility to use an analytical model for describing internal and outward distributions of T(r) for tP > t0, tT and internal distributions for 1  10–12 tP < t0, tT.

Thermal Confinement

The characteristic times t0 and t1 determine the temporal dependences of T0 (13, 14). The pulse duration tP should be less than the characteristic times t0 (t1) of NP cooling to provide efficient heating of NPs without heat loss [1, 13]. The fulfillment of thermal confinement means the achievement of a maximal value of NP temperature Tmax = T0(tP) and saving its own heat energy practically without heat exchange with ambience during “short” pulse action with tP < t0. In this case, one can find from (13) the following equation for 0 < t tP: tP < t0 T 0  T 1 þ

3I 0 K abs t ; 4r0 c0 r0

(17)

In the opposite case (“long” radiation pulses), the condition of NP thermal confinement is interrupted for tP > t0, and heat loss from NP by heat conduction has to be taken into account during the period of time 0 t tP. The case tP > t0 can be used for the heat exchange of NPs with an ambience and its heating. In this case from (13), one can have tP > t0 T 0  T 1 þ

I 0 K abs r0 4k 1

(18)

Characteristic time t0 is equal: t0
3.2  1011  3.2  109 s for the range of radii r0 = 5–50 nm and for ambient water with k1 = 6  103 W/cmK, while for r0 = 25 nm, t0
0.85 ns.

Page 9 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Thermo-optical Properties of Homogeneous Nanoparticles The achievement of maximal (or appropriate) value of NP temperature Tmax is essential for the initiation of different processes inside NP and in ambience. It is important to achieve Tmax using the minimal values of radiation exposure E0 or intensity I0, E0 = I0tP, and to minimize or to prevent undesired effects on ambience. One can use the NP thermo-optical parameter DT 0 =E 0 that determines the maximal value of the increase of NP temperature DT 0 ¼ T max  T 1 at the end of radiation action with exposure E0 = 1 J/cm2. This parameter is equal from (13): 
 DT 0 K abs r0 tP Lm  ¼ 1  exp  (19) E0 4k 1 tP t0 c0 Е 0 Equation (19) has to take into account the melting of NP material for Tmax > Tm, where Tm is the melting temperature for NP material and Lm is the heat of unit mass melting. The factor Lm/c0 in (19) and in what follows can be neglected for Tmax < Tm or DT0  Lm/c0. The parameter DT0/E0 for conditions of “short” tP < t0 and “long” tP > t0 pulses and for Tmax < Tm will be approximately determined by (see (17, 18, 19)) t P < t0

DT 0 3K abs DT 0 K abs r0  , t P > t0  E0 4r0 c0 r0 E0 4k 1 t P

(20)

These simplified parameters depend on the properties of NP, Kabs(r0, l), r0, c0, and r0; the radiation, l and tP; and the ambience, k1. Figure 4 presents the dependences of the parameter DT0/E0 (19) for NPs: Au and Cu, l = 532 nm, and Ag, l = 400 nm, on r0 (a) and for r0 = 25 nm on l (b) for the pulse durations tP = 1  108, 1  1010, and 1  1012 s. Lines for Au and Cu are close for the spectral region l = 300–600 nm. The condition of “short” pulses tp < t0 is applicable for tP = 1  1012 s in all ranges of r0 5 < r0 < 100 nm and for tP = 1  1010 s in the range r0 > 25 nm. The values of DT0/E0 (lines 2, 3 in Fig. 4) for r0 > 25 nm coincide with each other for tP = 1  1010, 1  1012 s, because the parameter DT0/E0 does not depend on tp for the case of “short” pulses (see (20)). The condition of “short” pulses is interrupted for r0 < 20 nm and tP = 1  1010 s that causes the divergence of curves. The maximal value of DT0/E0
2  106 Kcm2/J for Ag NPs with r0
18 nm (see Fig. 4) and the heating of NPs could achieve 1  103 K for tP 1  1010 s and E0 = 5  104 J/cm2. For “long” pulses tP = 1  108 s > t0 for all ranges of r0 = 5–100 nm, the values of DT0/E0 are much smaller (up to a few orders) than the values for the case of “short” pulses with tP = 1010 and 1012 s because of the dependence of DT0/E0
1/tP (see (20)). It means a sharp increase of energy loss by NP via heat conduction during the pulse action and a subsequent increase of the value of exposure necessary to achieve a particular value of DТ 0 with the increase of tP. Figure 5 presents the dependences of the parameter DT0/E0 (19) and Kabs on r0 for gold NPs, l = 532 nm, and for the pulse durations tP = 1  108, 1  1010, and 1  1012 s. Maximal values of Kmax abs (r0) and DT0/E0 (r0) have the different locations on the axis of r0, denoted by vertical lines in Fig. 5. Maximal values of DT0/E0 had been shifted in r0 by the value Dr0  10–15 nm to smaller values of r0 for tP = 1  1010 and 1  1012 s and to bigger values of r0 for tP = 1  108 s in comparison with the location of Kmax abs (r0) in Fig. 5. Combinations Kabs(r0)/r0 for “short” and Kabs(r0)r0 for “long” pulses in (20) determine the radii value r0 appropriate for the achievement of maximal value of T0. It means that for the achievement of maximal values of DT0/E0, one has to use the values of Kabs that are smaller than Kmax abs .

Page 10 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

a

b

ΔT0/E0, Kcm2/J 3 105

ΔT0/E0, Kcm2/J 105

2 103

1

1

103

0

20

2,3 40

60

80 r0, nm

300

600

900 λ, nm

Fig. 4 Dependences of the thermo-optical parameter DT0/E0 for NPs: Au (l = 532 nm, solid), Ag (l = 400 nm, short dot), and Cu (l = 532 nm, short dash dot) on r0 (a) and for Au (solid), Ag (short dot), and Cu (short dash dot) on r0 = 25 nm on l (b) and for tP = 1  108 (1), 1  1010 (2), and 1  1012 (3) s

Thermo-optical Properties of Core–Shell Nanoparticles Optical Properties of Core-Shell Nanoparticles A two-layered NP consists of a spherical homogeneous core of the radius r0 enveloped by a spherically symmetric homogeneous shell of the radius r1 with the shell thickness of Δr1 =r1 −r0. A few types of coreshell NPs are used in nanotechnology because of their superior physical-chemical properties – gold-silver and silver-gold (Ag–Au) [29, 37, 38], silica-core and gold-shell (SiO2–Au) [11, 28, 34], and others. Figure 6a, b presents the dependences of Kabs for spherical core-shell Ag–Au (a) and SiO2–Au (b) NPs with the core radii r0 =10, 20, 40 nm and the shell thicknesses Δr1 =5, 20, 40 nm on wavelength λ. We should take into account that lines on Figs. 6 and 7 are presented for the values of radius r1 =r0 +Δr1. The maximum values of Kabs for Ag–Au NPs in each curve (Fig. 6a) depend on the concrete relations between the core radii and the thickness of shell and accordingly on approximation to the plasmon peak values for Ag or Au NPs. The maximal values of Kabs ≈3.8 exist for the core radii r0 ~10, 20 nm, Δr1 = 20 nm and in the interval of the wavelengths 530 ÷ 535 nm. It is consistent with the plasmon resonance for Au NP. Small NPs with r0 =10 nm and thin shell Δr1 =5 nm exhibit two peaks in Kabs(λ): one peak is near Ag NP plasmon resonance (~400 nm) and the other one approximates to the Au NP plasmon resonance (~530 nm). When the shell thickness of two-layered nanospheres with r0 =10, 20 nm grows (Δr1 =20 ÷ 40 nm), one peak is formed in the curves Kabs (λ), approximately in the range of plasmon resonance of Au. The maximal values of Kabs ≈4.1; 10.2; 7.2 exist for SiO2–Au NPs with the core radii r0 =10, 20, 40 nm and thin shell Δr1 =5 nm. Increase of r0 from r0 =10 nm to r0 =40 nm leads to shifting of the placement of the maximal value of Kabs on axis λ from λ~570 nm to λ~840 nm. It is interesting to note the formation of second small peak of Kabs for r0 =40 nm consistent to the peak of Kabs for r0 =20 nm. The presence of thick shell with Δr1 =20, 40 nm leads to the formation of the peaks of Kabs consistent with the plasmon resonance for Au NP (530–540 nm). It means the dominant influence of thick Au shell on the optical properties of SiO2-Au NPs.

Thermo-optical Properties of Core–Shell Nanoparticles The heating of a two-layered core–shell NP by radiation and its cooling after the termination of pulse action is described by the equation that is based on the assumptions for equation (7): ðr0 c0 V 0 þ r1 c1 V 1 Þ

dT 01 1 ¼ I 0 K abs S 1  J C S 1 4 dt

(21)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

ΔT0/E0, Kcm2/J

Kabs 4,0

3

3,5

2 4

105

3,0

4

1 2,5

2,0 1

104

1,5 2 3 1,0

0,5 20

40

60

80

r0, nm

Fig. 5 Dependences of the parameter DT0/E0 (lines 1–3 refer to the left axis) and the factor of Kabs of NP (line 4 refers to the right axis) for gold NPs and for the pulse durations tP = 1  108 (1), 1  1010 (2), and 1  1012 (3) s and l = 532 nm on radius r0. Vertical lines denote the locations of maximal values of DT0/E0 and Kmax abs on axis r0

with the initial condition T 01 ðt ¼ 0Þ ¼ T 1

(22)

T01 is the uniform temperature over all NP volumes; r0, c0, and r1, c1 are the heat capacity and the density of core and shell materials, accordingly; and JC is the energy flux density removed from the particle surface by heat conduction. The volumes V0 and V1 of core and shell are respectively equal: V 0 ¼ 43 pr0 3 , V 1 ¼ 43 pðr1 3  r0 3 Þ, S 1 ¼ 4pr1 2 is the surface area of a spherical NP of the radius r1. One can find the maximal value of temperature Tmax at the end of pulse action with pulse duration tP, from (21) taking into account (9, 10, and 11): 2 0 13 T max ¼ T 1 þ

B I 0 K abs r1 6 61  expB @ 4k 1 4

c0 r0 r0

r 2 0 r1




C7 3k 1 t P 7
3 C A5 c1 r1 r1 1þ 1 c0 r0 r0 3

(23)

Characteristic time for core–shell NP is equal from (23): t01





 с0 r0 r0 2 r0 c 1 r1 r 1 3 r0 c1 r1 r1 3 ¼ 1þ 1 ¼ t0 1þ 1 3k 1 r1 c 0 r0 r 0 3 r1 c0 r0 r0 3

(24)

Page 12 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

a Kabs b Kabs

3,5 1

2

10

3,0 2,5 2

3

3

1

1

2,0

2

1

3

1,5 3

1,0

0,1

1

1

0,5 0,0

0,01 300 350 400 450 500 550 600 650

400

λ, nm

600

800

1000 λ,

nm

Fig. 6 Dependences of the factors of Kabs (a, b) for spherical core–shell Ag–Au (a) and SiO2–Au (b) NPs with the core radii r0 = 10 (1), 20 (2), and 40 (3) nm and the shell thicknesses Dr1 = 5 (solid), 20 (short dot), and 40 (short dash) nm on wavelength l

b ΔT01/E0, Kcm2/J

a ΔΤ01/Ε0, Kcm2/J

2,3

106 105

2,3

2,3

2,3 2,3

105

104 104 103

1

1 103

102 300 400 500 600 700 800 900 λ, nm

400

600

800

1000 λ, nm

Fig. 7 Dependences of DT01/E0 on l for spherical core–shell Ag–Au (a) and SiO2–Au (b) NPs with r0 = 20 nm and Dr1 = 5 (solid), 20 (short dot), and 40 (short dash) nm and for the radiation pulse durations tP = 1  108 (1), 1  1010 (2), and 1  1012 (3) s

and it is determined by core r0, c0,and r0 and shell r1, c1,and r1 parameters, where t0 (15). For core–shell NPs, thermo-optical parameter DT01/E0 = (Tmax  T1)/E0 is determined by: 2 0 13 B DT 01 K abs r1 6 61  expB ¼ @ E0 4k 1 t P 4

r0 c0 r0 r0 2 r1




C7 3k 1 tP 7
3 C A5 c1 r1 r1 1þ 1 c0 r0 r0 3

(25)

For “short” laser pulses with pulse duration tP < t01, the loss of heat from the NP by heat conduction during the time tP can be ignored. For “long” laser pulses tP > t01, the loss of heat from the particle by heat conduction will be significant. For “short” and “long” pulses from (25), one can get: Page 13 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

t p < t01

DT 01  E0

 4r0 c0 r0

3

3K abs r1 2 DT 01 K abs r1
3  , t p > t01  E0 4k 1 tP c1 r1 r1 1þ 1 3 c0 r0 r0

(26)

The expression (26) for tP > t01 is analogous to expression for homogeneous NP (20). These parameters (23, 25) are determined by core and shell geometrical, optical, and material characteristics. Figure 7a, b presents the dependences of DT01/E0 on l for spherical core–shell Ag–Au (a) and SiO2–Au (b) NPs with r0 = 20 nm and shell thicknesses Dr1 = 5, 20, and 40 nm and for the radiation pulse durations tP = 1  108, 1  1010, and 1  1012 s. There are a few joint features in the behavior of the dependences of DT01/E0 on l for spherical core–shell Ag–Au and SiO2–Au NPs. Lines 2 and 3 in Fig 7 a, b coincide with each other for tP = 1  1010 and 1  1012 s in accordance with (26) for tP < t01. The dependences of DT01/E0 (Fig. 7) follow the dependences of Kabs(l) (Fig. 6) with some changes. The decrease of tp up to 104 times (from 108 to 1012 s) leads to the increase of DT01/E0 up to 101 times in accordance with (25). The peak of DT01/E0 is placed for Ag–Au NPs with r0 = 20 nm and Dr1 = 5 nm near l
400 nm and for Dr1 = 20 and 40 nm near l
540 nm. First peak is situated near Ag NP plasmon resonance (
400 nm) and the second one approximates to the Au NP plasmon resonance (
530 nm). It means the dominant influence of the massive Ag core and thick Au shell, respectively, on the optical properties of Ag–Au NPs. The maximal value of DT01/E0 for SiO2–Au NPs with r0 = 20 nm and Dr1 = 5 nm is placed near l
670 nm and for Dr1 = 20 and 40 nm near l
580 nm. The optical properties of SiO2–Au NPs are determined by the dominant influence of the massive SiO2 core and thick Au shell, respectively. The maximal value of DT01/E0 is equal to DT01/E0  1.4  106 Kcm2/J for SiO2–Au NPs with r0 = 20 nm and Dr1 = 5 nm. It is connected with the maximal value of Kabs  10.2 (see Fig. 6b).

Applications of Thermo-optical Processes and Properties of Nanoparticles Radiation–NP interaction leads to the realization of different PT phenomena [1–32]. Specifically, these PT phenomena include (but not limited) processes leading to the initiation and realization PT processes inside NP that leads in turn to the initiation and realization processes around NP in the ambient medium. These processes are presented in Table 3. Thermo-optical processes and properties of homogeneous and core–shell NPs are used in PT nanotechnology, including light-to-thermal energy conversion and solar energy harvesting, laser nanomedicine, laser processing of nanoparticles, nonlinear optical diagnostics, catalysis, etc. [1–32]. Realization of maximal (appropriate) values of thermo-optical properties of NPs is very important for all mentioned fields. Achievement and selection of maximal value of DT0/E0 depend on the set of optical and thermophysical properties of NPs, characteristics of radiation, and the ambience. Light-to-thermal energy conversion with NPs and their use for nanoenergy applications [1–8] are determined by thermo-optical parameters (19) for homogeneous and (25) for core–shell NPs and the use of the processes 1–4 for NP and 3 and 4 for ambient medium. The main goal of light-to-thermal energy conversion is to achieve maximal value of efficiency parameter of DT0/E0 for NPs. It was established that maximal value of thermo-optical parameter (maximal NP temperature) can be achieved with the use of the absorption efficiency factor of NP smaller than its maximal value (Fig. 5). Light-to-thermal energy conversion can be used for solar radiation harvesting with NPs [5, 7]. Broadly absorbing metal or core–shell NPs should be matched to the solar optical spectrum for fulfillment of the optical confinements

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

Table 3 PT processes inside NP (left column) and around NP in ambient medium (right column) N 1 2 3

Processes inside NP ! Absorption and scattering of optical radiation by NP Conversion of absorbed radiation energy into NP thermal energy Heating of NP and heat transfer to ambient medium Change of material and optical properties of NP on its temperature

4

Heat transfer to ambient medium

5

8

Melting (solidification) of homogeneous NP and core or (and) shell of two-layered NP Evaporation of material (metal) of NP or shell of core–shell NP Decrease (increase) of r0 and r0, r1 transformation of NP shape (spheroidization) and structure Thermo-optical breakdown of NP

9

Explosion and fragmentation of NP

6 7

Processes in ambient medium – – Heating of ambient medium and formation of temperature distributions around NP Change of material and optical properties of ambient medium on its temperature in the heated vicinity of absorbing NP Thermo-chemical processes (thermal denaturation of tissue proteins) in ambient medium around NP Explosive evaporation of liquid, surrounding NP, accompanied by bubble formation and its expansion Influence on ambient medium Formation and expansion of vapor bubble from NP material around evaporating NP Influence on ambient medium Thermo-optical breakdown in ambient medium around NP. Formation and propagation of plasma and shock waves in ambient medium Expansion of NP pieces. Propagation of plasma and shock waves in ambient medium

(1–3). Solar illumination of NPs, dispersed in a liquid, can produce vapor without the heating the fluid volume [7]. All these phenomena can enable compact solar applications. The PT techniques may use NPs as exogenous contrast agents in laser nanomedicine and the processes 1–4, 8, and 9 for NP and 3, 4, 6, 8, and 9 for environment for the selective therapy of cancer or imaging tumor with high resolution and sensitivity [9–16]. Recently, various NPs demonstrated advantages as PT agents for possible clinical use [9–16], because of their high absorption for visible and near-infrared radiation with relatively deep penetration into tissues, low toxicity, photostability, absence of photobleaching or blinking effects, and capacity for molecular targeting using appropriate bioconjugation with antibodies (anti-EGFR, etc.), specifically targeted to malignant cells, proteins, and other ligands. Achievement of NP maximal temperature under minimal value of E0 is important for the lowering of scattered radiation action on ambient tissue. Among different nanostructures, gold NPs are the most promising candidates as artificial optical and PT agents for nanomedicine applications [9, 10, 12–14]. To provide the penetration through small physiological pores in the cell membrane and wall vessels, the NP radius should be small enough in the range r0 < 30–50 nm [16]. The thermal confinement (17, 26) is satisfied for these sizes at the short laser pulses. Nanosecond lasers with tP
5–8 ns and tP
0.5 ns are broadly used in laser medicine because they are simpler, less expensive than other lasers, and less harmful for healthy tissue. The condition tP < t0 (17) for nanosecond lasers can be fulfilled for gold NP, placed in water, for tP
5 ns in the range r0 > 60 nm and for tP
0.5 ns in the range r0 > 20 nm. The main advantage of core–shell silica–gold, silver–gold, and other two-layered NPs is the possibility to tune their optical properties in the visible and near-infrared regions between 400 and 1200 nm and more. Near-infrared silica–gold NPs with characteristic radii r0
65 nm were used for combined optical imaging and PT cancer therapy in [11]. The selection of the properties of metallic NPs and nanoshells and their thermo-optical analysis was carried out in [9–16] for laser applications in cancer nanotechnology. Page 15 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

The action of intensive radiation on NPs can lead to explosive vaporization of surrounding liquid (process 4, right column, Table 3). Formation and expansion of vapor nanobubbles are an attractive tool for applications in laser nanotechnology [2, 6, 13]. The resulting shell around laser-heated NP can cause spatially confined and highly localized thermo-mechanical selective damage of tissue on the cellular level in anticancer therapy. The damage to the surrounding medium could be undesired in some cases and should be taken into account for practical applications from the other side. Vapor nanoshells forming around laser-heated NPs [2, 6, 13] can serve as contrast agents in optical diagnostics and can be used for optical limiting and switching in nanosuspensions. In recent years, the laser–NP processing, including absorption of laser energy by NP, NP heating, and following PT processes 1–7 for NP and 4–9 for environment, has become a great interest and an increasing important topic in laser nanotechnology [17–23]. Laser–NP processing is based on the applications of thermo-optical properties of NPs. Different experimental and theoretical investigations of laser processing of NPs were carried out in [17–23], including laser-induced decreasing and increasing of NP sizes, transformation and modification of NP structure and shape, and NP fragmentation in different ambient media. The influence of thermo-optical properties of NPs, characteristics of laser radiation, and ambient media is significant on the results of laser processing. Diagnostics of NPs and media with NPs has been developed on the base of nonlinear thermo-optical processes 1–3 for NP and 3 for ambient medium arising under laser radiation action on NP and heat exchange with surrounding medium [19, 27–29]. It is possible to determine the temperature of heated NP and thermal change of refractive index of ambient medium in the heated vicinity of absorbing NP.

Conclusion Basic objects for the realization of PT nanotechnology can be different types of NPs. Recent advances in NP synthesis allow to produce and to use numerous types of homogeneous and two-layered NPs in nanotechnology. Unique properties of NPs emerge during their interaction with laser and optical (solar) radiation and open wide perspectives for the applications. High absorption of radiation by NPs can be used for conversion of absorbed energy into NP thermal energy, heating of NPs itself and ambience, and following PT phenomena. Development and availability of different optical and laser sources with high power, wavelengths from UV to infrared, and radiation durations from CW to ultrashort pulses have fuelled on the development of PT nanotechnology. Homogeneous NPs from metals and different materials can be used in different fields of nanotechnology. Gold and silver NPs are the most promising candidates as PT agents. Core–shell NPs are very attractive for biophysical and nanotechnological applications due to their unusual physical–chemical properties, especially due to their tuning of plasmon absorption peak. This tunability makes them ideal nanostructures for incorporation into different systems. Optical properties of homogeneous metallic and core–shell NPs have been investigated here taking into account the fulfillment of optical confinement of nanoparticles for successful applications of NPs in PT nanotechnology. Computer and analytical models presented here allow to describe the temporal dependences of the heating and cooling of NP. Dependences of T0 (t) (13–16) and T01 (t) (23) can be used for monitoring of current value of NP temperature during radiation action and after its termination in experiments. The analysis and selection of thermo-optical properties of homogeneous and core–shell spherical NPs have been presented using some materials, sizes, and compositions of NPs for different laser wavelengths on the base of the results of computer and analytical modeling. The fulfillment of optical (1–3) and

Page 16 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

thermal (17, 26) “confinements” improves the efficacies of NP applications and can be improved by the selection of the NP parameters from the other side. The influence of the parameters of radiation, NPs, and surrounding medium on the achievement of maximal value of DT0/E0 is established on the basis of investigation of an analytical model. It is possible to achieve the values of about DT0/E0
1  106 Kcm2/J for NPs and for tP 1  1010 s under radiation energy density E0 = 1  103 J/cm2, and the heating of such NP could achieve 1  103 K. Thermo-optical parameters (19, 25) can be used for the determination of NP temperature heating DT0 and DT01 under action of radiation with definite value of E0, and vice versa one can determine the value of E0 for heating of NP to definite values of DT0 and DT01. Most of the processes mentioned above have approximate characteristic temperatures T* for initiation of these phenomena [13]. The heating of NP up to the value of T* under radiation action can initiate the realization of these processes. Parameters (19, 25) allow to determine threshold values of radiation exposure E0*, leading to initiation of the processes. The presented analytical model can be used for approximate estimations of DT0/E0 (19), DT01/E0 (25), and E* with satisfactory accuracy. Comparison of theoretical results, based on this model, with experimental results shows good agreement [13, 23]. Thermo-optical properties of homogeneous and core–shell NPs and the processes 1–9 for NP and for ambience can be used in PT and laser nanotechnology, including nanophotonics and nanoelectronics, light-to-thermal energy conversion and solar energy harvesting, laser nanomedicine, laser processing of nanoparticles, nonlinear optical diagnostics, catalysis, etc. Here the authors proposed the platform for analysis, optimization, and use of the thermo-optical properties of NPs for their different applications in PT nanotechnology with improved efficiency and flexibility.

Acknowledgments I cordially thank my colleagues Dr. L. Astafyeva, Dr. A. Smetannikov, and Prof. Dr. W. Fritzsche for their collaboration.

References 1. V.K. Pustovalov, Theoretical study of heating of spherical nanoparticle in media by short laser pulses. Chem. Phys. 308, 103–108 (2005) 2. V. Kotaidis, A. Plech, Cavitation dynamics on the nanoscale. Appl. Phys. Lett. 87, 213102 (2005) 3. A.O. Govorov, H.H. Richardson, Generating heat with metal nanoparticles. Nano Today 2, 30–38 (2007) 4. G. Baffou, R. Quidant, F.J. Garcia de Abajo, Nanoscale control of optical heating in complex plasmonic systems. ACS Nano 4, 709–716 (2010) 5. D. Erickson, D. Sinton, D. Psaltis, Optofluidics for energy applications. Nat. Photon. 5, 8–12 (2011) 6. V. Pustovalov, L. Astafyeva, Nonlinear thermo-optical properties of two-layered spherical system of gold nanoparticle core and water vapor shell during initial stage of shell expansion. Nanoscale Res. Lett. 6, 448–456 (2011) 7. O. Neumann, A.S. Urban, J. Day et al., Solar vapor generation enabled by nanoparticles. ACS Nano 7, 42–49 (2013) 8. V. Pustovalov, L. Astafyeva, W. Fritzsche, Selection of thermo-optical parameter of nanoparticles for achievement of their maximal thermal energy under optical irradiation. Nano Energy 2, 1137–1141 (2013) Page 17 of 19

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_37-1 # Springer International Publishing Switzerland 2015

9. C. Pitsillides, E. Joe, X. Wei, R. Anderson Rox, Selective cell targeting with light-absorbing microparticles and nanoparticles. Biophys. J. 84, 4023–4032 (2003) 10. V.K. Pustovalov, V.A. Babenko, Optical properties of gold nanoparticles at laser radiation wavelengths for laser applications in nanotechnology and medicine. Laser Phys. Lett. 1, 516–520 (2004) 11. A.M. Gobin, M. Lee, N.J. Halas et al., Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy. Nano Lett. 7, 1929–1934 (2007) 12. X. Huang, P.K. Jain, I.H. El-Sayed, M.A. El-Sayed, Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Lasers Med. Sci. 23, 217–228 (2008) 13. V.K. Pustovalov, A.S. Smetannikov, V.P. Zharov, Photothermal and accompanied phenomena of selective nanophotothermolysis with gold nanoparticles and laser pulses. Laser Phys. Lett. 5, 775–792 (2008) 14. L. Kennedy, L. Bickford, N. Lewinsky et al., A new era for cancer therapy: gold nanoparticlemediated thermal therapies. Small 7, 169–183 (2010) 15. V. Pustovalov, L. Astafyeva, E. Galanzha, V.P. Zharov, Thermo-optical analysis and selection of the properties of absorbing nanoparticles for laser applications in cancer nanotechnology. Cancer Nanotechnol. 1, 35–46 (2010) 16. J. Wang, J. Byrne, M. Napier, J. De Simone, More effective nanomedicine through particles design. Small 7, 1919–1931 (2011) 17. H. Muto, K. Miyajima, F. Mafune, Mechanism of laser-induced size reduction of gold nanoparticles as studied by single and double laser pulse excitation. J. Phys. Chem. C 112, 5810–5815 (2008) 18. A. Pyatenko, M. Yamaguchi, M. Suzuki, Mechanisms of size reduction of colloidal silver and gold nanoparticles irradiated by Nd:Yag laser. J. Phys. Chem. C 113, 9078–9085 (2009) 19. V. Pustovalov, Modeling of the processes of laser-nanoparticle interaction taking into account temperature dependences of parameters. Laser Phys. 21, 906–912 (2011) 20. A. Warth, J. Lange, H. Graener, G. Seifert, Ultrafast dynamics of femtosecond laser-induced shape transformation of silver nanoparticles embedded in glass. J. Phys. Chem. C 115, 23329–23337 (2011) 21. A. Plech, V. Kotaidis, Laser-induced heating and melting of gold nanoparticles studied by timeresolved x-ray scattering. Phys. Rev. 70, 295423 (2004) 22. S. Hashimoto, D. Werner, T. Uwada, Studies on the interaction of pulsed lasers with plasmonic gold nanoparticles toward light manipulation, heat management, and nanofabrication. J. Photochem. Photobiol. C 13, 28–54 (2012) 23. V.K. Pustovalov, L.G. Astafyeva, Investigation of thermo-optical characteristics of the interaction processes of laser radiation with silver nanoparticles. Laser Phys. 23, 065901 (2013) 24. R. Narayanan, M.A. El-Sayed, Some aspects of colloidal nanoparticle stability, catalytic activity, and recycling potential. Top. Catal. 47, 15–23 (2008) 25. J.R. Adleman, D.A. Boyd, D.G. Goodwin, D. Psaltis, Heterogenous catalysis mediated by plasmon heating. Nano Lett. 9, 4417–4423 (2009) 26. P. Christopher, H.L. Xin, S. Linic, Visible-light-enhanced catalytic oxidation reactions on plasmonic silver nanostructures. Nat. Chem. 3, 467–472 (2011) 27. V.P. Zharov, D.O. Lapotko, Photothermal imaging of nanoparticles and cells. Sel. Top. Quantum Electron. 11, 733–751 (2005) 28. V. Pustovalov, L. Astafyeva, B. Jean, Computer modeling of the optical properties and heating of spherical gold and silica–gold nanoparticles for laser combined imaging and photothermal treatment. Nanotechnology 20, 225105 (2009) 29. A. Steinbr€ uck, O. Stranik, A. Csaki, W. Fritzsche, Sensoric potential of gold–silver core–shell nanoparticles. Anal. Bioanal. Chem. 401, 1241–1249 (2011) 30. U. Kreibig, M. Vollmer, Optical Properties of Metal Clusters (Springer, Heidelberg, 1995) Page 18 of 19

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31. V. Giannini, A. Fernandez-Dominguez, S. Heck, S. Maier, Plasmonic nanoantennas: fundamentals and their use in controlling the radiative properties of nanoemitters. Chem. Rev. 111, 3888–3912 (2011) 32. I. Mayergoyz, Plasmon Resonances in Nanoparticles (World Scientific Publishing, Singapore, 2013) 33. A. Chen, P. Holt-Hindle, Platinum-based nanostructured materials: synthesis, properties, and applications. Chem. Rev. 110, 3767–3804 (2010) 34. M.R. Jones, K.D. Osberg, R.J. Macfarlane et al., Templated techniques for the synthesis and assembly of plasmonic nanostructures. Chem. Rev. 111, 3736–3827 (2011) 35. M.B. Cortie, A.M. McDonagh, Synthesis and optical properties of hybrid and alloy plasmonic nanoparticles. Chem. Rev. 111, 3713–3735 (2011) 36. M. Rysenga, C.M. Cobley, J. Zeng, W. Li, Controlling the synthesis and assembly of silver nanostructures for plasmonic applications. Chem. Rev. 111, 3669–3712 (2011) 37. V. Pustovalov, W. Fritzsche, Nonlinear dependences of optical properties of spherical core-shell silver-gold and gold-silver nanoparticles on their parameters. Plasmonics 8, 983–993 (2013) 38. V. Pustovalov, L. Astafyeva, W. Fritzsche, Optical properties of core-shell gold-silver and silver-gold nanoparticles for near UV and visible radiation wavelengths. Plasmonics 8, 983–993 (2012) 39. C.F. Bohren, D.R. Huffman, Absorption and Scattering of Light by Small Particles (Wiley, New York, 1983) 40. P.B. Johnson, R.W. Christy, Optical constants of the noble metals. Phys. Rev. B 6, 4370–4378 (1972) 41. Refractive index database, http://refractiveindex.info/ 42. Z. Lin, L.V. Zhigilei, V.V. Celli, Electron–phonon coupling and electron heat capacity of metals under conditions of strong electron–phonon nonequilibrium. Phys. Rev. B 77, 075133 (2008) 43. S.I. Anisimov, B.L. Kapeliovich, T.L. Perelman, Electron emission from metal surface under action of ultrashort laser pulses. Sov. Phys. JETP 39, 375–383 (1974) 44. F. Kreith, W.Z. Black, Basic Heat Transfer (Harper and Row, New York, 1980)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

Dye Nanoparticle or Nanocomposite-Coated Test Papers for Detection at Ppb Levels of Harmful Ions Yukiko Takahashi* Department of Materials Science and Technology, Nagaoka University of Technology, Nagaoka, Niigata, Japan

Abstract We have proposed a next-generation simple method for water analysis with high sensitivity to trace ions at ppb levels, named “dye nanoparticle-coated test strip” (DNTS). The DNTS is loaded with a thin layer (400 nm ~ 3 mm) of indicator dye nanoparticles or nanocomposites on the top surface of a membrane filter and provides a remarkably concentrated color signaling surface. Therefore, almost all signals are available efficiently, but in contrast to conventional test papers, indicator dyes are distributed over the entire support. The DNTS is applicable not only to immersion test but also to filtration enrichment in which target metal ions are concentrated by passing sample solutions through it. In addition, we designed two fabrication methods of DNTSs for the purpose of producing a large number of test strips with various organic indicator dyes. One method is ideal for hydrophobic indicators and is based on nanoparticle preparation by reprecipitation method. The other is suitable for hydrophilic dyes and is based on the preparation of nanocomposite composed of a water-soluble dye and nano-adsorbent through electrostatic interaction and the following aggregation. By simple filtration of the respective nano-dispersions with a fine membrane filter having microscopic pores, various kinds of DNTSs are available.

Keywords Dye nanoparticle; Dye nanocomposite; Dye nanoparticle coated test strip; Harmful ions; water analysis; ppb level

Introduction Harmful inorganic substances have toxic and nondegradable properties that pose a particular hazard to bio-organisms and the ecosystems [1]. The World Health Organization has recommended that the water quality guideline be less than 50 ppb (g L 1) for toxic inorganic substances, including cadmium, lead, chromium(VI), mercury, selenium, and arsenic [2]. In line with the guideline, strict regulations for industrial effluents, drinking water, and natural water have been adopted worldwide. High-performance analytical instruments, such as AAS, ICP-OES, and ICP-MS, are extensively used as standard methods to determine trace levels of contaminant concentration. However, in addition to the costly initial/running expenses of instruments, specific technical skills are required for machine operation. Moreover, sample collection, transportation to the analytical laboratories, and quite-complicated sample pretreatment may take time. On-site analytical methods for harmful ions are desired for quick monitoring of industrial wastewater, evaluation of drinking water, and urgent assessment of well water in times of disaster, as well as in environmental education in schools [3]. Despite the increasing demands for a simple test method of

*Email: [email protected] Page 1 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

inorganic ions, the sensitivities of commercial test papers and test kits are insufficient to meet the criteria of water quality [4], limiting their usages to qualitative or semiquantitative tests. They are convenient and powerful for on-site monitoring of water quality without costly instruments; however, the detection limits remain at ppm level, which are insufficient to satisfy the concentration standards of heavy metal ions for industrial or environmental waters (ppb level). Additionally, real water samples frequently contain interfering substances, and therefore, high selectivity is required. Some optical sensors and ion-selective electrodes show quick response and high sensitivity, but are insufficient in selecting a target metal ion particularly in the presence of high levels of interfering ions [5]. Pretreatment of samples, including selective separation and enrichment of trace analyte, are recommended to attain high sensitivity and more reliable monitoring of water quality [6, 7]. Nanostructured sensors have been developed over the past decade. Owing to the extremely small size, nanoparticles/fibers provide high surface area and rapid responsibility. For example, electrospun nanofibrous membranes grafted with pyrene have been developed as fluorescent quenching-based optical sensors for Fe(III) and Hg(II) [8]. Dye compounds are encapsulated in nanostructured silicate cage of uniform size via ionic interaction for colorimetric detection of Pb(II), Cd(II), and Hg(II) [9]. Pb(II)specific composite membrane was fabricated from cerium phosphate nanofibers [10]. A free-standing film composed of protein and cadmium hydroxide nanostrands was demonstrated to detect glucose electrochemically [11]. Herein we have reported detection membranes loaded with dye nanoparticles and succeeded the detection at ppb level, named “dye nanoparticle-coated test strip” (DNTS) [12]. The fabrication method is very simple and feasible but applicable to a wide variety of indicator dyes by using two preparation processes of nano-dispersion.

The Basic Concepts of DNTS Distinctive structural and functional properties of DNTS based on preparative procedures and a thinlayered structure are outlined by a conceptual diagram in Fig. 1.

High Sensitivity The DNTSs attain their detection ranges to ppb level, and it depends on their distinct thin-layered structure. The thin dye layer composed of nanoparticle or nanocomposite (400 nm ~ 3 mm) is located on the top surface of the membrane filter (thickness > 100 mm), which provides a remarkably concentrated signaling surface where we can see all. Therefore, almost all the signals are available efficiently (Fig. 2a), but in case of conventional test papers that are prepared by soaking in dye solution, indicator dyes are distributed over the entire support (Fig. 2b). For that reason, the signal obtained from the top surface must be less intense. The cross-sectional SEM image (Fig. 2c) indicates that there is a thin dye layer.

Versatile and Simple Fabrication There are two simple preparative methods for DNTS fabrication; therefore, it is easy to convert most organic reagents into solid thin layers as nanoparticle or nanocomposite configurations on fine woven membrane filters. The essential details are described in section “General Preparative Methods of DNTSs”.

Firm and Uniform Coating

Dye particles or nanocomposites were firmly coated onto the membrane filter as a thin layer simply by filtering the dispersion. It is noteworthy that the reagent thin layers of DNTSs were prepared without any Page 2 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

Versatile and simple fabrication

Indicator dye A, B, C...

Dye nanoparticle coated membrane

nano-dispersion A nano-dispersion B nano-dispersion C

membrane filter

Controllable dye loading 100% dye layer (400 nm~ 3 µm)

nonoparticle

110µm

nonocomposite

High sensitivity

Firm and uniform coating 2 cm

0

0.654

3.27 6.54 Zn(II) / ppb

32.7

Intensity at 314 nm

0.4

65.4

Dye nanoparticle coated test Strip (DNTS)

0.3 0.2 0.1 0

110 µm DNTS

Thickness / nm

500 400 300 200 100 0 A

Conventional test strips

B

C

D

E

Pencil hardness test : 3H~4H

Fig. 1 A conceptual diagram of DNTS

additives such as coating polymers or modifiers. Yet the reagent is not removed from the support by rubbing with a finger or by immersion into water. The color intensity was almost constant across the manufactured membrane according to linear scanning of the dye zone by a TLC scanner, and this indicated uniform dispersion of the reagent on the membrane surface. On the contrary, 1–2-mm-sized particles prepared by milling formed irregular patches that gave a rough surface on the filter and were easily removed by rubbing with a finger.

Controllable Dye Loading

Nearly 100 % of dye nanoparticles are captured by filtration of nano-dispersion due to surface filtration mechanism, that means that the dye amount of coating and the resulting thickness of dye nanoparticle layer are easily controllable. Under optimum conditions for nanoparticle growth, dye nanoparticles that have wider diameters than the pore size of membrane filter are completely retained on the top surface of

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

b

a ~700 nm 110 mm

Dye nanoparticles loaded membranes

400-500 m m Conventional test strips

c Reagent thin layer (~700 nm) 110 µm

Fig. 2 Comparison of two types of test papers with respect to the concept and structure of the signaling layers. (a) DNTSs, (b) conventional test strips, and (c) a cross-sectional SEM image of DNTS (Reproduced from [13] by permission of The Royal Society of Chemistry)

the membrane. For example, more than 99.5 % of dithizone nanofiber was trapped on the membrane filter having 0.1 m pore, and the resulting layer was ca. 440 nm thick when 100 mL of 2 mM dithizone acetone solution was injected into 10 mL of water and the membrane having an effective area of 9.6 cm2 was used.

Two Detection Methods In general, ordinary test papers possess only one detection way known as dipping. On the contrary, DNTSs have two ways for detection: one is called immersion test similar to dipping and the other is distinctive filtration enrichment. The detailed procedures are explained in section “General Properties of Dye Nanoparticle or Nanocomposite-Coated Membranes.”

General Preparative Methods of DNTSs Two fabrication methods of DNTSs were designed for the purpose of producing a large number of test strips with various organic indicator dyes. These methods including two different preparation processes of nano-dispersion solution and a single filtration process of the dispersion with a fine membrane filter having microscopic pores were shown in Fig. 3. Typically, hydrophobic reagents are converted into nanoparticles composed of 100 % dye, while hydrophilic ones are converted into nanocomposites by treatment with different nano-adsorbents.

For Hydrophobic Reagents In order to fabricate DNTSs with hydrophobic water-insoluble indicator dyes, a simple process referred to as reprecipitation method [14, 15] was adopted as the preparation of aqueous dye nano-dispersion (Fig. 3 upside). Typical preparative process involves injection of water-miscible organic solution of a dye Page 4 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

Hydrophobic dyes

‘reprecipitation method’

Injection in vigorously stirred water

>100 nm

Dye solution dissolved in an organic solvent

nano-dispersion membrane filter (pore size:0.1 µm)

Hydrophilic dyes

suction

Aqueous dye solution

>100 nm Mixing

Nano-adsorbents (~100 nm)

nano-dispersion

Dye nanoparticle-coated membrane

Fig. 3 Two preparative methods of DNTSs for hydrophobic and hydrophilic dyes (Reproduced from [17] by permission of Elsevier)

compound into water under vigorous stirring. Optimized preparative conditions for aqueous dispersions of the indicator dyes are defined by the solution pH, growth period, and concentration and injection volume of dye organic solution. Water-miscible organic solvents such as acetone, THF, ethanol, etc. were used for dissolution of the dyes. The pH of the aqueous solution was controlled to maintain electroneutrality of the dye species by considering the pKa values of the respective compounds. Smaller particles are formed with increasing temperature in the aqueous phase and with decreasing dye concentration in the organic phase [16]. Dispersion of nano-sized dye compounds is formed immediately upon combining the aqueous solution. The growth time of nano-sized dye was decided as the time until the average size of dye nanoparticles become more than ca. 100 nm. After the growth period ended, the nanodispersion is simply passed through with a fine membrane filter. Then, by surface filtration mechanism, dye nanoparticles are uniformly and firmly attached to a membrane filter. The thicknesses of dye nanoparticle layers were experimentally observed between 400 and 700 nm, which depends largely upon the amount of reagent loaded and the molecular weight. Dithizone nanofiber-coated DNTS is shown as a typical example of DNTS preparation using hydrophobic indicator [13]. Dithizone shows low solubility in water, 0.2  10 5 g L 1 (pH 5–7) [18]. This property is particularly advantageous to prepare the dithizone nano-dispersion. The solution for preparation of the dithizone nanofiber was kept between pH 2 and 3 to keep neutral species of dithizone predominant (pKa of dithizone = 4.47). A dark green acetone solution of dithizone changed to a purple dispersion by injection into vigorously stirred water. Particulate nanocrystals of dithizone are formed immediately. Letting the dispersion stand for around 1 min gave the most suitable size of fiber (200–250 nm wide and 1–2 mm long) for coating. Through filtration at very early stages, small fibers were not retained but passed through the membrane filter (0.1 mm pore size). When the dispersion was left for a long time, overgrowth of crystals induced large aggregates, resulting in nonuniformity and low surface area of the dithizone fiber layer. Figure 4 shows scanning electron microscopy (SEM) images of TPP nanoparticles and PAN nanofibers [12]. Round particles (50–100 nm) were mainly formed from TPP (tetraphenylporphyrin) and bathophen (bathophenanthroline). In contrast, fibrous products were formed in the case of PAN, TAN, and Dith (dithizone). These dyes commonly have dissociative protons capable of forming intermolecular hydrogen

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

nanofiber

nanoparticle

5 µm

1 µm

SH N

N N H

N

N

N

N S

N

N

N HO

HO Dith

TAN

PAN

N

N H H N

TPP

N N

N

Bathophen

Fig. 4 Photographs of dye nanoparticle-/fiber-loaded DNTSs and the SEM images (Reproduced from [12] by permission of WILEY-VCH Verlag GmbH & Co. KGaA.)

bonds, which assist formation of three-dimensional fibers. By simple filtration of the nano-dispersion with a fine woven membrane filter, nanofibers of PAN, TAN, and Dith and nanoparticles of TPP and bathophen were firmly captured on membrane fiber. More than 99.5 % of hydrophobic dye particles/fibers are retained on the membrane.

For Hydrophilic Reagents On the other hand, reprecipitation method is inapplicable to hydrophilic charged dyes such as reagents having sulfone groups, pyridinium groups, etc. For these water-soluble indicator dyes, a nanoscale ion exchanger is used as a dye adsorbent to produce dispersion of hydrophilic dye/nano-adsorbent nanocomposite. In principle, a charged dye adsorbs onto the surface of nano-adsorbent having the opposite charge (1–100 nm in diameter), followed by decrease in the surface charge of the adsorbent, and then aggregation occurs (Fig. 3 downside). A preparative procedure of hydrophilic dye/nanoadsorbent-loaded DNTS is technically easy, only by mixing individual solutions under an appropriate pH for fabricating nanocomposite-coated DNTSs. Typical nano-adsorbents include silica, zirconia, alumina, titania, and trimethylamine-modified latex (Latex-NR3+), which are smaller than 100 nm in diameter and have sufficient positive or negative surface charges in aqueous solution based on pH0 [19] and are promising candidates as nano-adsorbents. The thicknesses of dye nanoparticle layers were experimentally observed ca. 1–4 mm, which depends on the amount and size of the nano-adsorbent used. For example, 10 mL of TMPyP/silica nanocomposite aqueous solution was prepared by mixing 100 ml of 2 mM TMPyP and 4  10 5 wt% of silica (ca. 10–14 nm in diameter) at pH 7.8 [20]. Figure 5 shows that the particle size of the TMPyP/silica mixture was significantly larger compared to the colloidal silica. It was noted that aggregation occurred when the positively charged TMPyP was added to the negatively charged silica SA dispersion and a nanocomposite was formed based on the electrostatic interaction. The diameter range of the TMPyP/silica nanocomposite was between 120 and 800 nm, while the colloidal silica diameters were between 9 and 80 nm.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015 20

Frequency

15

10

5

0

1

10

100

1000

Particle diameter (nm)

Fig. 5 Particle size distributions of silica colloid (■) and TMPyP/silica nanocomposite (□) (Reproduced from [20] by permission of Elsevier) 100000

80

40 1000

20 0

100

10 0

Zetapotential / mV

Particle size / nm

60 10000

−20 −40 2x10−5 4x10−5 6x10−5 8x10−5 1x10−4 [TPPS]initial in 10ml (mol L−1)

Fig. 6 Particle size (■) of TPPS/Latex-NR3+ nanocomposite and zeta potential of Latex-NR3+ (□) as a function of TPPS concentration (Reproduced from [21] by permission of The Japan Society for Analytical Chemistry)

Optimum preparation conditions on nanocomposite formation (growth time, reagent or nano-adsorbent concentration, etc.) have been decided by actual zeta potential of the surface of nano-adsorbent as well as the average particle size (more than ca. 100 nm) by DLS measurement. Figure 6 shows particle size of nanocomposite of TPPS and trimethylamine-modified latex nanoparticle (Latex-NR3+) (100 nm in diameter) and zeta potential of the surface of Latex-NR3+ as a function of TPPS concentration with the amount of Latex-NR3+ held constant [21]. Both values drastically change when the TPPS concentration is over 1  10 5 M; it means that TPPS was adsorbed onto the surface of Latex-NR3+ based on electrostatic interaction and the following aggregation was occurred. Additionally, the size of nanocomposite is required to be smaller than 10,000 nm for perfectly uniform and flat coating. Optimum TPPS concentration in terms of DNTS fabrication is between 1  10 5 M and 4  10 5 M for a reason of perfect formation of nanocomposite. By filtration in a similar way to that of hydrophobic dyes, roughly 100 % of the nanocomposite was coated as thin layer onto the surface of the membrane filter based on surface filtration. A wide variety of analytical dye compounds can be converted as nanoparticles or nanocomposites in aqueous solution by the abovementioned two methods and then DNTSs can be simply fabricated from Page 7 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

a

c

2 µm 1mm d

b

440 nm 3.35mm

20 µm 30mm

Fig. 7 SEM images of dithizone nanofiber DNTS (dye nanoparticle) and TPPS/Latex-NR3+ nanocomposite DNTS (nanocomposite). (a) A top view of dithizone nanofiber DNTS, (b) a cross-sectional image of dithizone nanofiber DNTS near boundary area of a membrane filter of 110 mm thickness, (c) a top view of TPPS/Latex-NR3+ nanocomposite DNTS, and (d) a cross-sectional image of TPPS/Latex-NR3+ nanocomposite DNTS (Reproduced from [13] and [21] by permissions of The Royal Society of Chemistry and The Japan Society for Analytical Chemistry)

them. Versatility of the preparative procedures of DNTSs enables a screening test of reagents against one target ion. Another meaning of the versatility is that DNTS is a novel platform technology to produce highly sensitive test strips for any target with common dye indicators.

General Properties of Dye Nanoparticle or Nanocomposite-Coated Membranes Figure 7 shows comparison of the top and cross-sectional SEM images between dithizone nanofiber DNTS and TPPS/Latex-NR3+ nanocomposite DNTS. Generally, the thicknesses of nanoparticle-/ nanofiber-embedded DNTSs made from hydrophobic dyes range from 400 to 700 nm, less than 1 mm. By contrast, those of nanocomposite loaded DNTSs prepared from hydrophilic indicators and the corresponding nano-adsorbents range from 1 to 3 mm, less than 4 mm. In case of the nanocompositecoated DNTSs, hydrophilic indicator dyes have an important role in adhesion between nano-adsorbents. Almost all the reagents invested were captured on the membrane filter due to the surface filtration mechanism. Surface density of dye indicators is decided in terms of sufficient color intensity for naked eye detection. For instance, surface concentrations were estimated at 2.08  10 8 mol cm 2 for bathophen

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

Fig. 8 Two detection modes for sensing ions with DNTSs (Reproduced from [17] by permission of Elsevier)

and PAN DNTS [12], 1.04  10 8 mol cm 2 for TMPyP/silica DNTS [19], and 2.08  10 8 mol cm 2 for ditizone DNTS [13]. Mechanical strength of the dye nanoparticle/nanocomposite layer is based on van der Waals interaction between dye nanoparticle and base material of supporting membrane. In case of using cellulose-based membrane as a supporting filter, dye nanoparticles were adhered well to the cellulose frame of the top surface of membrane, and therefore, they were not removed from the substrate by rubbing with a finger or by immersion into water. The dye layer’s mechanical strengths based on a pencil hardness test were reported to be higher than 4H grade for dithizone nanofiber DNTS [13], 4H for TMPyP/silica nanocomposite DNTS [20], and 3H for 5-Br-PADAP nanoparticle DNTS [22].

Detection Characteristics with DNTSs Dual Detection of Ions Using DNTSs

The DNTS is applicable not only to immersion test but also to filtration enrichment in which target ions are concentrated by passing sample solution through it (Fig. 8) [12]. Immersion test is just the same detection way as using any ordinary test papers such as urine, pH, ions etc., but it takes longer to complete sufficient color development with DNTS than those with other test papers well known as dip and read test. The major reason for this is that DNTSs detect a very low concentration of a target ion at ppb level. In addition, DNTSs are water-permeable and the dye nanoparticle layer is insoluble in water, and hence, trace ions are enriched on them simply by filtration of the sample solution. Filtration enrichment is a unique approach provided by DNTS and based on the fact that dye nanoparticle layer acts as a solid phase feasible to extract a target ion mainly by complex formation between a target ion and indicator dye. Generally, filtration enrichment is more sensitive than immersion test, and one of the examples performed by PAN nanofiber DNTS is introduced in section “PAN Nanofiber-Coated DNTS for Zn(II) Detection.” Moreover, filtration enrichment enables highly selective detection by optimizing the reaction conditions

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

a

2cm

0

6.54

32.7

65.4

130.8

780.5

1308

Zn(II) /ppb 2cm

b

0

0.654

3.27 6.54 Zn(II) /ppb

32.7

65.4

Fig. 9 Detection of ZnII by PAN nanofiber DNTS via immersion test and filtration enrichment. (a) Immersion test: Piece of test strip was dip into 10 mL of aqueous solution containing ZnII at pH 8.4 for 15 min. (b) Filtration enrichment: A 100 mL of aqueous solution containing ZnII at pH 8.4 was filtrated through the PAN membrane under ca. 6.9 mL min 1 flow rate (Reproduced from Ref. [12] by permission of WILEY-VCH Verlag GmbH & Co. KGaA.)

such as solution pH, masking reagent, flow rate, etc. and the example carried out by dithizone nanofibercoated DNTS, described in section “Dithizone Nanofiber-Coated DNTS for Hg(II) Detection”. No leakage of indictors and their colored complexes with target ions into sample solutions is the key to the detection with DNTS by using both immersion test and filtration enrichment. Therefore, it is important to control solution conditions such as pH and ionic strength. When the DNTSs with hydrophobic reagents are used, the pH of the sample solution must be controlled to maintain electroneutrality of the dye species by considering the pKa values of the respective compounds, which is similar to the way when the nanodispersion is prepared. When the DNTSs with hydrophilic water-soluble reagents are used, attention needs to be paid to ion strength of the sample solution because they are fabricated based on electrostatic interaction between ionic dyes and ion exchanger nano-adsorbents. In addition, DNTS is inapplicable to a target ion that forms a water-soluble complex with the reagents and then leaves from the test strip. If a water-soluble complex is formed but never eluted due to strong adsorption on the dye nanoparticle layer, they are applicable to the corresponding target ion.

PAN Nanofiber-Coated DNTS for Zn(II) Detection For example, membrane coated with 1-(2-pyridylazo)-2-naphthol (PAN) nanofibers was applied as test strips for the detection of Zn2+ in a test solution (pH 8.4) [12]. Figure 9a shows the color changes of PAN-coated strips in immersion test. Notably 65 ppb of Zn2+ was detected by naked eye color test. Sub-ppb concentrations of Zn2+ were successfully detected by filtration enrichment of 100 mL of the sample solution (Fig. 9b). This filtration-enrichment procedure amplifies the signal intensity capable of eye detection of ppb-level metal ions. Practically, leaking of reagents out of the sample solution was observed to be negligible during dip test and sample filtration procedures. We also monitored the color change and the relative color intensity with reflectance-absorption spectrometry. The peak at lmax = 550 nm indicates that neutral [Zn(PAN)2] is formed on the membrane filter as the major species. The increasing peak intensity with increasing ZnII concentration enables quantitative determination of test samples by comparison with the calibration curve.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

Table 1 Tolerance limits on the determination of 10 ppb of HgIIa Cations Na+ K+ CaII AlIII CrIII CrVI b MnII FeIII NiII CdII PbII CuII c ZnII c FeII d Ag+e

Concentration/ppm 10,000 5,000 5,000 500 200 3 100 100 100 10 100 6.4 100 70 0.05

Recovery % 99 101 99 102 95 98 99 98 104 100 100 102 98 102 105

Remarks [13] [13] [13] [23] [23] [23] [23] [13] [23] [13] [13] [13] [13] [23] [23]

a

0.01 mol dm 3 glycine buffer (pH 2.2–2.9) was added When 0.01 mol dm 3 ascorbic acid was added, the allowance value in the presence of CrVI was identical to that of CrIII c 2  10 4 mol dm 3 EDTA was added d 5 mM KBrO3 was added e Pretreatment of a sample solution by filtration with a membrane filter (0.1 mm open pores) after the addition of 1  10 4 mol dm 3 NaI (Reproduced from Refs. [13] and [23] by permissions of The Royal Society of Chemistry and The Japan Society for Analytical Chemistry) b

Dithizone Nanofiber-Coated DNTS for Hg(II) Detection

We demonstrated dithizone nanofiber thin film for highly sensitive and selective detection of Hg(II) [13, 23]. Dithizone nanofiber was prepared by reprecipitation method. Simply by filtration of the dispersion through the membrane filter, dithizone nanofiber thin film of ca. 440 nm in thickness was deposited firmly and uniformly on one side of the membrane filter. Determination of Hg(II) at ppb level was achieved by filtration enrichment of a sample solution and successive colorimetric analysis. Consequently, Hg(II) was concentrated in the film as reddish brown complexes at pH 2.7. More than 90 % of 10 ppb Hg(II) was retained in the film at the filtration rate of 1.3–9.3 mL min 1. The presence of Na+ (10,000 ppm), K+ (5,000 ppm), Ca(II) (5,000 ppm), Al(III) (500 ppm), Cr(III) (200 ppm), Mn(II) (100 ppm), Fe(III) (100 ppm), Ni(II) (100 ppm), Cd(II) (10 ppm), and Pb(II) (100 ppm) in the acidic solution at pH 2.7 did not interfere the detection of 10 ppb of Hg(II) at all (see Table 1). By adding masking reagent, EDTA was very effective for Cu(II) and Zn(II) by forming water-soluble complex and passing through dithizone DNTS. By adding iodine ion to a sample solution in combination with subsequent removal of AgI precipitate by filtration, the interference of Ag(I) was excluded effectively. The interference from Cr(VI) and Fe(II) also was eliminated based on oxidation-reduction reaction. The present method succeeded in determining simulated wastewater, river water, and seawater spiked with 10 ppb Hg(II). Calibration curves for Hg(II) were obtained when the sample volume was 100 mL, and the 3s detection limit was 0.057 ppb (n = 10) by TLC scanner at 500 nm.

TMPyP/Silica Nanocomposite-Coated DNTS TMPyP/silica DNTS was demonstrated by coating a nanocomposite layer of a,b,g,d-Tetrakis (1-methylpyridinium-4-yl)porphine (TMPyP) and silica on the top surface of a cellulose ester membrane filter based on simple filtration of an aqueous TMPyP/silica nanocomposite dispersion through a Page 11 of 13

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_38-1 # Springer International Publishing Switzerland 2015

membrane filter [20]. The nanocomposite formation of cationic TMPyP and negatively charged colloidal silica (10–14 nm) was based on electrostatic interaction and was confirmed in the 120–800 nm diameter range by a dynamic light scattering photometer (Fig. 4). A TMPyP/silica DNTS whose thickness was controlled to be on average 2.60 mm by controlling the amount of TMPyP and silica demonstrated the highest sensitivity to Cd(II) ion because it had the lowest background absorbance. In addition, factors that affected the percent retention of TMPyP, such as pH and TMPyP/silica ratio, were determined. More than 99 % of the TMPyP was retained on a membrane filter at pH 7.8 with a TMPyP and silica concentration of 2  10 5 M and 4  10 5 wt%, respectively. Filtration enrichment of 100 mL of an aqueous solution containing Cd(II), Zn(II), and Pb(II) at ppb levels was achieved by concentrating the metal ions in a nanocomposite layer (the effective TMPyP area was 1.77 cm2, pH 10.2). The signaling surface changed from a brown color to green when the ions were captured. The percent extraction for metal ions on a TMPyP/silica DNTS was estimated by TLC scanning and ICP-MS. It was observed that Cd(II) concentrations as low as 1 ppb were detectable at a filtration rate of 4.0–5.0 mL min 1. 5-Br-PADAP nanoparticle DNTS also succeeded in detecting Cd(II) at ppb level by improved immersion test [22].

Conclusions and Future Perspective The features of DNTS having the thin layer composed of dye nanoparticles or nanocomposites are its simplicity, extremely high sensitivity, and versatility. Particularly the versatility means that DNTS is a novel platform to produce highly sensitive test strips for any target with common indicator dyes. In order to realize “on-site” detection system by the present nanoparticle-/fiber-based chemical sensors, a compact kit which includes water sampler, pre-filtration membrane to remove insoluble particles, appropriate buffer, and masking reagents is necessary. Syringe-type sampling system sandwiched with the membranetype color sensor is a primary candidate for simultaneous achievement of sampling, removal of interfering ions, and signalization. By combination with handy reflectometer or diffuse reflectance spectrometer, present nanostructured chemical sensors can provide a quantitative monitoring method of trace heavy metals (ppb level) that has not been achieved by conventional test kits.

Acknowledgment This work was financially supported by the Environment Research and Technology Development Fund (B-1005) of the Ministry of the Environment, Japan, and a grant (Kakenhi 25281038) from the Japan Society for the Promotion of Science (JSPS).

References 1. W.W. Gorge (ed.), Reviews of Environmental Contamination and Toxicology (Springer, New York, 2000) 2. WHO, Guideline for Drinking Water Quality, 4th edn. (World Health Organization, Geneva, 2011) 3. Y.A. Zolotov, V.M. Ivanov, V.G. Amelin, Test methods for extra-laboratory analysis. Trends Anal. Chem. 21, 302–319 (2002) 4. M. Unger-Heumann, Strategy of analytical test kits. Fresenius J. Anal. Chem. 354, 803–806 (1996)

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5. I. Oehme, O.S. Wolfbeis, Optical sensors for determination of heavy metal ions. Mikrochim. Acta 126, 177–193 (1997) 6. J. Minczewski, J. Chwastowska, R. Dybczynski, Separation and Preconcentration Methods in Inorganic Trace Analysis (Ellis Horwood, Chichester, 1982), pp. 283–502 7. I. Liska, Fifty years of solid-phase extraction in water analysis-historical development and overview. J. Chromatogr. A 885, 3–16 (2000) 8. X. Wang, C. Drew, S.-H. Lee, K.J. Senecal, J. Kumar, L.A. Samuelson, Electrospun nanofibrous membranes for highly sensitive optical sensors. Nano Lett. 2, 1273–1275 (2002) 9. T. Balaji, S.A. El-Safty, H. Matsunaga, T. Hanaoka, F. Mizukami, Optical sensors on nanostructured cage materials for the detection of toxic metal ions. Angew. Chem. Int. Ed. 45, 7202–7208 (2006) 10. T.M. Suzuki, M.A.T. Llosa, D.A.P. Tanaka, H. Hayashi, Y. Takahashi, Simple detection of trace Pb2+ by enrichment on cerium phosphate membrane filter coupled with color signaling. Analyst 130, 1537–1542 (2005) 11. X. Peng, J. Jin, E.M. Ericsson, I. Ichinose, General methods for free-standing films of nanofibrous composite materials. J. Am. Chem. Soc. 129, 8625–8633 (2007) 12. Y. Takahashi, H. Kasai, H. Nakanishi, T.M. Suzuki, Test strips for heavy-metal ions fabricated from nanosized dye compounds. Angew. Chem. Int. Ed. 45, 913–916 (2006) 13. Y. Takahashi, S. Danwittayakul, T.M. Suzuki, Dithizone nanofiber-coated membrane for filtrationenrichment and colorimetric detection of trace Hg(II) ion. Analyst 134, 1380–1385 (2009) 14. H. Kasai, H.S. Nalwa, H. Oikawa, S. Okada, H. Matsuda, N. Minami, A. Kakuta, K. Ono, A. Mukoh, H. Nakanishi, A novel preparation method of organic microcrystals. Jpn. J. Appl. Phys. 31, L1132–L1134 (1992) 15. H. Kasai, H.S. Nalwa, S. Okada, H. Oikawa, H. Nakanishi, Fabrication and spectroscopic characterization of organic nanocrystals, in Handbook of Nanostructured Materials and Nanotechnology, ed. by H.S. Nalwa, vol. 5 (Academic, London, 2000), pp. 433–473 16. H. Oikawa, H. Kasai, H. Kamatani, H.S. Nalwa, S. Okada, H. Matsuda, N. Minami, A. Kakuta, K. Ono, A. Mukoh, H. Nakanishi, in Chemistry of Functional Dyes, ed. by Z. Yoshida, Y. Shirota, vol. 2 (Mita Press, Tokyo, 1993), pp. 755–758 17. Y. Takahashi, Dye nanoparticle-coated test strips for detection of ppb-level ions in water, in Nanotechnology Applications for Clean Water, 2nd edn., ed. by A. Street, R. Sustich, J. Duncan, N. Savage (Elsevier, Oxford, 2014) Chapter 4, pp. 63–72 18. H.M.N.H. Irving, Dithizone (The Chemical Society, London, 1977) 19. G.A. Parks, The isoelectric points of solid oxides, solid hydroxides, and aqueous hydroxo complex systems. Chem. Rev. 65, 177–198 (1965) 20. K.K. Latt, Y. Takahashi, Fabrication and characterization of a a,b,g,d-Tetrakis(1-methylpyridinium4-yl)porphine/silica nanocomposite thin-layer membrane for detection of ppb-level heavy metal ion. Anal. Chim. Acta 689, 103–109 (2011) 21. Y. Takahashi, Preparation and characterization of dye nanoparticle-coated test strips composed of anionic dyes and basic nano-adsorbents. Bunsekikagaku 63, 525–531 (2014) 22. Y. Takahashi, S. Souma, Y. Wakui, Preparation of 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol nanoparticle-coated test strip and its detection of trace CdII Ion by immersion test. Bunsekikagaku 61, 229–234 (2012) 23. Y. Takahashi, Elimination of interferences in the Mercury(II) determination with a dithizone nanofiber-coated test strip based on filtration-enrichment. Bunsekikagaku 61, 123–126 (2012)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Structural Studies of Lipid-Based Nanosystems for Drug Delivery: X-ray Diffraction (XRD) and Cryogenic Transmission Electron Microscopy (Cryo-TEM) Elisabetta Espositoa*, Paolo Marianib, Markus Drechslerc and Rita Cortesia a Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy b Department of Life and Environmental Sciences and CNISM, Università Politecnica delle Marche, Ancona, Italy c Bayreuth Institute of Macromolecular Research – Electron Microscopy, University of Bayreuth, Bayreuth, Germany

Abstract Lipid-based nanosystems have gained interest as matrixes able to dissolve and to control delivery of active, thereby improving their bioavailability and reducing side-effects. In particular, nanoparticles based on lipids have been widely proposed as novel drug carrier systems. For instance, solid lipid nanoparticles (SLN) add up the benefit of colloidal lipid emulsions and those of solid matrix particles. Nanostructured lipid carriers (NLC), the second generation of SLN, are a blend of a solid lipid matrix and a liquid lipid phase. Among lipid dispersion providing matrixes for the sustained release of drugs monooleine aqueous dispersions (MAD) can be mentioned. MAD are heterogeneous systems generated by the dispersion of an amphiphilic lipid, such as monoolein, in water. MAD are made by a complex lyotropic liquid crystalline nanostructures such as micelles and lamellar, hexagonal, and cubic phases. In order to characterize nanosystems, it is important to carry out detailed systematic investigations. X-ray diffraction and microscopy give information about shape, inner structure and dimensions of powders, and dispersions that could not otherwise be identified. This chapter provides an overview about the use of x-ray diffraction and cryogenic transmission electron microscopy as techniques for characterizing lipid nanosystems recently developed by our research group.

Keywords Solid lipid nanoparticle; Cubosome; Nanostructured lipid carriers

Introduction Recently, lipid dispersions have gained interest as matrixes able to dissolve and to control delivery of active molecules, in order to improve their bioavailability and to reduce side-effects [5, 20] (Table 1). Solid lipid nanoparticles (SLN) are delivery systems made of a solid matrix nanodispersed phase of crystalline solid lipids. These systems can preserve the degradation of the included molecules and also modulate their release [61, 48, 42, 71]. Nanostructured lipid carriers (NLC) are an improvement of SLN. They are composed of a solid lipid matrix and a liquid lipid phase leading to the formation of solid carriers with homogenous lipid

*E-Mail: [email protected] Page 1 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Table 1 Examples of studies on lipid dispersions Type of lipid dispersion SLN

NLC

Cubosome MAD

Liposome

SCLL

Technological aspects Production/ characterization Cosmetic use Inclusion in semisolids Production/ characterization Particle characterization Production/ characterization Structural characterization Stability improvement Production/creams inclusion Physicochemical characterization – Production/ characterization Production/ characterization Production/ characterization Model structure – Pegylated formulations Model membrane Mechanistic studies Model membrane Phospholipid composition – Mechanistic studies Lipid composition – Model membrane Lipid composition

Drug Ubidecarenone/tetracaine etomidate/retinol/coenzyme Q10/cyclosporine Coenzyme Q10/retinol –

Route of administration Oral/Pulmonary/Dermal/ Parenteral

Reference [48]

Topical (skin) Topical (skin)

[49] [42]

–

–

[47]

–

–

[33]

–

–

[71]

Coenzyme Q10

–

[73]

Retinol Retinol/coenzyme Q10

Skin Topical (skin)

[49] [51]

Betamethasone valerate

–

[70]

Bromocriptine Ubidecarenone

Parenteral (iv) –

[22] [5]

–

–

[34]

–

Mucosal

[59]

– Indomethacin Anthracyclines

Stratum corneum Percutaneous Parenteral (iv)

[38] [21] [52]

Doxorubicin/nucleic Acids Estradiol Estradiol dipotassium glycyrrhizinate Indomethacin Estradiol – ATRA – Naproxen

Parenteral (iv) Shunt route delivery Percutaneous Skin delivery

[67] [4] [19] [68]

Percutaneous Percutaneous Percutaneous Percutaneous Percutaneous Percutaneous

[54] [18] [7] [25] [19] [55]

nanocompartments (i.e., the mixture of caprylic/capric triglycerides mixed to tristearin) [33, 49, 51]. Dispersions of lipid nanoparticles are obtained after emulsifying the molten lipid and recrystallizing the obtained dispersed phase. The technique preparation above described allows the use of compositions based on physiological compounds, avoiding all these problems of toxicity associated with the

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

administration of polymeric nanoparticles [72, 22]. In reason of their lipophilic nature, solid triglyceride nanoparticles can be particularly useful to administer lipophilic drugs [70, 5]. Triglyceride nanoparticles, due to their small dimensions, can be administered parenterally by intravenous route. These systems are able to immobilize drugs more strongly as compared to emulsions, thus it is possible to use them as sustained release systems and carriers for drug targeting [48]. In addition, SLN can be used to enhance (i) the specificity towards cells or tissues, (ii) the bioavailability of drugs via the increased diffusion through biological membranes, and (iii) the protection against enzyme inactivation [47]. Among lipid dispersions providing matrixes for drug sustained release, monooleine aqueous dispersions (MAD) can be mentioned. When unsaturated long-chain monoglycerides (e.g., monoolein) are emulsified in water, nanostructured dispersions of complex lyotropic liquid crystalline phases, such as lamellar, hexagonal, and cubic, are formed [34, 59]. Depending on both temperature and water content of the system, it is possible to obtain a predominance of one species over the others [39]. Cubosomes are stable reverse bicontinuous structures where it is possible to distinguish two regions of water separated by a twisted bilayer [37]. The methods of preparation [63, 62] and the inner structure [46, 44, 50] of cubosomes have been widely studied. It has been observed that the structure and stability of the dispersed phase are influenced by the emulsifier [27, 3]. In fact its role is fundamental: on the one side, its nature influences the nanostructure and the stability of the disperse phases [74, 75] on the other, it can lead to enhanced solubilization of poorly water-soluble drugs. One of the more used surfactant is the Poloxamer 407 copolymer, possessing a very interesting thermoreversible behavior. Poloxamer 407 can emulsify monoolein in water, obtaining aqueous dispersions constituted of a blend of hexasomes, cubosomes, and vesicles [27, 39, 62]. MAD are suitable to deliver lipophilic drugs through the skin since the stratum-corneum-like structure of cubosome suggests the possible formation of a depot effect on the epidermis from which the encapsulated drug can be delivered in a controlled fashion [38, 21]. At last, in considering lipid-based nanosystems, the well-known liposomes deserve to be mentioned. Liposome use and advantages have been widely studied [60, 52, 67], in particular recently many efforts have been undertaken to deliver drugs through and into the skin using liposomes [4, 19]. Liposomes have been largely used for the dermal delivery of a number of active agent e.g., antiinflammatory drugs. In fact, several scientific works have demonstrated that entrapped anti-inflammatory drugs in liposomes are able to promote the localized delivery of the drug [68, 54]. The use of a lipid composition similar to Stratum Corneum (SC) lipids allows to obtain Stratum Corneum Lipid Liposomes (SCLL). These interesting vehicles are able to intimate interact with lipid component of SC affecting the release profile of the drug to the skin. In particular, the interaction between SC and SCC leads to an enhancement of SC capacity in terms of drug reservoir, whereas after the application on the skin, phosphatidyl choline (PC) liposomes promote the permeation of the entrapped drug [18, 7, 25, 19]. A recent study by Puglia et al. [55] demonstrated that lipid composition of liposomes could modify the permeation profile of a well-known NSAID, such as naproxen (NP). Since morphology of nanosystems is known to have an influence on the delivery of encapsulated molecules, an extensive characterization of the external and inner structures of nanosystems is of paramount importance. X-ray diffraction (XRD) and cryogenic transmission electron microscopy (cryo-TEM) represent precious means to shed light on internal organization, shape, and dimensions of the nanostructures.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Overview on X-ray Diffraction Lipid systems and lipid dispersions have been the object of numerous X-ray diffraction studies during the last 40 years [43, 45, 76]. As a result, it is well established that lipids can aggregate into a variety of structures by the interplay of parameters (such as temperature and water concentration or the presence of different components), which often remain within the range of physiological conditions. Recent works, emphasizing the remarkable ability of lipids to be subjected to polymorphic transitions as well as their surprising phase stability, have shown that many of these structures can be very relevant for drug delivery [39, 53, 6]. In particular, inverse lipid–water phases can establish stable dispersions in water by a fragmentation process. For instance, in the presence of polar lipids, cubic or hexagonal lipid phases can be dispersed favoring the formation of lamellar phases. Moreover, the presence of block copolymers can close the bilayer at the surface hiding the hydrocarbon chain core to water [6]. To prepare cubosomes (e.g., nanoparticles based on cubic-phase forming lipids, with bilayers curved as the P-, D-, or G-minimal surface) and hexasomes, this process has been used. It is evident that the relations between the physical structure and the lipid dispersion stability and the drug loading and releasing profiles are of fundamental importance, especially when “targeting” or surface-active molecules are added. The purpose of this paragraph is to briefly review some methods employed in X-ray diffraction structure analysis, with special emphasis on the lipid phases most frequently observed in drug delivery nanosystems, e.g., lamellar, hexagonal, and cubic phases.

Classification of the Lipid-Water Phases

Temperature

The number of phases observed in lipid-water systems as a function of composition and temperature is quite large (see the scheme in Fig. 1 and Table 2) [43, 44, 39]. The phases are described and classified according to different criteria. Here, we will make reference to the common property of lipids to segregate in water their polar and paraffinic moieties into distinct regions (called structure elements), where they combine a periodically ordered long-range organization of the structure elements (in 1, 2, or 3 dimensions) and a highly disordered short-range conformation of the hydrocarbon chains.

Ia3d, type I Inverse Micellar Solution

Pn3m

HII

Ia3d, type II

Lα

HI

Pm3n

Micellar Solution

Iai Ia3d

0

Water content, %

100

Fig. 1 Schematic representation of the structure of a few different phases that can be observed in a lipid system as a function of water concentration. Name and symbols as in the text Page 4 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Table 2 Structural and topological properties of some of the lipidic phases Phase Periodic in 1D: Lamellar Periodic in 2D: hexagonal Periodic in 3D: Cubic, P4332 Periodic in 3D: Cubic, Pm3n Periodic in 3D: Cubic, Pn3m Periodic in 3D: Cubic, Fd3m Periodic in 3D: Cubic, Im3m Periodic in 3D: Cubic, Ia3d

Type – I or II II I II II II I or II

Structure elements Lamellae Infinitely long rods Rod network and micelles Micelles Intertwined rod networks Micelles Intertwined rod networks Intertwined rod networks

Class – Rod-like Mixed rod-like and micellar Micellar Bicontinuous (IPMS D-surface) Micellar Bicontinuous (IPMS P-surface) Bicontinuous (IPMS G-surface)

Fig. 2 Representation of the inverse Pn3m cubic phase in term of different views. From the left: representation of the two 3-D networks of connected rods, mutually intertwined and unconnected; representation of the folded continuous lipid bilayer; representation of the infinite minimal D-surface, that in this case corresponds to the regions where CH3 end-groups of the hydrocarbon chains are located

In the lamellar phase, structure elements are lamellae and the phase can be described as an ordered 1-D succession of lipid and water planar sheets; in particular, the hydrophilic lipid groups cover the surface which separate the lipid and water moieties, while the hydrocarbon chains pack inside the lipid layer. In the hexagonal phase, the structure elements are cylindrical micelles, which are packed in a 2-D hexagonal lattice. In the type II (inverse) phase, each cylinder contains water and is covered by the hydrophilic lipid groups, while the hydrocarbon chains fill the region between the cylinders. In the type I (direct) phase, the hydrocarbon chains are inside the cylinders and water is outside; as before, the hydrophilic groups cover the cylinder surface. The description of the structure of the cubic phases is more difficult, as the existence of micellar and bicontinuous cubic phases have been proved [46]. The structure of micellar cubic phase is that of cubic-packed spherical or quasi-spherical micelles, every micelle being covered by lipid polar groups. In type I topology, micelles are filled by the lipid hydrocarbon chains and are separated by water (as in the Pm3n cubic phase); vice-versa, water is inside and hydrocarbon chains outside in type II (as in the Fd3m cubic phase). Bicontinuous cubic phases has been presented as paradigms of the infinite periodic minimal surfaces (IPMS) and described in terms of convoluted (folded) surfaces [44, 39], but their structure can be more conveniently visualized in terms of two 3-D networks of connected rods, mutually intertwined and unconnected [26, 46] (Fig. 2). In the Ia3d cubic phase (which is related to the IPMS gyroid G-surface), the rods are coplanarly joined 3 by 3; in the Pn3m cubic phase (related to the diamond D-surface), the rods are tetrahedrally joined 4 by 4, and in the Im3m cubic phase (related to the primitive P-surface), the rods are cubically joined 6 by 6. It should be noticed that the Ia3d bicontinuous cubic phase has been observed to exist both in type I (oil-in-water) or II (water-in-oil) topology.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Concerning the X-ray diffraction characterization of lipid systems, a convenient operational separation based on the analysis of two separate parts of the X-ray scattering spectra, the first at low angles (from several hundred Å to 10 Å, which correspond to a Q-domain in the diffraction profile from about 0.02 to 0.6 Å
1, where Q ¼ 4p sin y=l, where 2y is the scattering angle and l the X-ray wavelength), and a second at high angles (centred around the 4 Å region, corresponding to the Q value of about 1.5 Å
1) can be useful. Indeed, diffraction peaks observed in the low-angle region arise from the long-range organization of the structure elements and specify the crystalline lattice and unit cell repeat distance, while the high-angle signals give information about the short-range organization and the conformation of paraffinic chains. It must be noted that structures usually observed in lipid-based nanosystems are one-parameter structures, i.e., the unit cell is described by only one parameter, and belong to 1- (lamellar phase), 2(hexagonal phase), and 3-D (cubic phase) systems. Moreover, in all cases discussed, the hydrocarbon chains show a liquid-like conformation, so that only a large peak is typically detected in the high-angle region of X-ray spectra. This particular lipid conformation is called type a [43].

Structure Determination Phase Identification The first step in the characterization of a multicomponent lipid system is the structural identification of the formed phase and the assessment of its stability (e.g., the determination of the temperature and composition domain of existence of the phase) [58]. In each X-ray diffraction experiment, a few sharp peaks are observed in the low-angle region: if the phase is unique, data consist of a single set of Bragg reflections and the problem is to index the peaks and to identify the symmetry of the lattice. The indexing is easy, as the relative positions (spacings) of the sharp low-angle peaks (and usually their intensities) are distinctive of the lattice and symmetry of the phase [43, 46, 31]. However, as very intricate phase diagrams can be obtained (in particular when lipid mixtures, as complex as those occurring when the number of components is large or when natural products are used, are considered), and different phases can coexist at the equilibrium, it is important to identify the peaks related to each phase. In such cases, attention should be devoted to determine, for each phase observed, the peaks that are systematically absent for symmetry reasons from those whose intensity is only very weak [46, 31] (Table 3). The equations that define the reciprocal spacings of the Bragg reflections in the 1-D lamellar, 2-D hexagonal, and 3-D cubic lattices are shown in Table 3. The lattice is then derived by finding the equation that agrees with the spacings of all the peaks observed in the diffraction profile. At this point, the crystallographic space-group to which the phase belongs can be determined by considering the systematic absences in the diffraction pattern [46]. In the case of lipid dispersion, this process is often not trivial because the large intrinsically thermal disorder strongly reduces the intensities at large diffraction angles. Moreover, according to the whole dimensions of the nanoparticles, and then due to reduced size of the crystallites, only a few low-angle Bragg peaks are Table 3 Relevant equations defining the reciprocal spacings of the Bragg reflections that should be observed in lipid lamellar, hexagonal, and cubic lattices Lattice 1-D lamellar 2-D hexagonal 3-D cubic

Equation Qh00 ¼ 2pðh=d Þ with h = 1,2,3. . .
1=2
 = a√3 with h,k = 1,2,3. . . Qhk 0 ¼ 4p h2 þ k 2
hk
1=2 Qhkl ¼ 2p h2 þ k 2 þ l 2 =a with h,k,l = 1,2,3. . .

Peak ratios 1, 2, 3, 4 . . .. 1, √3, √4, √7, √9. . .. 1, √2, √3, √4, √5. . ..

h, k, and l indicate the Miller indices of the Bragg reflections, while d and a are the unit cell dimensions in the lamellar and in the hexagonal and cubic phases, respectively Page 6 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Table 4 Reciprocal spacings of the Bragg reflections which characterize the lipid cubic phases [46, 31] Cubic phase P4332 (space group 212) Pm3n (space group 223) Pn3m (space group 224) Fd3m (space group 227) Im3m (space group 229) Ia3d (space group 230)

Reciprocal spacings √2:√3:√5:√6:√8:√9:√10:√11:√12. . . √2:√4:√5:√6:√8:√10:√12:√13:√14:√16. . . √2:√3:√4:√6:√8:√9:√10:√11:√12:√14. . . √3:√8:√11:√12:√16:√19:√24:√27. . . √2:√4:√6:√8:√10:√12:√14:√16:√18. . . √6:√8:√14:√16:√20:√22:√24:√26. . .

In bold are indicated the peaks that usually show a very strong intensity Table 5 Geometrical parameters in lamellar, hexagonal, and in bicontinuous cubic phases Avogadro number NA M Lipid molecular weight c Lipid weight concentration (lipid/lipid + water) nlip and nw Lipid and water partial specific volumes (cm3/g)
1 Lipid volume concentration flip = (1 + nlip (1
c)/nlipc) Lamellar phase: Nlip = d flip NA 10
24/Mnlip Number of lipid molecules per unit surface in one lamella; dl = d flip Thickness of the lipid lamellar layer; Slip = 2/Nlip Area-per-lipid at the lipid/water interface Hexagonal phase (type II): Nlip = a2 √3/2 flip NA 10
24/Mnlip Number of lipid molecules per unit length per one 2D hexagonal cell 2 1/2 R = (a √3/2 (1
flip)/p) Radius of the water cylinder Slip = 2p R/Nlip Area-per-lipid at the lipid/water interface Bicontinuous cubic phases, type II (the structures are supposed to be composed by identical straight rods of circular cross sections): Nlip = flip a310
24/ nlip Number of lipid molecules per one 3D unit cell; Nrod (see table) Number of rods per unit cell; R (see following equations) Rod cross-sectional radius; kv, ks and L (see table) Geometric constant l=La Rod length f = (1
flip) a3/Nrod = pR2 l (1
kv R/l) Volume of each rod s = 2pR l (1
ks R/l) Surface area of each rod Slip = s Nrod/Nlip Area-per-lipid molecule at the lipid/water interface Phase Nrod L kv ks Pn3m 4 √3/2 0.780 1.068 Im3m 6 1 1.614 1.801 Ia3d 24 1/√8 0.491 0.735

usually detected. Indeed, six different cubic phases belonging to different space-groups have been clearly identified to date: according to the crystallographic selection rule, the identification of the permitted reflections defines unambiguously the cubic aspect of the phase [26, 46]. The spacing ratios observed in the different cubic phases are reported in Table 4. When the symmetry is found, the dimension of the unit cell can be finally derived [43] (see Table 4). It should be noticed that the unit cell corresponds to the total thickness of the lipid and water layers in the lamellar phase, and to the distance between the axis of the cylinders in the hexagonal phase. When unit cell, phase composition and partial volumes are known, only a few hypotheses are sufficient to derive Page 7 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

from simple geometrical calculations the dimensions of the structure elements and a few relevant molecular parameters (e.g., the area-per-molecule at the polar/apolar interface, the average length of the hydrocarbon chain, the number of hydrational water per lipid molecule, the cross-sectional area along the chain, the interface mean curvature, the molecular shape parameter; see also Table 5): first, the water is supposed to be excluded from the paraffinic regions; second, the polar/apolar interface is assumed to be covered by the hydrophilic groups of lipid molecules; third, the structure element shape is considered to be free to assume higher symmetry than that permitted from the space group (e.g., in the hexagonal phase, the rod section is expected to be circular). However, if the structure elements are not fully defined from the lattice symmetry, as in the case of some cubic phases, structural information can be obtained only from an analysis of the intensities of the reflections [46, 9]. Intensity Analysis The relation between the electron density distribution in the unit cell, r(r), (which may be interpreted to find the overall position of lipid and water molecules in the unit cell) and the observed structure factors, Fhkl, (which are directly obtained from the intensities of the observed peaks) is given by a Fourier transform: ð 0 F hkl ¼ c rðrÞ exp ðirQhkl ÞdV where c' is a normalization factor and the integral is carried out over the unit cell volume, and the term exp (
i2prQhkl) is known as the phase factor [31]. Therefore, electron density maps can be calculated from structure factors by inverse Fourier transform. In the case of periodic structures (like a liquid-crystalline phase), the inverse Fourier transform can be written as: rðrÞ ¼ c00 Shkl F hkl expð
irQhkl Þ where c" is a second normalization factor. The structure factors are calculated from the observed intensities but only their magnitude |Fhkl| can be derived. In terms of physics, this means that we know only the absolute value of the complex vector Fhkl but not its phase, ahkl. This fact is known in crystallography as the “phase problem.” Some unusual constraints are encountered when one tackles a lipid containing structure [26, 46]. In fact, as a consequence of the short-range disorder, the resolution of scattering experiments appears to be intrinsically low (typically, about 10–20 Å). Moreover, the delicacy of the thermo-dynamical phase equilibrium precludes the use of the isomorphous replacement technique, and it is in general difficult to grow single crystals of all phases observed in any system. On the other hand, it must be noted that one can take advantage of the variety of structures that a definite lipid forms and of the number of different lipid systems that present the same phase. Therefore, the use of chemical and physical criteria, which allow the shape and dimensions of structure elements and the lipid molecular parameters to be determined, may lead to convincing arguments to fix the correct set of phases for the structure factors and to derive the best – the real – electron density map and then the structure of the phase. Different indirect and direct methods have been proposed and successfully applied to solve the phase problem: among them, indirect trial-and-error model approaches [58, 9] and those based on the Shannon theorem, as the swelling series experiment [10] and the “pattern recognition approach” [46] should be indicated.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Chemical Criteria As usual in crystallography, a convincing argument to support the proposed structure is the agreement with chemical information not concerned with the intensity analysis. Some fundamental criteria cannot be disregarded – for example, the fact that the dimension of the structure elements calculated from the chemical data and measured from the electron density maps must agree. Moreover, the lipid phases follow a few chemical rules [43, 44, 46, 58], which the proposed structure must satisfy. Among other things, the structure element dimensions must be consistent with the volumes of the water and hydrocarbon regions; the distance between the polar/apolar interface and any point of the hydrocarbon regions must be compatible with the maximum length of the hydrocarbon chains; the area-per-lipid at the polar/apolar interface, which must range around reasonable values, can only increase, or at least not decrease, by increasing temperature and water content, even at phase transitions. These criteria are essential in assessing the final proposed structure.

Cryogenic Transmission Electron Microscopy (cryo-TEM) The first attempts to study unstained, fully hydrated colloidal dispersions in thin vitreous ice films by TEM started in the last third of the twentieth century [24, 30, 65, 66]. However, such approaches did not lead to routine applications until the development of a method for rapid freezing of thin aqueous films in the early 1980s by Jacques Dubochet and his colleagues [13, 14] at the EMBL in Heidelberg. Aqueous dispersions could then be routinely prepared as frozen-hydrated specimens, with untreated, i.e., unfixed and unstained colloids embedded within a thin layer of vitreous resp. non-crystalline “ice.” Thus, the new field of higher resolution cryogenic electron microscopy of colloidal dispersions using unstained vitrified specimens, produced by the “thin film” technique, was established [1]. The tremendous time and effort invested in the investigation and understanding of the theoretical and technical fundamentals of cryofixation, the practical application to aqueous dispersions of colloids [40, 41] helped to provide answers to many structural and functional questions in pharmaceutical and biological colloid sciences (for review see [15, 16, 69]). Several books, reviews, and monographs in the broad field of cryogenic electron microscopy appeared in the last 20 years which cannot be listed here completely [29, 57, 8, 36, 17, 35]. For the successful electron microscopy of thin films of frozen-hydrated specimens, preparation techniques [1] and the routine cryogenic TEM should follow some rules. The formation of a thin aqueous film containing a single layer of well-spaced colloidal particles that spanned the holes of a lacey carbon support film is obtained by a direct and thorough contact with a filter resp. blotting paper to get rid of excess material. The cryofixation by rapidly plunging the specimen into the liquid cryogen such as liquid ethane follows directly after the thin film formation. The vitrified samples should be constantly kept at low temperatures well below the recrystallization temperature for further procedures like the subsequent transfer into the TEM. For this purpose, special liquid-nitrogen cooled low temperature holders are used which prevent the vitrified samples from recrystallization. Furthermore, the contamination with moisture from the environment which leads to ice crystals covering the surface of the thin film is prevented by the use of special shutter systems. In addition, the TEM should be supplied with efficient anti-contamination devices which are cooled well below the sample temperature to minimize the accumulation of hexagonally crystalline ice particles and the formation of vitreous ice layers on the surface of the thin film during the examination in the TEM. Unstained and unfixed aqueous colloidal systems mainly consisting of hydrocarbons show only a very weak amplitude contrast in the TEM and additionally are very sensitive to radiation damages due to the electron beam irradiation. As a consequence thereof the TEM must be operated under low dose conditions and with an optimal defocus or, if possible, with the help of an energy Page 9 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

filtering system combined with a phase plate to enhance the weak contrast and hence make it possible to reveal fine details of the sample.

Experimental Technique for Structural Determination X-ray Diffraction Technique X-ray diffraction experiments can be performed using conventional powder diffractometers or exploiting synchrotron SAXS beam-lines. In our laboratory, diffraction experiments are performed using two 3.5 kW Philips PW 1830 X-ray generators equipped with a Guinier-type focusing camera operating with bent quartz crystal monochromator (l = 1.54 Å). Diffraction patterns are recorded on a GNR Analytical Instruments Imaging Plate system. Diffraction data can be collected at different temperatures, as the sample-holder temperature is controlled by a Haake F3 thermostat system. X-ray scattering experiments were also performed at the A2 beam-line of the DESY synchrotron facility in Hamburg (Germany) (investigated Q-range from 0.02 to 0.35 Å
1) or at the Elettra synchrotron facility in Trieste (Italy) using the 5.2 L SAXS beamline with a SAXS/WAXS set-up. In this case, the ferreted Q-range was between 0.035 and 0.70 Å
1 (for the SAXS) and from 1.4 to 3.8 Å
1 (for the WAXS). In both the beam lines, scattering data were on a bi-dimensional CCD camera of 1,024  1,024 pixels, radially averaged and corrected for dark, detector efficiency and sample transmission.

Cryogenic Transmission Electron Microscopy (cryo-TEM)

For cryo-TEM studies, a drop (~2 ml) of the aqueous dispersion is placed on a lacey carbon film-coated copper TEM grid (200 mesh, Science Services). Most of the liquid is removed with blotting paper, leaving a thin film stretched over the carbon film holes. The specimens are put in a temperature-controlled freezing unit, subjected to freeze by immersion into liquid ethane (Zeiss Cryobox, Zeiss Microscopy GmbH) and cooled to approximately 90  K. This leads to a thin vitrified film of the specimen. The temperature is monitored and kept constant in the chamber during all of the preparation steps. Frozen specimens are inserted into a cryo-transfer holder (CT3500, Gatan) and transferred to a Zeiss EM922 OMEGA EFTEM instrument. Examinations were realized around 90  K. The microscope operates at an acceleration voltage of 200 kV. Zero-loss filtered images (DE = 0 eV) are taken under reduced dose conditions. Images are digitally recorded by a bottom-mounted CCD camera system (Ultrascan 1000, Gatan), combined and processed with a digital imaging processing system (Gatan Digital Micrograph 3.9 for GMS 1.4).

Lipid Based Nanosystems Characterization General Methodology of Nanosystem Production Production of Nanoparticles SLN and NLC can be prepared by different methods [42, 47, 11, 32], in particular our group has studied a method based on stirring followed by ultrasonication [22]. One gram of lipid mixture (consisting of tristearin in the case of SLN, or tristearin/caprylic/capric triglycerides Miglyol 812 2:1 w/w, for NLC) is melted at 75  C. The fused lipid phase is dispersed in 19 ml of an aqueous poloxamer-188 solution (2.5 % w/w). The emulsion underwent to ultrasonication (Microson TM, Ultrasonic cell Disruptor) at 6.75 kHz for 15 min and then chilled till room temperature in a water bath. Afterward, NLC are stored at room temperature.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Table 6 Composition of liposome formulations Formulation SCL liposome PC/CHOL liposomes

Ceramides type III 2 mg/ml 0.2 % p/p –

Cholesterol 1.25 mg/ml 0.125 % p/p 1,25 mg/ml 0,125 % p/p

Cholesteryl sulfate 0.5 mg/ml 0.05 % p/p –

Palmitic acid 1.25 mg/ml 0.125 % p/p –

Soybean phosphatidyl choline

5 mg/ml 0,5 % p/p

Naproxen 1.5 mg/ml 0.15 % p/p 1.5 mg/ml 0.15 % p/p

In the case of drug containing nanoparticles, the drugs are added to the molten lipidic mixture and dissolved before addition to the aqueous solution. Production of Monooleine Aqueous Dispersions (MAD) MAD can be produced by different methods such as high-energy microfluidization succeeded by heat treatment, dilution of an hydrotrope and by the hot homogenization method [39, 63, 62, 3]. The hot homogenization method is based on the emulsification of monooleine (4.5 % w/w) plus Poloxamer 407 (0.5 % w/w) in water (90 % w/w), as reported by Esposito et al. [21]. After emulsification, the dispersion is homogenized at 15,000 rev min-1 (Ultra Turrax, Janke & Kunkel, Ika-Werk, Sardo, Italy) at 60  C for 1 min; afterward, it is cooled and kept at 25  C in glass vials. Production of Liposomes Liposomes have been obtained by different methods [64, 12]. In particular, stratum corneum lipid liposomes (SCLL) and soybean phosphatidyl choline/cholesterol (PC/CHOL) liposomes can be produced by reverse phase evaporation (REV) and by thin layer evaporation (TLE) method [55]. For the REV method, in order to prepare 2 ml of SCLL dispersion, the lipid mixture indicated in Table 6 is solubilized in 10 ml of a methylene chloride/methanol mixture (1:1 v/v) afterwards it is vacuum-dried by a rotary evaporator. The obtained dried lipid film is solubilized in 8 ml of diethyl ether, then 2 ml of warm (40  C) phosphate buffer is added, afterward the two phase system is subjected to sonication at 30  C for 30 min in a bath sonicator (Branson 2200, Branson Europe, The Netherlands) obtaining an emulsion. The organic solvents are evaporated from the emulsion at room temperature by rotating evaporation at reduced pressure, resulting in a turbid liposome suspension. Phosphate buffer is added to the liposome suspension to a final volume of 2 ml. To produce drug containing SCLL, 3 mg of drug (1.5 mg/ml, 0.15 % p/p) are added and solubilized in the lipid mixture. PC/CHOL liposomes can be prepared by the same procedure above reported for SCL liposomes, using the lipid mixture indicated in Table 6. Moreover, SCL liposomes and soybean PC/CHOL liposomes can be produced by TLE method. Shortly, SCLL are prepared by dissolving the lipid mixture reported in Table 6 in 10 ml of a methylene chloride/methanol mixture (1:1 v/v). After rotating evaporation of solvent, the resulting dried lipid-film is re-hydrated with 2 ml of warm (40  C) phosphate buffer, afterward the mixture is spinned and sonicated at 60  C for 10 min in a bath sonicator to give more homogeneous sized vesicles.

Examples of Structural Determination SLN and NLC for Bromocriptine Delivery The possibility to employ SLN to control the delivery of the dopamine receptor agonist bromocriptine (BC) in the treatment of Parkinson’s disease (PD) has been reported in a study by Esposito et al. [22]. In Page 11 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Fig. 3 Cryogenic transmission electron microscopy images (cryo-TEM) of SLN dispersions constituted of Tristearin (a), Tristearin-Monostearin (2:1) (b), Tristearin-Tricaprin (2:1) (c), Behenin (d), and Tristearin-Tricaprin (2:1) containing bromocriptine (BC) (e). The insets show in more detail the shape of the SLNs versus NLCs. Each panel has its own scale bar

particular, the authors have determined in vivo the capability of BC containing SLN to lessen motor deficits in 6-hydroxydopamine (6-OHDA) hemilesioned rats, a model of PD. A thorough characterization of morphology, size, inner structure, and drug distribution of SLN was performed before in vivo experiments. In particular, cryogenic electron transmission microscope analyses were carried on in order to obtain information on the internal structures of SLN. Figure 3 reports electron microscopic images of SLN dispersions made of Tristearin (A), Tristearin-Monostearin (2:1) (B), Tristearin-Tricaprin (2:1) Page 12 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

b Intensity, a.u.

Intensity, a.u.

a

1000

100

1

2

3 4 5 6 2θ scattering angle

7

8

d

1

2

1

2

3 4 5 6 2θ scattering angle

7

8

7

8

5000

4

4000 Intensity, a.u.

Intensity, a.u.

3000

1000 800 600

c 10

5000

1000

3000 2000 1000

100

1

2

3

4

5

6

2θ scattering angle

7

8

0

3

4

5

6

2θ scattering angle

Fig. 4 Low-angle X-ray diffraction profiles obtained from tristearin-tricaprin samples with and without BC. Top frames, from left to right: SLN dispersions constituted of Tristearin-Tricaprin (2:1) (sample e), and Tristearin-Tricaprin (2:1) containing BC (sample f). As comparison, lower frames show the low angle diffraction profiles form Tristearin-Tricaprin (2:1) powder mixed with BC before SLN production (left frame) and a crystalline powder of BC (right frame)

(C), Tribehenin (D) and BC-containing Tristearin-Tricaprin (2:1) SLN dispersion (E). Since in all panels, SLN and NLC are viewed at the top and aside, different structures can be observed, such as deformed hexagonal, elongated circular platelet-like particles (top views) or dark, “needle” like structures (side views). The nanoparticle thickness ranges between ca. 5 nm and 40 nm depending on the number of layers in the platelets. It should be stressed that it is not easy to measure the exact thickness due to the tilt of the particles. Panel c shows hexagonal and circular SLN top views andthe “needles” more elliptically shaped with respect the SLN viewed on side. This could be ascribed to the formation of caps on the surfaces of the SLNs due to the presence of glycerol tricaprylate, which is liquid at room temperature. Nonetheless, the presence of BC does not further affect nanoparticles shape (panel e). In order to obtain information on the internal morphology of the particles, X-ray diffraction profiles were analyzed considering independently the small angle diffraction region, providing eruditions on the long-range organization of the lipid structure elements (Fig. 4), and the wide angle diffraction region, giving elucidations about the nature of the short-range lipid conformation (Fig. 5). Data for samples from a to d are not reported. Two narrow Bragg peaks in the small angle region are reported in the x-ray diffraction profile for sample d, while in the wide angle region a series of reflections are shown. Since the position of the small angle peaks indexes in a 1-D lattice, the lamellar organization can be deducted. Anyway, that the order inside the lamellae is crystalline, as indicated by the wide-angle region. The comparison between the two profiles suggests that the tristearin lattice is not modified by the BC presence. A smaller number of Bragg reflections is shown in samples a and c, both at small and at large angles. In the small angle region, diffuse (wide) peaks can be observed, and a second order (possibly confirming a lamellar lattice presence) is hardly detectable. Only a few peaks can be found in the wide-angle region, indicating a scarcely periodic order of the hydrocarbon chains. In both cases, the phase is probably gel lamellar. Thus, a very low degree

Page 13 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

a

b

1000

1000

Intensity, a.u.

Intensity, a.u.

800 600 400 200 17

18

19

20

21

22

23

24

25

100 17

18

c

2000

Intensity, a.u.

2θ scattering angle

1500

19

20

21

22

23

24

25

2θ scattering angle

1000 500 0 17

18

19

20

21

22

23

24

25

2θ scattering angle

Fig. 5 High angle X-ray diffraction profiles obtained from tristearin-tricaprin samples with and without BC. From the top: SLN dispersions constituted of Tristearin-Tricaprin (2:1) (sample e), and Tristearin-Tricaprin (2:1) containing BC (sample f). As a comparison, the high angle diffraction profile observed from a crystalline powder of BC is also shown in the lower frame Table 7 Structural organization of SLN at different lipid compositions as derived by X-ray diffraction analysis Lipid composition a Tristearin/Monostearin b Tristearin c Behenin d Tristearin /Tricaprin (2:1) + BK powder e Tristearin/Tricaprin f BK Tristearin /Tricaprin (2:1)

Phase LG Lc LG Lc LG LG

Unit cell 48.2 Å 45.3 Å 59.9 Å 44.3 Å 47.8 Å 47.8 Å

Hydrocarbon chain conformation gel crystalline gel crystalline gel gel

of order is shown in a and c samples, possibly related to a small extension of the crystallite or to a numerous defects presence. The effect of the addition of BC was studied in detail in the tristearin–tricaprin system. Figure 4 reports the small angle diffraction profiles for the samples, as well as the analogous profile obtained by a crystalline powder of BC. One can observe the presence of two peaks indicating a lamellar phase formed by the triglyceride systems, both in the presence and in absence of the drug. Data reported in Table 7 suggest that the addition of BC has no influence on the lamellar unit cell. It is interesting to note that the dissolution of BC in the mixture results in a disappearance of the peak present in the drug powder. The wide-angle data and the diffraction profile attained by tristearin–tricaprin (2:1) powder are shown in Fig. 5. Since the addition of BC does not change the diffraction profile, it can be suggested that the order inside the hydrocarbon chains is still maintained. Therefore, it can be asserted that the triglyceride mixture perfectly solubilize the drug [23].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Fig. 6 Panels a, b: Cryo-transmission electron microscopy (cryo-TEM) micrographs of placebo monooleine dispersion. Panels c, d: Cryo-TEM micrographs of IND monooleine dispersion. The inset of panel b shows the diameter of the aqueous channel (indicated by the white arrow) and the spacing of the unit cell. The bar equals 200 nm in panel a, 150 nm in panels b and c, and 60 nm in panel d. The disperse phase constituted of monooleine/Poloxamer 407 90:10 w/w; the disperse phase/ dispersing phase ratio was 5:95; the dispersion was produced by mechanical stirring followed by hot homogenization

MAD for Indomethacin and Curcumin Delivery The performances of MADs as new cutaneous delivery systems for indomethacin (IND), taken as model drug, were investigated by our group [21]. Firstly, IND-MAD dispersions have been produced and characterized, afterward an in vitro and an in vivo study was performed to understand the release mechanism of IND after dispersion administration on the skin. The obtained results suggest a sustained anti-inflammatory activity exerted by IND. MAD have been characterized by cryo-TEM and X-ray diffraction. In particular, the inner structure of the dispersed particles in MAD has been investigated by cryo-TEM analyses to detect possible structural changes due to IND presence. Micrographs taken from MAD (panels a and b) and IND containing MAD (panels c and d) are shown in Fig. 6. The typical ordered cubic texture characterizing regular-shaped cubosomes, together with vesicles, are present both in the placebo and in IND containing MAD. The inset of panel b shows a spacing of a repeat unit measuring 6.7 nm, indicating a tilt of the cubosome. The 3.5-nm spot evidences the diameter of the intercalating cubosomal aqueous channel. The ultrastructure of the disperse phase is not affected by the presence of IND. Panels a and c show vesicular structures attached on the surface of cubosomes as reported by other cryo-TEM and XRD studies. The authors hypothesize that a conversion may turn up through time from clusters of partially fused vesicles to well-ordered particles [28, 2].

Page 15 of 23

Intensity (a.u.)

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

IND cubosomes

blank cubosomes 1

2

3 4 2θ (angle scattering)

5

6

Fig. 7 Small angle X-ray diffraction profiles of a monooleine-poloxamer dispersion prepared in the absence and in the presence of IND. The dotted line represents the X-ray diffraction patterns measured after 3 months from the sample preparation

More than 100 cryo-TEM micrographs were taken both for blank or IND-containing monooleine dispersions (data not shown). The measured diameters evidence two different populations: one constituted of large cubosomes (mean diameter > 200 nm) and another of smaller cubosomes and vesicles (mean diameter  100 nm). X-ray diffraction allowed to determine the structural organization of MAD. In particular in Fig. 7 is reported a series of diffraction profiles, obtained from MAD and IND containing MAD respectively. In both samples, several Bragg peaks can be identified. The spacing ratio of reflections (√2: √4: √6: √8: √10. . .) suggests the formation of a bicontinuous cubic phase with a symmetry of Im3m (Q 229) type designated by two 3-D networks constituted of rods orthogonally connected 6  6. Moreover, a diffuse small angle scattering, possibly due to large micelles and/or vesicles, is detected. X-ray diffraction qualitative results and cryo-TEM observations agree well (Fig. 6), showing the concurrence of vesicles and cubic particles. It should be noted that both MAD and IND containing MAD samples are characterized by a similar cubic unit cell dimension, being 10.8 and 10.6 nm, respectively. The peak intensity profile analysis evidences that IND almost maintains the cubosome structure, even if the presence of the drug could be responsible of the small reduction of the unit cell. From the unit cell, it is derivable that the 2-D periodically ordered (7.6 nm) domains found by cryo-TEM are normal to the [110] crystallographic axis of the cubic unit cell. The shrinking of the cubosomes during the cryo preparation could be responsible for the small differences found between the repeating unit calculated by cryo-TEM (6.7 nm) and the spacing obtained from X-ray diffraction (7.6 nm). X-ray diffraction data analysis allow also to obtain the aqueous channels radius of the Im3m cubic phase, in particular by considering a lipid hydration around 40 %, as the case of pure monoolein in excess of water [46], for samples in the absence and in the presence of IND, radii of 1.81 and 1.77 nm can be conceived respectively. The values agree very well with the dimension of the aqueous channels found in cryo-TEM micrographs. Finally, the same samples analyzed by X-ray diffraction after 3 months revealed a cubic structure strongly stable (with the same unit cell and intensity profile). This stability indicates a reduction of the number of vesicles through time, as suggested by the reduced small angle diffuse scattering.

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

Recently, Puglia and colleagues investigated the potential of MAD based on different emulsifiers as curcumin (CU) delivery systems [56]. In particular, MAD were alternatively stabilized by poloxamer 0.5 % w/w (MP), or by a mixture of sodium cholate 0.15 % w/w and sodium caseinate 0.07 % w/w (MCC). X-ray diffraction data analysis enabled obtaining information of the inner structural organization of MAD. Two different profiles, represented by a different pattern of Bragg peaks, were obtained for MP and MCC and indicate a different structure organization of the MAD. In the case of MP, the inner structural organization was assigned as Pn3m, indicating cubic and hexagonal phase symmetries, while the inner structure of MCC was assigned as hexagonal. Therefore, MP contained cubosomes while MCC hexasomes. No transitions were observed in the investigated temperature range (from 25  C to 45  C); in both cases, temperature only induced a small reduction of the unit cell size. The increase of temperature from 25  C to 45  C resulted in a reduction of the cubic unit cell from 95.5 to 83.2 Å for MP, while for MCC the hexagonal unit cell decreases from 61.4 to 54.6 Å. This reduction is clearly related to the decreasing of the hydrocarbon chain order parameter caused by heating. When MADs were produced in the absence of CU, no changes were detectable in diffraction profiles. The inner structure of MP and MCC remained indeed similar, the presence of CU only resulted in a larger unit cell. The negative curvature of the polar/apolar interface increases, probably due to the CU amphiphilic nature, leading to an increased hydration. SCLL for Naproxen Delivery We have recently evaluated different liposomal formulation as tools for percutaneous administration of naproxen (NP) [55]. Figure 8 reports cryo-TEM images of SCLL obtained by TLE (panels a–c) and by REV (panels d–f) methods. In particular, panels a and d refer to blank dispersions, while panels b, c, e, and f show NP containing dispersions, while SCL VET400 (vesicles extruded through 400 nm pore size polycarbonate membranes) are shown in Panel f.

Fig. 8 Cryo-transmission electron microscopy images of SCLL produced by TLE (panels a–c) and by REV (panels d–f). Panels a and d: dispersions produced in the absence of NP; Panels b, c, e, and f: dispersions produced in the presence of NP. Panel f shows SCL VET400 Page 17 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

In panels a and b are present both spherical vesicles and bigger irregular elongated nanoparticles. In panel b, the presence of dark spots confers a “marbled” aspect. These spots could be attributed to the drug, as similarly observed in the ubiquinone containing SLNs reported by other authors [5]. At this regard, it can be hypothesized that NP is partly encapsulated into nanoparticles, the differences in cryo-TEM appearance could be related to the different chemico-physical interaction of NP with vesicles and nanoparticles. The formation of nanoparticles could be attributable to the different composition of SCL with respect to PC/CHOL (ceramides, cholesteryl sulphate, and palmitic acid) that could result in different structures by TLE method. In the image reported in panel c, referring to the same sample of panel b, nanoparticles are absent. In the case of REV (panel d–f), a different procedure has been employed (e.g., ratio between the organic and the aqueous phases), nanoparticles are not detectable by cryo-TEM, while spherical and elongated multivesicular and multilamellar vesicles can be observed. In the case of SCL VET400 (panel f), concentric oligolamellar vesicles and unilamellar vesicles are noticeable. Both spherical and elongated unilamellar and multilamellar vesicles were obtained in the case of PC/CHOL liposomal dispersions containing NP and prepared by TLE and by REV protocols (data not shown). Any X-ray diffraction experiment resulted in up to three sharp small angle reflections, whose spacing ratios were measured. The lamellar lattice was evidenced in all the diffraction patterns, confirming a multilamellar structure in all samples. Furthermore, hydrocarbon chains are characterized by different conformation in the different samples, as indicated by the scattering in the wide-angle region. The diffuse scattering found in PC/CHOL samples suggests a disordered conformation of fluid lamellar phase type; conversely in the case of SCL samples, the rather narrow band observed in the wide-angle diffraction region suggests a more rigid (type b) conformation of hydrocarbon chains (Table 5).

Table 8 X-ray diffraction data of liposome dispersions collected at different temperatures Sample PC/CHOL, TLE

T = 25  C La

SCL, TLE

Lb

PC/CHOL, REV

La

SCL, REV

Lb

PC/CHOL/NP, TLE

La

SCL/NP, TLE

Lb

PC/CHOL/NP, REV

La

SCL/NP, REV

Lb

dlam = 51.5 Å TLEyc = 4.5 Å (b) dlam = 41.9 Å TLEyc = 4.39 Å (n) dlam = 51.5 Å TLEyc = 4.5 Å (b) dlam = 41.9 Å TLEyc = 4.39 Å (n) dlam = 51.4 Å TLEyc = 4.5 Å (b) dlam = 41.8 Å TLEyc = 4.39 (n) dlam = 51.5 Å TLEyc = 4.5 Å (b) dlam = 42.0 Å TLEyc = 4.39 Å (n)

T = 40  C La Lb La Lb La Lb La Lb

dlam = 48.8 Å TLEyc = 4.5 Å (b) dlam = 42.0 Å TLEyc = 4.39 Å (n) dlam = 48.8 Å TLEyc = 4.5 Å (b) dlam = 41.9 Å TLEyc = 4.39 Å (n) dlam = 48.7 Å TLEyc = 4.5 Å (b) dlam = 41.9 Å TLEyc = 4.39 Å (n) dlam = 48.8 Å TLEyc = 4.5 Å (b) dlam = 41.9 Å TLEyc = 4.39 Å (n)

dlam unit cell dimension (interlamellar distance); TLEyc packing distance between the hydrocarbon chains; b broad high angle scattering band; n narrow high angle scattering band; La or Lb indicates the final structure (experimental errors are  0.2 Å on dlam,  0.01 Å on TLE in the case of narrow peaks, and  0.05 Å on TLE in the case of the broad band) Page 18 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

In Table 8, a higher inter-lamellar distance for PC/CHOL obtained by TLE and REV methods (around 50 Å) than for SCL liposomes (around 40 Å) has been found. The presence of NP does not affect this distance. The wide angle data reveal that SCL liposomes are characterized by a rigid gel-like conformation of the hydrocarbon chain, while PC/CHOL liposomes show a liquid-like conformation. In this view, it is suggested that the two preparations have a different hydrational degree and in particular a lower amount of water between the lipid layers of SCL liposomes [70, 73]. At last one should observe the absence of extra X-ray diffraction, possibly due to the presence of the elongated nanoparticles found by cryo-TEM, in samples obtained by the TLE procedure. Nonetheless, the two considerations are not discordant, since the elongated particles are so broad that in the investigated Q-range no X-ray diffraction can be detectable.

Conclusions This chapter has illustrated the importance of X-ray diffraction and cryogenic TEM use in characterizing lipid nanosystems. Thanks to X-ray diffraction it was possible to understand the hydrocarbon chain conformation of BC containing SLN, discerning between lamellar or gel lattice. In the case of IND containing MAD, Bragg peaks have been observed, indicating a bicontinuous cubic phase, while a contemporary presence of micelles and vesicles was detected, due to the diffuse small angle diffraction. Moreover, it was possible to measure the radius of the aqueous channel in the cubic phases. With regard to CU-MAD, the different pattern of Bragg peaks allowed to recognize hexasome and cubosome presence in MAD alternatively stabilized by poloxamer or by Na cholate-Na caseinate mixture. In the case of NP containing liposomes, X-ray diffraction was essential since it enabled to identify different conformations of the hydrocarbon chain as a function of liposome composition, namely a gel-like conformation for SCL liposomes and a liquid-like one for PC-CHOL. The use of cryo-TEM allowed obtaining captivating images of nanoparticles, MAD, and liposomes. By this technique, it was possible to evidence the shape of nanoparticles from different planes of view as well as the lamellae presence and the nanoparticle dimensions. Moreover, the typical ordered cubic structures were clearly identified together with the diameter of the intercalating aqueous channel of cubosome. In the case of liposomes, the different types of vesicles were visualized together with the presence of nanoparticles in SCLL produced by TLE. Due to these advantages, X-ray diffraction and cryo-TEM techniques appear as prerequisite in the nanotechnology research field.

References 1. M. Adrian, J. Dubochet, J. Lepault, A.W. McDowall, Cryo-electron microscopy of viruses. Nature 308, 32–36 (1984) 2. M. Almgrem, K. Edwards, G. Karlsson, Cryo transmission electron microscopy of liposomes and related structures. Colloids Surf. A 174, 3–21 (2000) 3. J. Barauskas, M. Johnsson, F. Joabsson et al., Cubic phase nanoparticles (cubosome): principles for controlling size, structure, and stability. Langmuir 21, 2569–2577 (2005) 4. B.W. Barry, Drug delivery routes in skin: a novel approach. Adv. Drug Deliv. Rev. 54, S31–S40 (2002) Page 19 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

5. H. Bunjes, M. Drechsler, M.H.J. Koch et al., Incorporation of the model drug ubidecarenone into solid lipid nanoparticles. Pharm. Res. 18, 287–293 (2001) 6. H. Bunjes, T. Unruh, Characterization of lipid nanoparticles by differential scanning calorimetry, X-ray and neutron scattering. Adv. Drug Deliv. Rev. 59, 379–402 (2007) 7. L. Coderch, J. Fonollosa, M. de Pera et al., Influence of cholesterol on liposome fluidity by EPR. Relationship with percutaneous absorption. J. Control. Release 68, 85–95 (2000) 8. H. Cui, T.K. Hodgdon, E.W. Kaler, L. Abezgauz, D. Danino, M. Lubovsky, Y. Talmon, D.J. Pochan, Elucidating the assembled structure of amphiphiles in solution via cryogenic transmission electron microscopy. Soft. Matter. 3, 945–955 (2007) 9. G.M. Di Gregorio, P. Mariani, Rigidity and spontaneous curvature of lipidic monolayers in the presence of trehalose: a measurement in the DOPE inverted hexagonal phase. Eur. Biophys. J. 34, 67–81 (2005) 10. G.M. Di Gregorio, P. Ferraris, P. Mariani, Wetting properties of dioleoyl-phosphatidyl-choline bilayers in the presence of trehalose: an X-ray diffraction study. Chem. Phys. Lipids 163, 601–606 (2010) 11. A. Dingler, S.H. Gohla, Production of solid lipid nanoparticles (SLN): scaling up feasibilities. J. Microencapsul. 19, 11–18 (2002) 12. J.S. Dua, A.C. Rana, A.K. Bhandari, Liposome: methods of preparation and applications. Int. J. Pharm. Stud. Res 3, 14–20 (2012) 13. J. Dubochet, A.W. McDowall, Vitrification of pure water for electron microscopy. J. Microsc. 124, RP3–RP4 (1981) 14. J. Dubochet, J.-J. Chang, R. Freeman, J. Lepault, A.W. McDowall, Frozen aqueous suspensions. Ultramicroscopy 10, 55–62 (1982) 15. J. Dubochet, M. Adrian, J. Lepault, A.W. McDowall, Cryo-electron microscopy of vitrified biological specimens. Trends Biol. Sci. 10, 143–146 (1985) 16. J. Dubochet, M. Adrain, J.-J. Chang, J.-C. Homo, J. Lepault, A.W. McDowall, P. Schultz, Cryoelectron microscopy of vitrified soecimen. Quart. Rev. Biol. 21, 129–228 (1988) 17. J. Dubochet, Cryo-EM – the first thirty years. J. Microsc. 245(3), 221–224 (2012) 18. G.M.M. El Maghraby, A.C. Williams, B.W. Barry, Skin delivery of estradiol from deformable and traditional liposomes: mechanistic studies. J. Pharm. Pharmacol. 51, 1123–1134 (1999) 19. G.M.M. El Maghraby, B.W. Barry, A.C. Williams, Liposomes and skin: from drug delivery to model membranes. Eur. J. Pharm. Sci. 34, 203–222 (2008) 20. E. Esposito, N. Eblovi, S. Rasi et al., Lipid-based supramolecular systems for topical application: a preformulatory study. AAPS Pharm. Sci. 5(4), article 30 (2003) 21. E. Esposito, R. Cortesi, M. Drechsler et al., Cubosome dispersions as delivery systems for percutaneous administration of indomethacin. Pharm. Res. 22, 2163–2173 (2005) 22. E. Esposito, M. Fantin, M. Marti et al., Solid lipid nanoparticles as delivery systems for bromocriptine. Pharm. Res. 25(7), 1521–1530 (2008) 23. E. Esposito, P. Mariani, L. Ravani et al., Nanoparticulate lipid dispersions for bromocriptine delivery: characterization and in vivo study. Eur. J. Pharm. Biopharm. 80(2), 306–314 (2012) 24. H. Fernández-Morán, Low temperature preparation techniques for electron microscopy of biological specimens based on rapid freezing with liquid helium. II. Ann. N. Y. Acad. Sci. 56, 801–808 (1960) 25. M.J. Fresno Contreras, M.M. Jimenez Soriano, A. Ramirez Dieguez, In vitro percutaneous absorption of all-trans retinoic acid applied in free form or encapsulated in stratum corneum lipid liposomes. Int. J. Pharm. 297, 134–145 (2005) 26. A. Gulik, V. Luzzati, M. De Rosa et al., Structure and polymorphism of bipolar isopranyl ether lipids from archaebacteria. J. Mol. Biol. 182, 131–149 (1985) Page 20 of 23

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_39-1 # Springer International Publishing Switzerland 2015

27. J. Gustafsson, H. Ljusberg-Wharen, M. Almgrem et al., Cubic lipid-water phase dispersed into submicron particles. Langmuir 12, 4611–4613 (1996) 28. J. Gustafsson, H. Ljusberg-Wharen, M. Almgrem et al., Submicron particles of reversed lipid phases in water stabilized by a nonionic amphiphilic polymer. Langmuir 13, 6964–6971 (1997) 29. J.R. Harris, Negative Staining and Cryoelectron Microscopy (BIOS Scientific Publishers, Oxford, 1997) 30. T.E. Hutchinson, D.E. Johnson, A.P. Mackenzie, Instrumentation for direct observation of frozen hydrated specimens in the elctro microscope. Ultramicroscopy 3, 315–324 (1978) 31. E. Arnold, D.M. Himmel, M. G. Rossmann, Eds, International Tables for Crystallography, Volume F, 2nd Edition, Crystallography of Biological Macromolecules Dordrecht, Kluwer Academic Publishers, The Netherlands (2012). 32. V. Jenning, A. Lippacher, S.H. Gohla, Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenisation. J. Microencapsul. 19, 1–10 (2002) 33. K. Jores, W. Mehnert, M. Drechsler et al., Investigations on the structure of solid lipid nano-particles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J. Control. Release 95, 217–227 (2004) 34. J.S. Kim, H.K. Kim, H. Chung et al., Drug formulations that form a dispersed cubic phase when mixed with water. Proc. Int. Symp. Control. Rel. Bioact. Mater 27, 1118–1119 (2000) 35. L.F. Kourkoutis, J.M. Plitzko, W. Baumeister, Electron microscopy of biological materials at the nanometer scale. Annu. Rev. Mater. Res. 42, 33–58 (2012) 36. J. Kuntsche, J.C. Horst, H. Bunjes, Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems. Int. J. Pharm. 417, 120–137 (2011) 37. T. Landh, K. Larsson, Particles, method of preparing said particles and uses thereof. U.S. Patent 5,531,925 38. N. Lars, A.-A. Ashraf, Stratum corneum keratin structure, function, and formation: the cubic rod-packing and membrane templating model. J. Invest. Dermatol. 4, 715–732 (2004) 39. K. Larsson, Aqueous dispersion of cubic lipid-water phases. Curr. Opin. Colloid Interface Sci. 5, 64–69 (2000) 40. J. Lepault, F.P. Booj, J. Dubochet, Electronmicroscopy of frozen biological suspensions. J. Microsc. 129, 89–102 (1983) 41. J. Lepault, F. Pattus, N. Martin, Cryo-electron microscopy of artificial biological membranes. Biochim. Biophys. Acta 820, 315–318 (1985) 42. A. Lippacher, R.H. Muller, K. Mader, Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles. Int. J. Pharm. 214, 9–12 (2001) 43. V. Luzzati, X-ray diffraction studies of lipid-water systems, in Biological Membranes (Academic, New York, 1968) 44. V. Luzzati, R. Vargas, P. Mariani et al., Cubic phases of lipid-containing systems. Elements of a theory and biological connotations. J. Mol. Biol. 229, 540–551 (1993) 45. V. Luzzati, H. Delacroix, A. Gulik et al., The cubic phases of lipids, in Lipid Polymorphism and Membrane Properties, ed. by R.M. Epand. Current topics in membrane, vol. 44 (Academic, San Diego, 1997), pp. 3–24 46. P. Mariani, V. Luzzati, H. Delacroix, Cubic phases of lipid-containing systems. Structure analysis and biological implications. J. Mol. Biol. 204, 165–189 (1988) 47. W. Mehnert, K. Mader, Solid lipid nanoparticles: production, characterization and applications. Adv. Drug Deliv. Rev. 47, 165–196 (2001) 48. R.H. Muller, K. Mader, S. Gohla, Solid lipid nanoparticles (SLN) for controlled delivery-a review of the state of the art. Eur. J. Pharm. Biopharm. 50, 161–177 (2000) Page 21 of 23

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49. R.H. Muller, M. Radtke, S.A. Wissing, Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug. Deliv. Rev. 54, S131–S155 (2002) 50. M. Nakano, A. Sugita, H. Matsuoka et al., Small angle X-ray scattering and 13 C NMR investigation on the internal structure of cubosomes. Langmuir 17, 3917–3922 (2001) 51. J. Pardeike, A. Hommoss, R.H. M€ uller, Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. Int. J. Pharm. 366, 170–184 (2009) 52. J.W. Park, Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 4, 95–99 (2002) 53. M. Pisani, S. Bernstorff, C. Ferrero et al., Pressure induced cubic-to-cubic phase transition in monoolein hydrated system. J. Phys. Chem. B 105, 3109–3119 (2001) 54. C. Puglia, D. Trombetta, V. Venuti et al., Evaluation of in vivo topical anti-inflammatory activity of indomethacin from liposomal vesicles (LUV). J. Pharm. Pharmacol. 56, 1225–1232 (2004) 55. C. Puglia, F. Bonina, L. Rizza et al., Evaluation of percutaneous absorption of naproxen from different liposomal formulations. J. Pharm. Sci. 99, 2819–2829 (2010) 56. C. Puglia, V. Cardile, A.M. Panico et al., Evaluation of monooleine aqueous dispersions as tools for topical administration of curcumin: characterization, in vitro and ex-vivo studies. J. Pharm. Sci. 102, 2349–2361 (2013) 57. A.W. Robards, U.B. Sleytr, Low Temperature Methods in Biological Electron Microscopy (ElsevierScience Publishers B.V., Amsterdam, 1991) 58. J.M. Seddon, R.H. Templer, Polymorphism of lipid-water systems, in Handbook of Biological Physics, ed. by R. Lipowsky, E. Sackmann, vol. 1 (ElsevierScience Publishers B.V., Amsterdam, 1995) 59. J.C. Shah, Y. Sadhale, D.M. Chilukuri, Cubic phase gels as drug delivery systems. Adv. Drug Deliv. Rev. 47, 229–250 (2001) 60. A. Sharma, U.S. Sharma, Liposomes in drug delivery: progress and limitations. Int. J. Pharm. 154, 123–140 (1997) 61. B. Siekmann, K. Westesen, Submicron-sized parenteral carrier systems based on solid lipids. Pharm. Pharmacol. Lett. 1(3), 123–126 (1992) 62. B. Siekmann, H. Bunjes, M.H.J. Koch et al., Preparation and structural investigations of colloidal dispersions prepared from cubic monoglyceride-water phases. Int. J. Pharm. 244, 33–43 (2002) 63. P.T. Spicer, K.L. Hayden, Novel process for producing cubic liquid crystalline nanoparticles (cubosomes). Langmuir 17, 5748–5756 (2001) 64. F. Szoka, D. Papahadjopoulos, Comparative properties and methods of preparation of lipid vesicles (Liposomes). Annu. Rev. Biophys. Bioeng. 9, 467–508 (1980) 65. K.A. Tayler, R.M. Glaeser, Electron diffraction of frozen, hydrated protein crystals. Science 186, 1036–1037 (1974) 66. K.A. Taylor, R.M. Glaeser, Electron microscopy of frozen hydrated biological specimens. J. Ultrastruct. Res. 55, 448–456 (1978) 67. M.A. Tran, R.J. Watts, G.P. Robertson, Use of liposomes as drug delivery vehicles for treatment of melanoma. Pigment Cell Melanoma Res. 22(4), 388–399 (2009) 68. M. Trotta, E. Peira, F. Debernardi et al., Elastic liposomes for skin delivery of dipotassium glycyrrhizinate. Int. J. Pharm. 241, 319–327 (2002) 69. P.N.T. Unwin, The use of cryoelectron microscopy in elucidating molecular design and mechanisms. Ann. N. Y. Acad. Sci. 483, 1–4 (1986)

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70. K. Westesen, H. Bunjes, M.H.J. Koch, Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J. Control. Release 48, 223–236 (1997) 71. K.Westesen, M. Drechsler, H. Bunjes, Colloidal dispersions based on solid lipids, in Food Colloids. Special Publication 258 (London, Royal Society of Chemistry, 2004), pp. 103–115 72. K. Westesen, B. Siekmann, Biodegradable colloidal drug carrier systems based on solid lipids, in Microencapsulation, ed. by S. Benita (Marcel Dekker, New York, 1996), pp. 213–258 73. S.A. Wissing, R.H. Muller, L. Manthei et al., Structural characterization of Q10-loaded solid lipid nanoparticles by NMR spectroscopy. Pharm. Res. 21, 400–405 (2004) 74. G. Worle, M. Drechsler, M.H.J. Koch et al., Influence of composition and preparation parameters on the properties of aqueous monoolein dispersions. Int. J. Pharm. 329, 150–157 (2007) 75. A. Yaghmur, O. Glatter, Characterization and potential applications of nanostructured aqueous dispersions. Adv. Colloid Interface Sci. 147, 333–342 (2009) 76. P.L. Yeagle, The Structure of Biological Membranes, 2nd edn. (CRC Press, Boca Raton, 2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Nanoparticles as Nonviral Transfection Agents Nelisa T€ urkoğlu Laçin* and Kadriye Kızılbey Science and Technology Application and Research Center, Yıldız Technical University, Istanbul, Turkey

Abstract A series of studies have been carried out for delivery and controlled release of genes, miRNAs, peptide structures, siRNAs, and pharmacological agents to the target tissues through different nanoparticles. Agents to be delivered are either attached on or entrapped in nanoparticle structure. In the delivery process, the nanocarriers face many different delivery tasks and different physiological microenvironments. Considering the changes in the environment, nanocarriers are designed and synthesized in such a manner that enables these structures to overcome the challenges faced during delivery. In this chapter nanoparticle structures as cationic lipids, polycationic polymers, and dendrimers used in drug and gene delivery are reviewed.

Keywords Nanocarriers; Controlled release; Gene therapy

Introduction For medicine and healthcare, the ability to design and synthesize efficient drug delivery systems is very important. Progressions in drug delivery systems have been achieved by innovations in material chemistry, which produces biodegradable, environment-responsive, biocompatible, and targeted delivery systems, and in nanotechnology, which allows one to control the size, multi-functionality, and shape of particulate drug delivery systems [1]. Simple drug-containing capsule systems are not an effective way of drug delivery. An ideal drug delivery system has to release the drug at a steady and uniform rate. It is very hard to achieve required specifications for controlled drug delivery by adopting conventional formulations. Controlled drug delivery is the release of pharmaceutical compound from a material in accordance with the quantities required for the therapeutic effect. Various polymeric systems have been developed for the sustained release of the therapeutic agent in a controlled manner. Polymeric material used to prepare a drug carrier could be natural or synthetic. Various controlled drug delivery systems such as nanoparticles, microspheres, liposome-based systems, and drug–polymer conjugates have thus been developed. Nanoparticles are particles of less than 1 mm in diameter that are prepared from natural or synthetic polymers. Nanoparticles have ability to deliver a wide range of drugs to different regions of the body for sustained periods of time. A successful nanodelivery system should have a high drug-loading capacity, thereby reducing the quantity of matrix materials for administration. Drug solubility in the excipient

*Email: [email protected] Page 1 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

matrix material, which is solid polymer or liquid dispersion agent, determines drug-loading and entrapment efficiency. This depends on the matrix composition, drug–polymer interactions, molecular weights, and the presence of end functional groups such as ester or carboxyl in either the matrix or the drug [2–6]. When developing a nanoparticulate delivery system, drug release rate and polymer biodegradation are important components. In general, the determinants of drug release rate are as follows: (i) (ii) (iii) (iv) (v)

The solubility of the drug The desorption of the adsorbed drug The diffusion of the drug through the nanoparticle matrix The erosion or the degradation of the nanoparticle matrix The combination of erosion and diffusion processes

The five main factors above determine the release process of the drug from matrix. Drug release from nanosphere occurs by diffusion from the matrix or erosion of the matrix. The drug has to be uniformly distributed in the matrix. The drug release from the polymeric membrane is controlled by diffusion in the cases where the nanoparticle is coated by a polymer. Membrane coating acts as a drug release barrier; therefore, drug solubility and diffusion in or across the polymer membrane becomes a determining factor in drug release. The mechanism of release is largely controlled by a diffusion process where the diffusion of the drug is faster than matrix erosion. The rapid, initial release, or “burst,” is mainly attributed a state where the drug is weekly bound to the carrier. It is clear that the method of incorporation has an effect on the release profile. Additionally, the release rate can be affected by ionic interactions between the drug and auxiliary ingredients [6]. The current focus of research on nanoparticle drug delivery system is on selecting and combining carrier materials to achieve the optimum drug release speed, on modifying the surface of nanoparticles in order to improve their targeting capability, on preparing nanoparticles in ways that will increase their drug delivery ability in clinical applications, and on investigating in vivo processes to shed light on how nanoparticles interact with blood, targeting tissues and organs, and so on. Polymeric materials used for preparing nanoparticles for drug delivery must be biocompatible at its best and nontoxic at the very least [7]. The purity of natural polymers varies and they often need cross-linking, which can denature the embedded drug. Consequently, synthetic polymers have been used significantly more in this field. The polymers most widely used for nanoparticles are poly(lactic acid) (PLA), poly (glycolic acid) (PGA), and their copolymers, poly(lactide-co-glycolide) (PLGA), chitosan, solid lipids, liposomes, block copolymers, poly(ethylene glycol), polycaprolactone, polycyanoacrylate, dextran, polyL-lysine, silica, gelatin, etc. Nanoparticles are solid colloidal particles. Based on the preparation process, two types of nanoparticles exist: nanospheres that have a monolithic-type structure in which drugs are dispersed or adsorbed onto their surfaces and nanocapsules that have a membrane-wall structure, which entraps the drugs in the core or adsorbs them onto their exterior. Usually the nanocapsules contain an outer surfactant adsorption layer. Polyalkylcyanoacrylates and polylactides are some of the polymers used for the outer coating. The term “nanoparticles” is adopted because it is often very difficult to unambiguously establish whether these particles are of a matrix or a membrane type [8]. The most important goal in the controlled drug delivery is to increase therapeutic effect and minimize side effects. Ongoing researches are based on the tissue or cellselective targeting of drugs which can be achieved by delivering the drug to the target area of the body. Over the past few decades, there has been considerable interest in developing polymeric nanoparticles for targeted delivery of pharmaceutical compounds, gene peptide structures, siRNAs, etc. Naturally, researches to improve already the existing drug delivery systems or to invent novel and more effective controlled drug delivery ones are still going on. Page 2 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Gene therapy is the transfer of genetic material into specific cells of a patient in order to correct or supplement defective genes responsible for the development of the disease. Transferring genetic material into the target cell is maintained by using two major vectors: viral and nonviral. Viral vectors are also called biological nanoparticles. However, disadvantages of viral vectors such as immunogenic/inflammatory responses, low loading capacity, large-scale manufacturing, and quality control have limited their application in gene delivery. In contrast to viral vectors, nonviral vectors have several advantages, such as ease of synthesis, cell/tissue targeting, low immune response, and unrestricted plasmid size [9, 10]. In general, transfection efficiency and gene expression levels of nonviral vectors are low compared to viral vectors. In recent years, newly developed nonviral methods adopted in vector technology have yielded nonviral vectors whose transfection efficiencies are similar to those of viral vectors. Consequently, the advantages stated above resulted in the use of nonviral vectors such as liposomes (lipoplexes), polycationic polymers (polyplexes), and organic or inorganic nanoparticles (nanoplexes) in the ongoing researches on the matter.

The Importance of Polycationic Vectors in Gene Therapy Cationic phospholipids and cationic polymers are the two major types of nonviral gene delivery vectors currently being investigated. Polycationic vectors are indispensible for delivering therapeutic agents/ genetic materials to target tissue. In gene therapy, plasmid DNA is introduced to the target cell and expresses the therapeutic proteins. Dissimilarly, in antisense therapy, oligonucleotides are used to suppress the expression of a disease-causing gene. In the event of in-cell transfection, the naked plasmid can only exceed a trace amount of cell membrane. Cationic polymers have become increasingly popular among nonviral vectors due to their ability to easily form polyelectrolyte complexes between plasmid DNA and cationic polymers. Moreover, they protect DNA from enzymatic degradation, facilitate transfection by condensing DNA into nanoparticles, and ease cell uptake and endolysosomal escape [11]. An ideal carrier system should be biocompatible and non-immunogenic. Nowadays, studies focus on how to reduce the toxicity while increasing the transfection efficiency of polycationic carriers. For an effective transfection of a genetic material, nanoparticle has to compact genetic material and the complex has to migrate through the blood circulation which is expected to arrive at the target tissue without any harm.

Importance of Particle Size and Surface Charge During Its Travel Through the travel, vector has to prevent genetic material from getting degradated and prevent interactions by the reticuloendothelial system (RES) components, enter the cell via endocytosis, and deliver genetic material to the nucleus (Fig. 1). Escape from RES depends on three main factors: particle size, particle charge, and surface hydrophobicity. In drug delivery applications, size of the particulate is important for treatment efficacy. Macro size has important drawbacks compared to nanosize in biomedical applications. Conventional micron-sized drug delivery techniques in cancer therapy carry the following disadvantages: delivery inefficiency, toxic effects on health, and impaired transport to tumor sites. Yet, delivery vehicles that are micron sized (mm) are not able to passively traverse through cells and cell pores, including tumor cells with pore sizes as large as 380–780 nm. Consequently, nanodelivery would be the ideal system for biological applications [12, 13].

Page 3 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Fig. 1 Schematic representation of gene delivery by polycationic nanoparticles

The submicron size of nanoparticles offers a number of distinct advantages over microparticles. Cell uptake efficiency of nanoparticles is relatively higher in comparison with microparticles. The cell uptake efficiency of 100 nm sized particles has been 15–250-fold higher than larger-sized microparticles [14]. The approaches to modify surface charge and hydrophilicity are initially based on the adsorption of hydrophilic surfactants, such as block copolymers of the poloxamer and poloxamine series. Size, surface charge, and chemistry of nanoparticles affect their clearance by the RES. In general, nature and concentration of the surfactant play an important role in determining the particle size, as well as the surface charge. PEGylation of a carrier system (usage of PEG for surface modification) makes system invisible against RES. PEG contains the terminal primary hydroxyl groups suitable for derivatization. Polyethylene glycol (PEG) is nontoxic, non-immunogenic, nonantigenic, and highly soluble in water, thanks to these favorable properties that have been approved by the FDA for human use. PEG is a highly preferred polymer in drug delivery systems due to its ease of preparation, relatively low cost, and controllable molecular weight. Looking at in vitro particle internalization by transmission electron microscopy reveals that unmodified polyplexes enter the cells as large aggregates, whereas PEGylated particles stay small and discrete both within and outside the cells. Unmodified and PEGylated particles enter cells via the endocytic pathway, and they assemble in a perinuclear region. Immunolabeling shows unpackaged exogenous DNA in the nuclei and the cytoplasm. All particle types seem to travel toward the nucleus in vesicles and undergo degradation in vesicles and/or the cytoplasm. Then eventually some exogenous DNA enters the nucleus, where it is transcribed. Polyplexes and their PEGylated variants are significantly different in their cellular uptake, particle morphology, and resultant expression [15]. PLA, PLG, or poly(caprolactone) nanospheres coated with PEG are suitable to use for intravenous drug delivery. PEG and PEO are essentially identical polymers used for the same purpose. Their only difference is that PEO’s methoxy groups may replace PEG’s terminal hydroxyls. The PEG coating of

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

the nanospheres protects against interaction with blood components and removes foreign particles from the blood. Due to the safety and stability of the hydrophilic coat, the use of diblock copolymers made of poly (lactic acid) (PLA) and poly(ethylene oxide) (PEO) is widely accepted. To achieve this purpose, the copolymer is dissolved in an organic solvent and is then emulsified in an external aqueous phase to orient the PEO toward the aqueous surrounding medium. In a different method, the PLA–PEO copolymer is adsorbed onto preformed PLGA nanoparticles. This was found to effectively prolong the nanosphere circulation time after following intravenous administration. In a study, the poly(lactide-co-glycolide) nanoparticles coated with a 5–10 nm thick layer of polypropylene (PPO)–PEO block copolymer or with tetrafunctional (PEO–PPO)2–N-CH2-CH2-N–(PPO–PEO)2 have been prepared by nanoprecipitation technique. The result is that PEO chains have formed a steric barrier which hinders the adsorption of certain plasma proteins onto the surface, and the PEO-coated nanospheres have not been recognized by macrophages as foreign bodies and are not attacked by them. Recently, by adopting recombinant DNA techniques, many proteins were produced in large quantities, and these have become important new drugs. Protein drugs have certain disadvantages such as susceptibility to degradation by proteases, low solubility, short circulating half-life in vivo, rapid kidney clearance, and propensity to generate neutralizing antibodies, which may limit their usefulness. Thus, extensive research has been conducted in recent years to overcome these inherent problems of protein drugs. Scientists investigated different strategies to enhance the clinical properties of proteins, which include changing amino acid sequencing via protein engineering techniques in order to decrease proteolytic degradation and antigenic side effects, producing chimeric protein drugs fused to albumin in order to improve half-life or incorporation into appropriate drug delivery vehicles. Among these strategies, nowadays surface modification of protein drugs via covalent attachment of poly(ethylene glycol) (PEG) is viewed as a very important technique that makes protein drugs more water soluble, non-aggregating, non-immunogenic, and more stable to proteolytic digestion [16].

Biodegradability of a Vector Is an Important Feature Biodegradable polymers have enjoyed significant interest in the past few decades especially for applications in drug delivery. Biodegradability of a polymeric vesicle is an important feature in order to release drugs or bioactive agents in a controllable manner. A variety of biodegradable polymers have been used to deliver drugs, macromolecules, cells, and enzymes. The important feature of these polymers is the manipulation of biodegradability. Poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) have been the most extensively investigated polymeric structures for drug and biomolecule delivery. Poly(D,L-lactic-co-glycolic acid) is the most commonly used structure thanks to its biodegradable feature and metabolizable decay products, which make it far more preferable in comparison with other structures. PLGA is approved by FDA for therapeutic use in humans. Release of drugs from such structures occurs by controlled biological degradation of polymeric structure or diffusion-controlled mechanism. One can adjust the size of PLGA particles by modifying the chemical composition as well as the method of fabrication. The rate of drug release from PLGA NPs can be controlled by changing the molecular weight of PLA, which determines the rate by which the vesicle degrades [17]. PLGA nanoparticles are generally formulated by using emulsion solvent evaporation or solvent displacement techniques [18]. For example, pDNA (alkaline phosphatase, AP, a reporter gene) has been encapsulated in submicron-sized poly(D,L-lactide-co-glycolide) particles. Transfection efficiency of pDNA–NP has resulted in significantly higher in comparison to naked pDNA, in vitro. Additionally, a sustained release of pDNA has been observed for a month [19]. In those years, Labhasetwar et al. have Page 5 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

prepared nanoparticles containing bovine serum albumin (BSA) as a model protein and 6-coumarin as a fluorescent marker by a double-emulsion/solvent evaporation technique and observed the endocytosis, exocytosis, and intracellular retention of poly(D,L-lactide-co-glycolide) nanoparticles in vitro. They have observed the model protein carried along with nanoparticles inside the cells [20]. In subsequent studies, the rapid endolysosomal escape of the PLGA nanoparticle carrier has been demonstrated. It has also been suggested that endolysosomal escape of these NPs occurs thanks to their selective surface charge reversal in the acidic endolysosomes. Additionally, NPs deliver their cargo in the cytoplasm at a slow rate, leading to a sustained therapeutic effect [21]. Biodegradable PLGA–PEG–PLGA triblock copolymer systems have been developed by researchers for nonviral gene transfection in vitro and in vivo [22, 23]. Another study to control blood glucose has been performed by encapsulation of the incretin hormone glucagonlike peptide (GLP-1) into biodegradable triblock copolymer of PLGA–PEG–PLGA (Choi et al. 2004). Besides, many pharmaceutical agents such as 9-nitrocamptothecin, paclitaxel, cisplatin, dexamethasone, triptorelin, and insulin have been entrapped into PLGA nanoparticles for several therapeutic purposes [24–27]. The PLA–PEG and PLGA–PEG are especially useful for encapsulation of hydrophobic drugs. They have also been investigated for the intravenous and mucosal delivery of proteins, oligonucleotides, and genes. All results have proved to be encouraging [28]. For the inhibition of restenosis and to decrease intimal hyperplasia, anti-MCP-1 plasmid-encapsulated PLGA NPs synthesized by double-emulsion/solvent evaporation technology were used, and it has been observed that NPs have a steady in vitro release of 95 % of the total enclosed DNA within 30 days and a significant decrease in intimal hyperplasia [29]. In recent years, a new modified nanoprecipitation method was suggested to fabricate DNA-loaded PLGA nanoparticles instead of the conventional doubleemulsion/solvent evaporation method [30]. Semete et al. have conducted an in vitro cytotoxicity study to assess the cell viability following exposure to PLGA nanoparticles. Greater than 75 % cell viability has been observed for PLGA nanoparticles. The extent of tissue distribution and retention following oral administration of PLGA particles have shown that the particles remain detectable in the brain, heart, kidney, liver, lungs, and spleen after 7 days of the issue. 40.04 % of the particles have been localized in the liver, 25.97 % in the kidney, and 12.86 % in the brain. The lowest percentage of PLGA nanoparticles has been observed in the spleen, and they have suggested that toxic effects observed with various industrial nanoparticles will not be observed with PLGA nanoparticles [31]. Some of the examples for PLGA-based polycationic nanoparticles for drug and biomolecule delivery are given in Table 1.

Targeted Drug Delivery There are different modes of drug administration such as oral, nasal, transdermal, intra venal, etc., in drug delivery applications. Oral and nasal delivery result in high drug levels in the blood and have poor release profiles. Aerosol design is complex and problematic about loading issues. Transdermal delivery does not have targeting and damages healthy cells as well. These shortcomings resulted in the development of targeted drug delivery as a means of overcoming the delivery problems [32]. In targeted delivery approach, targeting molecules are attached to the surface of vectors so that the vectors travel to the target tissue selectively. Targeting and reduced clearance of nanocarrier lowers the therapeutic agent amount required for the treatment of disease. Targeted delivery occurs by either passive or active targeting. Passive targeting results from extravasation of nanoparticles at the disease site with leaky microvasculature. Tumors and inflamed tissues are examples of diseases where passive targeting of nanocarriers can be achieved. In order for the passive targeting to succeed, the nanocarriers should Page 6 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Table 1 Poly(DL-lactide-co-glycolide) (PLGA)-based biodegradable polycationic nanoparticles for drug and biomolecule delivery Polymeric materials PLGA PLGA

Agent pDNA Dexamethasone

Usage Model Antiproliferative

PLGA Biodegradable triblock copolymer (PEG–PLGA–PEG) (PLGA) nanosphere

pDNA pDNA

Model Model

Target cells NIH 3T3 cells Human arterial smooth muscle cells (HASMCs) (Prostate cancer) PC3 cells HEK 293 cells

Pigment epitheliumderived factor (PEDF) pDNA

Antiproliferative

Ocular transport

Model

Skin wound, in vivo

Glucagon-like peptide (GLP-1)

To control blood glucose level

Zucker diabetic fatty rats In vitro, In vivo

Pigment epitheliumderived factor (PEDF) 9-nitrocamptothecin

Antitumor agent (antiproliferative) Anticancer drug

Ocular transport In vitro drug release

Antitumoral activity Anticancer drug Anticancer agent

NCI-H69 cell line In vitro Drug encapsulation

PLGA–mPEG nanoparticles PLGA nanoparticles (PLGA–mPEG) nanoparticles

Paclitaxel Dexamethasone Triptorelin Peptide delivery Cisplatin Insulin Cisplatin

Anticancer agents To reduce blood glucose level Antitumoral

(PLGA–mPEG) nanoparticles

Cisplatin

Antitumoral

PLGA NPs

Inhibition of restenosis

PLGA NPs

Anti-MCP-1 (antisense) Gene delivery

In vivo BALB/c mice In vivo LNCaP prostate cancer cells Adenocarcinoma HT29 cells Smooth muscle cell (SMC) In vivo

PLGA NPs

VEGF

Biodegradable triblock copolymer (PEG–PLGA–PEG) Biodegradable triblock copolymer (PLGA–PEG–PLGA) PLGA nanosphere Poly(ethylene glycol)-modified PLGA (PLGA–PEG) NPs PLGA nanoparticles PLGA nanoparticles PLGA nanospheres

For the treatment of atherosclerotic cardiovascular disease Myocardial infarction

Rabbit

circulate in the blood for an extended time for the nanocarriers to have multiple possibilities to pass through the target site. Due to the body’s natural defense mechanisms that work to eliminate nanoparticles after opsonization by the mononuclear phagocytic system, nanoparticles usually have short circulation half-lives. Localized diseases such as inflammation or cancer have leaky vasculature and overexpress some epitopes or receptors that can be used as targets. Thus, nanomedicines may also be actively targeted to these sites. Ligands specifically binding to surface epitopes or receptors that are preferentially overexpressed at target sites have been coupled to the surface of long-circulating nanocarriers (Koo et al. 2005). Targeting of a drug may be provided through two different approaches: direct targeting method and pretargeting multistep method. In direct targeting approach, the targeting ligand is attached onto the nanoparticles. In the pretargeting approach, the ligand, intended to be concentrated and localized in the target tissue, is administered before the administration of drug-loaded carrier. Page 7 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Popular targeting molecules are monoclonal antibodies (mAb) and their fragments, folate, transferrin, avidin–biotin, RGD(Arg-Gly-Asp) peptide, IKVAV, cell adhesion molecules (E-selectin, ICAM-1, VCAM-1,and P-selectin), etc. In the avidin–biotin targeting system, targeting of drug/biomolecule is maintained at three steps. Firstly, biotinylated targeting ligands are sent to target tissue, after which avidin administration is performed. Finally, biotinylated drug-loaded nanoparticles are administrated (Breitz et al. 1999; Cremonesi et al. 1999; Knox et al. 2000). MMP-2 is one of the enzymes in MMP family and is essential for angiogenesis. MT1–MMP is linked to metastasis and angiogenesis and is observed to be expressed on endothelial cells and certain types of tumor cells, which include malignancies of lung, gastric, colon, breast, and cervical carcinomas, gliomas, and melanomas. One of the main targets of MMP is the membrane type-1 matrix metalloproteinase (MT1–MMP), which is an activator of MMP-2 [33]. For example, anti-HER2 (trastuzumab, Herceptin) and anti-CD20 (rituximab, Mabthera) have been conjugated to poly(lactic acid) nanoparticles. Cell uptake efficiency of nanoparticles with targeting molecules has increased sixfold compared to nanoparticles without targeting molecules (Nobs et al. 2006). In another study, Chung et al. have encapsulated tissue-plasminogen activator (t-PA) into CS-GRGD-coated PLGA of nanoparticles to accelerate thrombolysis (Chung et al. 2008). In cancer treatments, anticancer drug carriers have to deliver the drug to the target tissue at prolonged times and required rates in a controlled manner. Combination of controlled-release systems with targeted drug delivery systems provides more efficient delivery of the nanocarriers in cancer therapy. Conventional chemotherapeutic agents get nonspecifically distributed in the body, where they influence cancerous and normal cells. This limits the dose that can be achieved within a tumor and results in a suboptimal treatment because of excessive toxicities. In order to overcome the conventional chemotherapeutic agents’ lack of specificity, one approach that has emerged is molecularly targeted therapy [34]. In recent years, chemotherapeutic agent loaded in nanoparticles is targeted to improve their therapeutic efficiency and functionality in cancer treatments. The targeting scheme for the avb3 integrin focused on the three amino acid sequence arginine–glycine–aspartic acid (RGD). The avb3 integrin is an endothelial cell receptor for extracellular matrix (ECM) proteins that harbor the RGD sequence, which contains von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, osteopontin, and fibronectin [35]. Signals from receptors for growth factors and ECM molecules regulate angiogenesis. For instance, integrin avb3 inhibition during bFGF stimulation suppresses the sustained phase of extracellular signal-related kinase (ERK) signaling, which leads to endothelial apoptosis and inhibition of angiogenesis. Despite the fact that anti-avb3 blocks bFGFmediated angiogenesis, anti-avb5 disrupts VEGF-induced angiogenesis, showing that distinct signaling pathways regulate angiogenesis. Hood et al. have emphasized avb3 targeting by an RGD non-peptide mimetic coupled to a nanoparticle for anti-angiogenesis therapies [36]. Another example of targeted drug delivery in cancer treatment is the folate-conjugated PEG-co-poly (lactic-co-glycolic acid) (PEG–PLGA) micelles loaded with the anticancer drug doxorubicin, which express folate on the micelle surface. Increased cytotoxicity and decreased tumor growth for folateconjugated micelles have been reported compared to nontargeted micelles and free DOX [37]. A different example for active targeting of a nanoparticle is RNA A10 aptamers specific for the prostrate-specific membrane antigen. Compared to nontargeting NPs, these have been successfully conjugated onto PLA-block-PEG polymers and showed increased drug delivery to prostate tumor cells [38].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Blood Brain Barrier The blood–brain barrier (BBB) is one of the hard-to-pass barriers for drugs such as anticancer agents, antibiotics, peptides, oligo-molecules, and macromolecules. This is due to the presence of “tight junctions between the endothelial cell linings in the brain blood vessels.” Nanoparticles seem to be an attractive solution to overcome the BBB. The size and surface modification/functionalization enable the transport of nanodelivery vehicles across the BBB. Yet, there is a widely speculated possibility of unintended intrusion into the brain via the BBB, and thus high selectivity is critical for any BBB uptake in order to avoid unwelcome particles. One successful drug delivery system to the brain uses nanoparticles coated with polysorbate 80. Nanoparticles of drug vehicles coated with polysorbate 80 result in better uptake across the BBB. Notably, during the delivery of doxorubicin, the drug delivery was more efficient with the polysorbate-coated nanoparticles compared with the non-coated nanoparticles [39].

Smart Polymers Respond Microenvironmental Changes Smart polymers are known to be stimulus-responsive, intelligent polymers or environmentally sensitive polymers. They have become an important class of polymers and have a significantly increasing application [40]. In the body, some environmental variables, such as pH, temperature, ionic strength, etc., are found. The characteristic special property that actually makes them “intelligent” is their ability to respond to the changes in the surrounding environment. The lower critical solution temperature (LCST) is the critical temperature that the polymers are soluble in a solvent (water) at temperatures below LCST but which become insoluble as the temperature rises above the LCST. The LCST behavior of a copolymeric structure depends on the monomer ratios, polymer degree of polymerization, composition, and branching of the polymer. Poly(N-alkyl-substituted acrylamides) and poly(N-vinylalkylamides) are the common thermosensitive polymers with LCST of 32  C and 32–35  C, respectively. As an example: Chung et al. have designed thermoresponsive polymeric micelles comprising AB block copolymers of PIPAAm (poly (N-isopropylacrylamide)) blocks and PBMA (poly(butyl methacrylate)) or PSt (polystyrene) blocks that are able to encapsulate adriamycin, which is a hydrophobic drug. PIPAAm-PBMA micelles were observed to release the drug only above the reversible thermoresponsive phase transition of PIPAAm. [41]

pH-responsive polymers respond to the pH changes in the microenvironment by changing their dimensions. Depending on the pH of the environment, pH-responsive polymers become soluble or collapse. This is due to the existence of certain functional groups in the polymer chain. Protonation/ deprotonation takes place depending on the presence of ionizable functional groups (–COOH, –NH) in certain pH. pH-sensitive polymer’s pH-induced phase transition usually switches within 0.2–0.3 unit of pH and tends to be very sharp. Copolymers of methyl methacrylate and methacrylic acid go through a sharp conformational transition and collapse at low pH, around 5. Copolymers of methyl methacrylate with dimethylaminoethyl methacrylate are soluble at low pH, but they collapse and aggregate in slightly alkaline conditions [40]. For example, exendin-4 (an insulinotropic agent) incorporated pH-sensitive nanoparticle vehicles that have been developed to administrate this agent in the small intestine. The pH-sensitive nanoparticle vehicles have been designed to stay intact in the stomach and then dissolve in the small intestine. The system has exhibited a prolonged glucose-lowering effect [42].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Tumor Microenvironment It is common for cancer cells to display increased aerobic glycolysis. Biological adaptation to metabolic changes due to mitochondrial dysfunction, hypoxia, and oncogenic signals makes the malignant cells addicted to glycolysis and dependent on this ATP generation pathway. These changes in the energy metabolism and the following increased glycolytic enzyme expression and other pro-survival molecules give the cancer cells an advantage in surviving. Moreover, lactate accumulation due to increased glycolysis results in an acidic tumor microenvironment, which provides a tissue environment that selects the cancer cells that have high survival capacity and malignant behaviors. These biological modifications cause important problems in cancer treatment, evidenced by the cancer cells in hypoxic environment becoming resistant to chemotherapeutic agents and radiation therapy. Yet, the growing dependency of cancer cells on glycolysis to generate energy also presents a biological mechanism to preferentially kill the malignant cells through inhibiting glycolysis. According to strong evidence from recent studies, cancer cells with mitochondrial defects or that are under hypoxia are highly sensitive to glycolysis inhibition. It has been found that several glycolytic inhibitors have promising anticancer activity in vitro and in vivo, and some of them have begun to be tested in clinical trials [43]. There are some improved systems that combine two stimulus-responsive mechanisms into one polymer system such as temperature-sensitive polymers which also responds to pH changes. For example, Zhang et al. have prepared a thermo- and pH dual-responsive nanoparticle, which encapsulates an anticancer drug (paclitaxel) that was assembled from a diblock copolymer comprised of a hydrophilic poly(N-isopropylacrylamide-co-acrylic acid) block and a hydrophobic polycaprolactone block. Nanoparticles aggregated in a pH of 6.9 at body temperature. It has been found that faster drug release was associated with higher temperature and lower pH. Both of these conditions are advantageous for tumor-targeted anticancer drug delivery [44]. Another approach is the development of multidrug-loaded nanoparticles against drug-resistant cancers. Advances in nanoparticle-based combination strategies against clinical cancer drug resistance were reached through the co-encapsulation of drugs with differing physicochemical characteristics, organizing ratiometric control over drug loading and temporal sequencing of drug release. These new strategies lead the way for better-tailored combinatorial solutions for clinical cancer treatment [45]. The following studies are some of the examples for stimulus-responsive drug delivery: Brown et al. have prepared doxorubicin-loaded nanoparticles, formulated by nanoprecipitation of acidended poly(lactic-co-glycolic acid) and have achieved the controlled release of doxorubicin in a pH-dependent manner to breast cancer cells (Betancourt et al. 2007). Also, via the copolymerization of NIPAAm and DMAEMA, with Ce4+ ions and tris(hydroxymethyl)methylamine as a redox initiator system, an amphiphilic star block consisting of a hydrophobic PMMA block and a hydrophilic tri-arm poly(NIPAAm-co-DMAEMA) was synthesized. The star copolymer goes through self-assembly to the micellar nanoparticles with a core–shell structure and the thermo-/pH dual response, resulting from the thermosensitivity of PNIPAAm and the pH sensitivity of PDMAEMA [46]. Poly(ethylene oxide)modified poly(b-amino ester) nanoparticles for tumor-targeted delivery of hydrophobic drugs have been developed as a pH-sensitive system [47]. Acid-sensitive dexamethasone-loaded polyketal nanoparticles in diameter between 200 and 600 nm have been designed as a delivery system to tumors, inflammatory tissues, and phagosomes. Nanoparticles were produced from poly(1,4-phenyleneacetone dimethylene ketal) (PPADK), which is a new hydrophobic polymer containing ketal linkages in its backbone. The polyketal nanoparticles go through acid-catalyzed hydrolysis to become low-molecularweight hydrophilic compounds, thus releasing the therapeutics encapsulated in them at a faster rate in acidic environments [48]. Page 10 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

Lin et al. have developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo. L1 (1,5-dihexadecyl N-glutamylL-glutamate) and L2 (1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate) are the glutamic acid-based lipids which are used in liposomal drug delivery systems as the pH-responsive pieces of the vehicle that should give a response to endosomal PH. Application of pH-responsive liposomes has indicated efficient intracellular drug delivery by the L1and L2-containing liposomes and higher DOX toxicity toward HeLa cells in comparison with conventional DPPC liposomes [49].

Liposome or Lipid-Based Nanoparticles in Drug/Gene Delivery The drug delivery system has seen much progress from the design and synthesis of different biocompatible materials. For clinical application, liposome has been the most successful candidate. Most DDS that are approved by the FDA are lipid based or liposome. Liposomes are shown to be useful for the delivery of pharmaceutical agents. “Contact-facilitated drug delivery” that is used by these systems involves binding or interaction with the targeted cell membrane. Such nanosystems can serve as drug depots exhibiting prolonged release kinetics and long persistence at the target site [6]. Liposomes are small, artificial, spherical vesicles that self-associate into bilayers in order to encapsulate genes, drugs, and other biomolecules on aqueous interior. They are composed of nontoxic phospholipids and cholesterol. Liposomes vary in size 25 nm to 10 mm, depending on the method of their preparation. Currently, certain therapeutic agent-loaded liposomes are in the process of being tested comprehensively for targeted delivery against cancers. Liposomes that have certain sizes, typical instance being less than 400 nm, can quickly infiltrate tumor sites from the blood. Yet, they are kept in the bloodstream by the endothelial wall in healthy tissue vasculature. In order to have effective therapeutic concentrations at the tumor site, liposomes are perforated through nanovasculature. These are able to restrict and/or decrease certain common side effects such as headache, nausea, vomiting, and hair loss. Several types of nanoscale liposomes have been widely used in treatments for cancer (Tangri). Size is an important factor in determining the efficiency of targeting and the associated therapeutic effects of liposomes. It has been shown that size determines the efficacy of therapy, liposomal accumulation in tumor site, cross-vessel permeation, level of toxicity, and overall transport in the body. Moreover, the smaller the size, the better the extent of targeting and therapy efficacy. This can be associated with the drug amount that reaches the site of the tumor. Liposomes that are 100 nm in size and below have shown better targeting and accumulation in the tumor site [50]. Due to the aggregations of liposomes in the presence of plasma proteins and the rapid clearance of liposomes from the bloodstream via the reticuloendothelial system (RES), the in vivo application of liposomes through intravascular injection is limited. In order to avoid detection of the RES, “stealth” or long-circulating liposomes have been designed. This kind of lipid-based drug carriers for in vivo delivery is prepared by using cholesterol, amphiphilic stabilizers, or phosphatidylinositol. Grafting polyethylene glycol (PEG) chains on the liposome surface to make a hydrophilic surface is another approach. These liposomes that are sterically stabilized serve as long-circulating drug reservoirs, and they allow drug targeting to non-RES target sites. In order to achieve specific tissue targeting, ligands such as antibodies can be conjugated to the PEG chains that are on PEG-stabilized liposomes [35]. Some examples for the current liposomal formulations are PEGylated liposomal doxorubicin (Doxil R Ortho Biotech, Caelyx(R) Schering-Plough), non-PEGylated doxorubicin (Myocet R Elan Pharma), and liposomal daunorubicin (DaunoXome R, Gilead Sciences). Not only these approved agents but also many liposomal chemotherapeutics are presently in the process of evaluation in clinical trials. The Page 11 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

upcoming liposomal drug generation could be immunoliposomes that may selectively transport the drug to the desired locations. Wang et al. have developed the folate–PEG-coated polymeric liposome that combines both advantages of polymer nanoparticles and liposomes [36]. Surface-functionalized target liposomes are presently being investigated, and it is hoped that the targeted systems could further ameliorate these drug delivery systems’ efficacy and safety qualities. Using liposomal drug delivery systems in combination with the polymeric systems will result in prolonged and more selective drug delivery [51]. Currently, several kinds of cancer drugs have been applied to these lipid-based systems using a variety of preparation methods. Below are some examples for the subject; Chen et al. have developed a FGFRmediated drug delivery system in order to target the FGFR-overexpressed tumor cells with chemotherapeutic agents. Using electrostatic force, they linked a shortened truncated human basic fibroblast growth factor (tbFGF) peptide to the surface of cationic liposomal doxorubicin (LPs–DOX) and paclitaxel (LPs–PTX) [33]. Similarly, Banerjee et al. have designed anisamide-targeted doxorubicin-loaded stealth liposomes for targeted drug delivery to human prostate cancer cells. It is shown that some human malignancies, such as prostate cancer, overexpress sigma receptor. Sigma receptor is a membrane-bound protein, which binds haloperidol and various other neuroleptics with high affinity. When a polyethylene glycol phospholipid was derivatized with an anisamide ligand and was put into the DOX-loaded liposome, this resulting anisamide-conjugated liposomal DOX had significantly higher toxicity for DU-145 cells than the nontargeted liposomal DOX [52]. Cationic lipids are also used for gene therapy. DNA/lipid complexes formed by the interaction of positively charged lipids at the physiological pH with the negatively charged DNA through electrostatic attractions. Cationic lipids used for gene therapy are composed of three basic domains: a positive-charged headgroup, a hydrophobic chain, and a linker which joins the polar and nonpolar regions. The polar and hydrophobic domains of cationic lipids may have dramatic effects on both transfection and toxicity levels. The stability and particle size of these delivery vesicles partly determine their transfection efficiency in vitro. Yet, these liposomes or DNA/lipid complexes frequently show decreased efficiency of transfection in vivo. In general, overcharging is toxic to a variety of cell types, different reagents have varying toxicity degrees for cells, and toxicity is cell specific [53]. There are also liposome-based systems developed for the delivery of nucleic acid-based therapeutics such as antisense, aptamers, and RNAi molecules.

Polysaccharide-Based Nanoparticles as Drug Delivery Systems Polysaccharides, the polymers of monosaccharides, have various resources of algal origin (e.g., alginate), plant origin (e.g., pectin, guar gum), microbial origin (e.g., dextran, xanthan gum), and animal origin (chitosan, chondroitin) in nature. Polysaccharides possess a broad range of molecular weight (MW), a great number of reactive groups, and differing chemical compositions, and these factors contribute to their diverse structures and properties. Polysaccharides are easy to chemically and biochemically modify because of their various derivable groups on molecular chains, and this leads to multiple types of polysaccharide derivatives. Polysaccharides have the following properties: they are highly stable, hydrophilic, biodegradable, nontoxic, and abundant in nature and have low process cost. Specifically, most natural polysaccharides possess hydrophilic groups such as hydroxyl, carboxyl, and amino groups that can form non-covalent bonds with biological tissues, mostly epithelia and mucous membranes, and create bioadhesion. To give an example, chitosan, starch, and alginate are good bioadhesive materials. This is advantageous because nanoparticle carriers that are created using bioadhesive polysaccharides may Page 12 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

prolong the resistance time and thereby increase the absorbance of loaded drugs. In recent years, a large number of studies have been conducted on polysaccharides and their derivatives for their potential application as nanoparticle drug delivery systems [54]. Currently, natural polysaccharides are widely preferred when developing solid dosage forms for drug delivery to the colon. The reason for this lies in the following fact: due to the colon being inhabited by a large variety and number of bacteria that secrete many enzymes such as b-D-glucosidase, b-D-galactosidase, amylase, pectinase, xylanase, b-D-xylosidase, and dextranase, there exists large amounts of polysaccharidases in the human colon. Fermentable coating of the drug core, embedding the drug in the biodegradable matrix, and formulating drug–saccharide conjugate are some of the major approaches that use polysaccharides for colon-specific delivery. Many polysaccharides, such as chitosan, pectin, chondroitin sulfate, cyclodextrin, dextrans, guar gum, inulin, amylose, and locust bean gum, have already been investigated as colon-specific drug carrier systems [55]. Dextran, a polysaccharide made up of glucose units that are coupled into long branched chains mainly through a 1–6 and some 1–3 glycosidic linkages, is a colloidal, hydrophilic, water-soluble substance, which is inert in biological systems and does not influence cell viability. Dextrans have been explored for the delivery of various pharmaceuticals. Alginate, an anionic polysaccharide, is widely dispersed in brown algae cell walls, and in those cell walls, it forms a viscous gum by binding with water. It absorbs water quickly in its extracted form, and it has the ability to absorb 200–300 times its own weight in water. Alginates are one of the most versatile biopolymers, and they are employed in a wide variety of applications. Alginate’s thickening, gel forming, and stabilizing properties underlie its use as an excipient in drug products. In order to achieve prolonged and better control of drug administration, the demand for tailor-made polymers has increased. Hydrocolloids such as alginate may have an important part in the design of a controlled-release product [56]. Aynie et al. have designed a new antisense oligonucleotide (ON) carrier system that was based on alginate nanoparticles. They investigated whether it would be able to protect ON from degradation when the serum was introduced. They have reported that this new alginate-based system was able to protect [33P]-radiolabeled ON from degradation in bovine serum medium [57]. Chitosan (CS) is a polysaccharide consisting linear b(1–4)-linked monosaccharides which is similar to cellulose in structure. The important difference between cellulose and CS is the 2-amino-2-deoxy-hD-glucan units combined with glycosidic linkages. Chitosan is derived from the deacetylation of chitin, naturally available in marine crustaceans. Chitosan is used extensively in drug delivery applications due to its favorable properties such as positive-charge, biocompatibility, and mucoadhesive character. Chitosan, a cationic polysaccharide in neutral or basic pH conditions, has free amino groups and is thus insoluble in water. Since in acidic pH, amino groups can undergo protonation, which makes it soluble in water, CS solubility is dependent on the distribution of free amino and N-acetyl groups. Due to its characteristics of not causing allergic reactions and rejection, chitosan is biocompatible with living tissues. Chitosan slowly breaks down into harmless products, which the human body can completely absorb. Chitosan derivatives are nontoxic and can be easily removed from the organism without resulting in any side reactions [58]. Chitosan-based nanoparticles are attractive gene delivery devices. Huang et al. have evaluated the effects of the molecular weight and the deacetylation degree of chitosan on cellular uptake and gene transfection efficiency. They have reported that an N/P ratio of 6 was optimal for producing the chitosan–DNA NP. Abovementioned N/P ratio is optimal to prepare chitosan nanoparticles with mean size of 150–300 nm which is suitable for gene delivery. They also reported chitosan vectors with lower Mw or DD to be less-efficient retainers of DNA upon dilution. Thus, they were observed to be less able to protect the condensed DNA from DNase and serum component degradation. Decreasing the Mw or DD of the chitosan vector significantly reduced the cellular uptake of the NP [59]. Page 13 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_40-1 # Springer International Publishing Switzerland 2015

The transfection efficiency of chitosan/pDNA complex greatly depends on the microenvironment’s pH, since the protonated amines of chitosan help it bind to negatively charged DNA. Zhao et al. investigated pH’s effect on transfection efficiency, and they obtained the highest expression efficiency at pH 6.8 and 7.0. When pH of transfection medium was increased to 7.4, the transfection efficiency was observed to dramatically decrease. They have defined the decrease in transfection efficiency by the dissociation of free plasmid from the complex at the higher pH [60]. In another study, chitosan-g-poly(ethylene glycol)-folate nanoparticles for gene delivery have been prepared. PEGylation increased its solubility, and folate conjugation improved the efficiency of gene transfection resulting from the promoted uptake of folate receptor-bearing tumor cells. Because of its targeting ability, low cytotoxicity, solubility in physiological pH, and efficiency in condensing DNA, modified chitosan is a favorable gene carrier [34]. In the following years, chitosan nanoparticles functionalized by attachment of different targeting molecules to achieve side-specific/targeted drug delivery have been prepared. As an example, Mohan et al. developed a folic acid (FA)-conjugated carboxymethyl chitosan coordinated to manganese-doped zinc sulfide quantum dot (FA–CMC–ZnS:Mn) nanoparticles. This system has been utilized for controlled drug delivery, targeting, and cancer cell imaging [38]. In another study, an amphiphilic copolymer has been designed. Firstly, N-octyl-N-phthalyl-3,6-O-(2-hydroxypropyl) chitosan (OPHPC) is synthesized and then conjugated with folic acid (FA–OPHPC) in order to create a targeted drug carrier for tumorspecific drug delivery. Paclitaxel is loaded into OPHPC micelles with a loading efficiency of 50.5–82.8 %. The paclitaxel-loaded OPHPC has shown a significantly higher cellular uptake efficiency in human breast adenocarcinoma cell line compared to Taxol ®. Moreover, the cellular uptake of the drug in drug-loaded FA–OPHPC micelles (paclitaxel-FA–OPHPC) is 3.2-fold more effective than that of paclitaxel-loaded OPHPC [49]. Recently, chitosan nanoparticles have been studied for the delivery of tamoxifen. Tamoxifen-loaded chitosan nanoparticles have been constructed as pH-responsive drug carries for effective antitumor activity. Because cancer cells have an acidic extracellular tumor environment, this mechanism is especially appealing for cancer therapy. It has been observed that tamoxifen-loaded chitosan nanoparticles augmented the tamoxifen accumulation in tumor cells, caused caspase-dependent apoptosis, and increased anticancer activity.

Peptide and Protein Delivery The peptides, proteins, and other compounds that are acquired via biotechnological processes have a complex nature, and this causes various challenges when one aims to understand their therapeutic and physicochemical behaviors [61]. The number of amino acid residues generally determines the classification of peptides. Proteins are molecules with more than 50 amino acids, and molecules with 10–50 amino acids are called peptides. A peptide is a chemical compound that has two or more amino acids coupled by a peptide bond. This bond is the linkage of the nitrogen atom of one amino acid with the carboxyl carbon atom of another amino acid. Polypeptide refers to molecules that have molecular weights that range from several thousand to several million daltons. It can be observed that the terms protein and polypeptide are used interchangeably. In 1901, Emil Fischer in collaboration with Ernest Fourneau discovered the first synthetic peptide glycyl–glycine. In 1953, Vincent du Vigneaud synthesized the first polypeptide (oxytocin – nine amino acid sequence). Specific primary, secondary, tertiary, and quaternary structures of a protein play key roles in defining the integrity and biological activity of biomacromolecules. The primary structure of a protein is the amino acid linear sequence of the polypeptide chain. The secondary protein structure is the specific geometric shape caused by intramolecular and intermolecular hydrogen bonding of amide groups. Alpha helix and beta sheets are two main types of secondary structure. These secondary structures are defined by patterns Page 14 of 25

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of hydrogen bonds between the main-chain peptide groups. The third type of structure found in proteins is called tertiary protein structure. Tertiary structure refers to three-dimensional structure of a single-protein molecule. The tertiary structure is the final specific geometric shape of a protein. Quaternary structure is the three-dimensional structure of a multi-subunit protein. An important point is that whereas a small peptide’s function only depends on the functional groups of different amino acids, a protein’s function depends on the maintenance of a precise 3D structure. Thus, it is understandable that protein delivery technologies undergo a more hard task than it is in the case of peptide delivery. The nature of 3D structure must not be spoiled while loading into the vector so that the protein functions properly [61]. Oral administration is the most convenient route for drug delivery. Yet, due to the instability of peptide and protein drugs in the gastrointestinal tract and their low permeability across the intestinal mucosa, their bioavailability following oral administration happens to be very low. Nowadays, numerous types of bioactive peptides are available. Several approaches have been investigated to improve their oral bioavailability such as chemical modification of peptide drugs, the use of an absorption enhancer to promote drug absorption, and the use of protease inhibitor to protect drugs against degradation. Encapsulating or incorporating peptides in polymeric nanoparticles seems to be a promising approach. The use of nanoparticles should at least protect peptide drugs against degradation and, in some cases, also enhance their absorption. Below are some examples of nanoparticle-based peptide delivery. PLGA nanoparticles have also been used to deliver peptides. A model synthetic long peptide has been encapsulated in PLGA nanoparticles. Silva et al. developed an encapsulation method where they used an apparent inner phase pH above the pI of the encapsulated SLP. This can lead to future advances in encapsulating peptides that have amphiphilic and/or hydrophilic qualities. They have also observed encapsulation and release characteristics to depend strongly on the first emulsion’s pH [62]. In another study, exendin-4 a glucagon-like peptide-1 mimetic for type 2 diabetes treatment was conjugated to low-molecular-weight chitosan (LMWC). The LMWC–exendin-4 conjugate formed a nanoparticle structure via complexation between the positively charged LMWC backbone and the negatively charged exendin-4, a structure that had a mean particle size of 101  41 nm; absorbed exendin-4 showed a significantly increased hypoglycemic effect, suggesting that it may be employed as a possible oral antidiabetic agent for type 2 diabetes treatment [63].

siRNA-/Nanoparticle-Based Therapy An important part of gene regulation in gene expression is the control of translation and mRNA degradation. Small RNA molecules, which are common and effective modulators of gene expression in many eukaryotic cells, can be either endogenous or exogenous microRNAs (miRNAs) and shortinterfering RNAs (siRNAs). There are a lot of studies carried out for the treatment of diseases through the delivery of RNA molecules. Small interfering RNA (siRNA) is short, double-stranded RNA consisting of 20–25 nucleotides. It causes the degradation of target mRNA and blocks the production of the associated protein, thus resulting in RNA silencing. The possibility of silencing genes, involved in the formation of the disease using siRNA, has led to a rapidly evolving area in drug discovery. In case of direct injection of naked siRNA, high doses are required due to RNA instability, besides the nonspecific cellular uptake is a disadvantage. The most important issue in the use of siRNA-based therapies for gene silencing by systemic administration is to help siRNA to reach the cytoplasm of the target cell without spoiling its structure. Stealth property and surface charge of the siRNA-encapsulated polycationic-based vector are important parameters for siRNA’s stability and for the system to escape from RES components as it is the case in polycation-based drug/gene delivery systems. For effective siRNA delivery, positive surface charge of Page 15 of 25

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Table 2 Polymeric nanoparticles used for therapeutic agent delivery Polymeric materials Liposome-based nanoparticle Cyclodextrin (CDP)–AD–PEG nanoparticles Chitosan/siRNA NP encapsulated in PLGA nanofibers Transferrin (Tf) grafted–poly (lactide-co-glycolide) (PLGA) nanoparticles Penetratin-modified PLGA nanoparticles Nonaarginine-modified PLGA nanoparticles CDP–AD–PEG–Tf nanoparticles

Agent KLF5-siRNA siRNA

Usage Antitumor Anticancer therapeutics Gene silencing

Target cells PC3 cell tumors PC3 tumors

miR-155

To enhance the transport of nevirapine (NVP) miR-155 replacement

Human brain microvascular endothelial cells (HBMECs) pre-B cell tumors

Antisense oligonucleotide

miR-155 inhibition

pDNA

Anticancer therapeutics Immunotherapy of cancer Treatment of type 2 diabetes Target gene silencing

Inhibition of protooncogene, MCL1 PC3 tumors

PLGA nanoparticles

Synthetic peptides

Low-molecular-weight chitosan (LMWC) PLGA nanoparticles PLGA–PEI nanoparticles Lactosylated gramicidin-based lipid nanoparticles (Lac-GLN) PLA–PEG NPs PLGA NPs PLGA–PVA nanoparticles

Glucagon-like peptide-1 (GLP-1) (Exendin-4) siRNA

MDA-kb2 cells

Procaine hydrochloride

microRNA-155 inhibition Drug delivery

Hepatocellular carcinoma (HCC) cells In vitro drug release

Dexamethasone

Antiproliferative Anticancer drug

PLGA nanoparticles

CyA (as a chemosentizing drug) with doxorubicin (Dox) Vincristine and verapamil

Human vascular smooth muscle cells (VSMCs) P388 resistant cells

Polyalkylcyanoacrylate nanoparticle

Liposomal NPs

pDNA

PLGA nanoparticles/CPP penetrated PLGA

Plasmids encoding for luciferase

siRNA Nevirapine (NVP)

Anti-miR155

For the treatment of drug-resistant cancers Gene delivery

Gene delivery

H1299 cells

CD8+ T cells INS-1 cell line

MCF-7/ADR, a human breast carcinoma cell line Mouse bone marrowderived dendritic cells (BMDC) A549 human lung epithelial cells

vector/siRNA complex is an advantage because it facilitates binding to negatively charged cell membranes and it induces cell uptake. On the other hand, for in vivo applications, an excessive positive surface charge is rather a handicap because of interactions with negatively charged serum proteins which makes them detectable by the macrophages. Various cationic polymer/siRNA conjugates have been developed for targeted siRNA delivery. Most nonviral vector systems, developed for plasmid DNA delivery, have been adopted for siRNA delivery. PLGA nanoparticles are widely used in controlled release of oligonucleotides such as siRNAs, thanks to their solid structure. Solid structure of PLGA nanoparticles makes them stable and prevents the degradation of nucleic acids when circulating in the blood stream. Its solid phase is favorable for longterm storage and convenient for clinical use. PLGA is a biodegradable polymer and during its degradation

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through hydrolysis, there is a slow release of siRNA that results in the sustained knockdown of the target gene. The ability to precisely conjugate up to three different ligands to the nanoparticle surface leads to flexibility during their modification for different potential applications. These multifunctional nanoparticles have multiple benefits over other siRNA delivery technologies [60]. Some of the examples for polymeric nanoparticles used for therapeutic agent delivery are given in Table 2. Another method for the efficient protection and delivery of siRNAs in vitro and in vivo relies on polyethylenimine complexation. Urban-Klein et al. have reported that upon PEI complexation, siRNAs are efficiently protected from RNase and nuclease degradation. Additionally, it has been stated that no siRNAs were found neither nor in nontargeted organs. The results have indicated that the detected signals were derived from siRNA molecules actually internalized by the cells of the respective target organ [64]. Below are some of the examples about the topic. Angiogenesis is essential for tumor proliferation. The suppression of gene expression of VEGF is an important approach for the prevention of tumor growth. Vascular endothelial growth factor (VEGF) is a critical mitogen that induces angiogenesis. Huang et al. have developed amine-modified PVA–PLGA/siRNA nanoparticles for pulmonary siRNA delivery. This polymer is considered to be promising siRNA carrier for pulmonary gene therapy because of its following qualities: nanoparticle stability during nebulization, high specific knockdown, and fast degradation in conjunction with low cytotoxicity [59]. Yagi et al. have developed a systemically injectable siRNA vehicle, which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. Nanoparticle system has provided the protection of siRNA from enzymatic digestion for 24 h. The result is that the complex has leaked from blood vessels within tumors into the tumor tissue and transfected into the tumor cells [65]. Davis et al. developed a cyclodextrin- and PEG-containing polymer with a human transferrin molecule on its surface, which is a targeting ligand to directly transferrin receptors that are typically found on cancer cells [66]. Dohmen et al. have prepared siRNA-encapsulated nanoparticles on which there is a ligand targeting folic acid receptor-expressing cells. Targeted nanoparticles have been shown to be specifically internalized into folic acid receptor-expressing cells, and efficient receptor-specific gene silencing is achieved [67].

Inhibition of miRNAs MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the posttranscriptional level. miRNAs take part in various cellular mechanisms such as proliferation, apoptosis, etc. In recent years, the role of miRNAs in human cancers has been discovered and used for cancer treatment quite popularly. Current RNA-based therapeutics are based on the association of synthetic nucleic acids with cellular RNA targets. The gene therapy method antisense oligonucleotide bound to mature microRNA inhibits microRNA-mediated gene regulation, and the method of splicing junctions on pre-mRNA induces alternative splicing [52]. Several studies have demonstrated the utility of inhibiting miRNAs by using complementary anti-miR molecules, chemically modified antagomirs, and peptide nucleic acids (PNAs) which show particular promise in vivo. The backbone of peptide nucleic acid (PNA), which is an artificially synthesized polymer, consists of repeating N-(2-aminoethyl)-glycine units that are linked via peptide bonds. The various purine and pyrimidine bases are connected to the backbone. The backbone of PNA contains no charged phosphate groups. Thus, the absence of electrostatic repulsion in the binding between PNA/DNA strands makes it stronger than the one between DNA/DNA strands. PNA oligomers have great specificity when binding to complementary DNAs, and this same specificity and strength are present in PNA/RNA duplexes as well. PNAs are stable over a wide pH range, and nucleases and proteases cannot easily Page 17 of 25

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recognize them. Because of their stability and excellent binding affinity, PNAs are ideal anti-miRs. A naked PNA cannot be across cell membrane, easily. Cheng et al. have stated that PNA encapsulation into nanoparticles is uniquely independent from electrostatic interactions between cargo and delivery vehicle due to their charge-neutral backbone unlike most nucleic acids. They have also reported that with standard preparation methods, less than 5 % of the naked siRNA can be encapsulated into PLGA nanoparticles. However, precomplexing siRNA with a polycation can improve loading efficiency into nanoparticles to approximately 50 %. They have used the same method for encapsulation of PNAs and have reported similar encapsulation efficiency (approximately 50 %). Chang et al. state that even though polycations are commonly used for nucleic acid delivery, they may contribute to adverse side effects in cellular and physiological environments due to their charge density. For a nucleic acid delivery system that is potentially more benign and more effective than other strategies, charge-neutral PNAs can be loaded into nanoparticles. Chang et al. attached a cell-penetrating peptide, penetratin, to the nanoparticle (100–2,000 nm in diameter) surface in order to increase the capability of PLGA nanoparticles to deliver cargo intracellularly. To achieve this, they utilized an effective surface attachment strategy, which permits conformational flexibility and a high density of ligand deposition. Chang et al.’s experiments show that pre-B cells uniquely favored the uptake of nanoparticles that were coated penetratin (ANTP–NP) and not the uptake of other cell-penetrating peptides such as TAT and polyarginine [68].

miRNA-Restoration-Based Therapy The genomic loss or downregulation of miRNAs can be restored using miRNA mimetics or mimics, which are synthetic double-stranded RNA where the guide strand is identical to the endogenous mature miRNA needing to be restored and the passenger strand is completely complementary to the guide strand. miRNA mimics need chemical modification via the strategies explained above for the anti-miRs so that their stability can be increased and nuclease degradation can be avoided. Yet, ensuring the proper loading of the guide strand into the RISC complex and the degradation of the passenger strand requires that the chemical modifications of both strands be different. miRNA mimics are usually conjugated or encapsulated into different carriers, whereas anti-miRs can successfully be delivered in vivo naked. Similar to the miRNA transfection methods developed in vitro, the field has also seen the development of lipid-based strategies for in vivo delivery. Liposomes are vesicles that have a lipidic bilayer, which can be loaded with various molecules including miRNAs. The use of cationic lipids compensates for the negative charge of nucleic acids, leading the particles to have a net positive charge, and this facilitates the cellular uptake. Neutral lipid liposomes were developed following the observation of the adverse immune response effects resulting from cationic liposome administration. Neutral lipid liposomes are utilized in delivering miRNAs locally and systemically without apparent toxicity [69].

Some Other Polycations in Drug/Gene Delivery Poly-L-lysine (PLL), one of the first polymers used in nonviral gene delivery, is biodegradable but its high toxicity prevents its use in vivo. Transfection efficiency of PLL−nucleic acid complexes remain lower when compared to other transfection agents. It is believed that inefficient transfection is due to the lack of amino groups with a pKa 5−7 which offers endosomolysis and nucleic acid release. Many hydrophilic polymers have been linked covalently to poly-L-lysine and copolymers such as poly-L-lysine–poly(ethylene glycol) block. Reports are also available on synthesis of lipid-bearing Page 18 of 25

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poly-L-lysines, where lipid units are attached to terminal lysine amino units. The covalent attachment of both hydrophilic and hydrophobic units to poly-L-lysine and further formation of nanoparticles are available as well. As an example, Kim et al. have synthesized a cationic diblock copolymer, poly(L-lysine) poly(ethylene glycol) folate (PLL PEG FOL), to improve their site-specific intracellular delivery against cancer cells that overexpress folate receptor. PLL PEG FOL-coated PLGA nanoparticles have demonstrated enhanced cellular uptake into KB cells even in the presence of serum proteins [70]. Whereas most proteins have negative charges at the physiological pH, the amine side chains of poly(L-lysine) are positively charged. Because of multiple electrostatic interactions, the polymer can encapsulate protein molecules in aqueous solutions. Block copolymers composed of the cationic segment and hydrophilic segments are expected spontaneously to associate with polyanionic DNA to form block copolymer micelles. Wei et al. constructed a hydrophilic star block copolymer PEI–PLL–b-PEG with a poly(L-lysine) inner shell as a potential nanocarrier that may easily encapsulate proteins such as insulin. At the physiological pH, the loaded insulin in the star block copolymer displayed a sustained release; it showed a significantly accelerated release upon charge switching of the protein molecules [51]. Poly(alkylcyanoacrylate)-based nanosystems include various types of nanoparticles suitable to use in vivo drug delivery in a well-controlled manner. Thanks to its favorable properties such as biocompatibility and biodegradability, simple preparation process for the entrapment of bioactives, especially proteins and peptides and poly(alkylcyanoacrylate) nanoparticles, has sparked extensive interest as drug delivery systems. DeVerdière et al. have loaded polyalkylcyanoacrylate (PACA) nanoparticles with doxorubicin. Previously they found that tumor cells do not digest PACA nanoparticles, and here they report the crucial necessity of a direct interaction between nanoparticles and cells to overcome resistance. They showed that the degradation products of PACA, mainly polycyanoacrylic acid, have the ability to increase both accumulation and cytotoxicity in the presence of doxorubicin. They interpret this finding to suggest that a doxorubicin–polycyanoacrylic acid ion pair has formed. They conclude that both the increased doxorubicin diffusion by the accumulation of an ion pair at the plasma membrane and the adsorption of nanoparticles to the cell surface work together to overcome resistance. Hillaireau et al. have encapsulated cidofovir (CDV) and azidothymidine-triphosphate (AZT-TP) in poly(iso-butylcyanoacrylate) (PIBCA) aqueous-core nanocapsules. However encapsulation efficiency is low and additionally the rapid leakage of the small and hydrophilic molecules through the thin polymer wall of the nanocapsules is observed. Then, various water-soluble polymers as increasing Mw adjuvants are used for the entrapment of mononucleotides (CDV, AZT-TP) has been done in the study conducted with oligonucleotides into these PIBCA aqueous-core nanocapsules. It has been reported that in the presence of cationic polymers (i.e., poly(ethyleneimine) (PEI) or chitosan), encapsulation of AZT-TP and ODN has been successful. Nanocapsule of poly(iso-butylcyanoacrylate) finds a chance of applications in drug delivery as well [71]. Polyethylenimines (PEIs) are synthetic linear or branched polymers. Their molecular weights vary in the range of 1,000 kDa. PEIs have a protonable amino group in every third position and a high cationic charge density. These properties allow PEIs to make non-covalent interpolyelectrolyte complexes with DNA. Cells can efficiently take up these small colloidal particles, which intracellularly buffer the low endosomal pH. The proton-sponge effect results in an increased proton and water influx, leading to the eventual burst of endosomes and the release of complexes into the cytoplasm. Making use of this mechanism enabled the introduction of certain PEIs as transfection agents to a variety of cell lines and to animals for DNA delivery. In general, higher molecular weights associated with augmented cytotoxicity and low-molecularweight PEIs (85 %) with significant increases in ethene concentration. They attributed CVOCs degradation to direct abiotic dechlorination by nZVI followed by biological reductive dechlorination which is supposed to be stimulated by the corn oil present in the emulsion.

Supporting Materials Several techniques have been developed in the past decade to enhance nZVI dispersion and enable its application in continuous flow systems, using different porous materials as mechanical supports. The practice of supporting/immobilizing nZVI on a solid support simultaneously provides four advantages: (i) it controls the growth of nanoparticles as well as aggregation; (ii) it provides protection to nanoparticles against oxidation and hydrolysis in water; (iii) it preconcentrates the target contaminant around nZVI via adsorption, which in turn enhanced the overall reactivity of nZVI; and (iv) it is more convenient in terms of their real application [83, 84]. As per literature, hydroxylic, carboxylic, or amine groups have been used as chelating sites for attaching nZVI to substrates such as carbon, silica, clays, etc. For instance, Schrick et al. [6] proposed anionic hydrophilic carbon (Fe/C) and polyacrylic acid (PAA) (Fe/PAA) as delivery vehicles for nZVI. They compared the transport of Fe/C and Fe/PAA nanoparticles with unsupported nZVI by elution through soil- and sand-packed column and observed that anionic surface charge over supported nanoparticles significantly reduces the sticking coefficient of nZVI in soil, facilitating rapid transport through the columns. In contrast, unsupported nZVI rapidly agglomerates in water and is efficiently filtered by soil. Zhang et al. [39] developed surfactant (HDTMA)-modified zeolite (SMZ)/zero-valent iron (ZVI) pellets having high hydraulic conductivity, high surface area, and excellent mechanical strength. In comparison to unmodified pellets (zeolite/ZVI), HDTMA-modified zeolite/ZVI was found to have three times higher reduction rate for perchloroethylene. Similar results were observed by Li et al. [85] while studying chromate transport through columns packed with HDTMA-modified zeolite/ZVI pellets. In their study, chromate removal capacity of about one order of magnitude higher in comparison to

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unmodified pellets was obtained using SMZ/zeolite/ZVI. Column experiments further revealed that chromate retardation factor also gets enhanced (fivefold) in the presence of sorbed HDTMA. Silica compounds are known to exhibit high affinity for the surface of iron oxides and hydroxides, especially polymeric silica is known to bind strongly with iron and thus can be utilized efficiently as supporting material for nZVI. The adsorbed silica layer influences the surface chemistry, particle mobilization, coagulation, and iron corrosion [86]. Li et al. [87] demonstrated that iron nanoparticle, supported on silica fume or coated with SiO2, improves the stability and mobility of the nanoparticles in soil as well as enhances the reactivity of iron toward Cr(VI) removal. It was further reported that silica inhibits the formation of Fe(III)/Cr(III) precipitation on iron nanoparticles’ surface, which in turn enhanced the deactivation resistance of iron. Wan et al. [40] also confirms that SiO2-coated iron nanoparticles improved nanoparticles’ reducing capacity as well as enhanced its antioxidation abilities. nZVI particles supported on polymeric resin were employed by Ponder et al. [84] in order to remove Cr (VI) and Pb(II) from aqueous solutions. As compared to bare nZVI, supported nZVI showed 5- and 18-fold higher removal capacities for Cr(VI) and Pb(II), respectively. Wu et al. [83] used cellulose acetate as support for bimetallic ZVI/Ni nanoparticles. For preparation, ZVI/Ni nanoparticles were mixed with a cellulose acetate–acetone solution followed by phase inversion resulting in the formation of a 100-mmthick porous membrane. The nanoparticles were reported to exist as dispersed clusters within the membrane permitting good access to nanoparticle surface by the target contaminants. Parshetti and Doong [88] successfully immobilized bimetallic Fe/Ni nanoparticles in Nylon 66 and polyvinylidene fluoride (PVDF) membranes. In comparison to PVDF, the distribution of iron was reported more uniform in Nylon 66 and the intensity of Ni layer was also found higher. The size of nanoparticles in Nylon 66 and PVDF were reported to be 55  14 and 81  12 with Ni layers of 15  2 and 12  3 nm, respectively. Due to the presence of more numbers of multifunctional chelating groups in Nylon membrane as compared to PVDF, relatively low aggregation was noticed in nZVI/Ni. Park et al. [89] reported immobilization of nZVI on an ion exchange resin sphere, which not only combats the problem of agglomeration but also reduces the amount of ammonia produced during nitrate reduction which otherwise is a major limitation for nZVI. Chang et al. [90] utilized activated carbon as supporting material for bimetallic nZVI/Cu nanoparticles and reported that the iron nanoparticles get strongly attached to the surface of carbon and also incorporated in the mesopores of activated carbon. Similar results were reported previously by Schrick et al. [6] while synthesizing hydrophilic carbon-supported iron nanoparticles. Parshetti and Doong [91] used polyethylene glycol as the cross-linker for immobilizing bimetallic nZVI/Ni nanoparticles on four different membranes, namely, polyvinylidene fluoride, Millex GS, cellulose ester, and Nylon 66. Among these four membranes, Nylon 66 was found to display more uniform dispersion because of its hydrophilic nature. The dechlorination efficiency of all the membrane immobilized Ni/Fe nanoparticles were also tested under anoxic conditions and highest dechlorination rate was found with Nylon 66 immobilized nZVI/Ni nanoparticles. A few clay minerals such as zeolites, bentonites, kaolinite, and montmorillonite have also been used/ employed successfully as support for nZVI [23, 35, 85, 92]. The ion exchange property of these natural clay minerals facilitates incorporation of iron in their porous structure. Several interlayer meso- or micropores were formed through intercalation of Fe into the pillared layers of bentonite; as a consequence of which, transport channels were formed for the target contaminants. Bentonite was also reported to increase the surface area and decrease the aggregation of nanoparticles when used as support for nZVI [23]. Zhang et al. [93] proposed kaolinite as an ideal support for nZVI and demonstrated its use in removing Pb(II) from aqueous solution. More recently, Chen et al. [94] synthesized kaolinite-supported nZVI (K-nZVI) as a multifunctional composite and used it for degradation of a cationic dye crystal violet (CV). In their study, it was found that presence of kaolinite not only decreased nanoparticle aggregation Page 12 of 18

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but also enhanced the CV degradation efficiency. Experimental results showed that K-nZVI removed 97.23 % of CV, whereas nZVI and kaolinite removed only 78.72 % and 39.22 % of CV after 30 min, respectively. The performance of nZVI can also be enhanced by immobilizing nZVI on montmorillonite. The cation exchange property, swelling abilities, and interlayer space at nanometer scale provide a good platform to accommodate nZVI as well as the contaminants. Fan et al. [95] noted that montmorillonite-supported nZVI is well dispersed on clay surface with high monodispersity, free from boron-related impurity, and is oxidation resistant. Jia and Wang [92] synthesized montmorillonite-supported nZVI using two different pathways, viz., heterogeneous nucleation and homogeneous nucleation processes. Their results showed that during the heterogeneous nucleation process, dispersed nZVI with an average size 0.5 nm gets intercalated in montmorillonite interlayers. However, the particle sizes ranged from 0.62 nm for nZVI intercalated in montmorillonite interlayers to 1–50 nm for the nZVI residing on an external surface when homogeneous nucleation pathway was used for synthesis. Furthermore, the reactivity of nZVI synthesized by heterogeneous nucleation was reported to be higher than that by homogeneous nucleation.

Conclusions This chapter is intended to present the current status of knowledge on stabilization practices of nZVI with special reference to polymers and surfactants. Extensive studies have demonstrated that both polymers and surfactants are effective in inhibiting nZVI aggregation and enhancing mobility in the subsurface for emplacement. Besides surface modification, two other approaches, i.e., emulsification and conjugation with support, also proved to provide protection to nZVI against aggregation and surface oxidation as well as enhance transport under subsurface environments. The stabilization methods not only increase the mobility but also the reactivity of nZVI toward hazardous/toxic environmental contaminants. Although stabilized nZVI have improved mobility and reactivity, still there are some unresolved issues which limit the applicability of nZVI in real scenario such as toxicity, fate, and behavior in the environment, and its potential impact on the ecosystem. Before the nZVI-based technology becomes a promising tool for the remediation of environmental contaminants, assessing the overall impact of surface-engineered nZVI and their stabilizing agent under field-relevant conditions is necessary. In addition, the uncertainties over the toxicity, persistence, and environmental fate of iron nanoparticles also need to be addressed.

References 1. A.B. Cundy, L. Hopkinson, R.L.D. Whitby, Use of iron-based technologies in contaminated land and groundwater remediation: a review. Sci. Total Environ. 400, 42–51 (2008) 2. X.Q. Li, D.W. Elliott, W.X. Zhang, Zero-valent iron nanoparticles for abatement of environmental pollutants: materials and engineering aspects. Crit. Rev. Solid State Mater. Sci. 31, 111–122 (2006) 3. R.A. Crane, T.B. Scott, Nanoscale zero-valent iron: future prospects for an emerging water treatment technology. J. Hazard. Mater. 211–212, 112–125 (2012) 4. W. Zhang, Nanoscale iron particles for environmental remediation: an overview. J. Nanopart. Res. 5, 323–332 (2003) 5. B. Nowack, Pollution prevention and treatment using nanotechnology, in Nanotechnology, Environ Aspect, ed. by H. Krug, vol. 2 (Wiley-VCH, Weinheim, 2008), pp. 1–15 6. B. Schrick, B.W. Hydutsky, J.L. Blough, T.E. Mallouk, Delivery vehicles for zerovalent metal nanoparticles in soil and groundwater. Chem. Mater. 16, 2187–2193 (2004) Page 13 of 18

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7. N. Saleh, K. Sirk, Y. Liu, T. Phenrat, B. Dufour, K. Matyjaszewski, R.D. Tilton, G.V. Lowry, Surface modifications enhance nanoiron transport and NAPL targeting in saturated porous media. Environ. Eng. Sci. 24, 45–57 (2007) 8. F. He, D. Zhao, J. Liu, C.B. Roberts, Stabilization of Fe-Pd nanoparticles with sodium carboxymethyl cellulose for enhanced transport and dechlorination of trichloroethylene in soil and groundwater. Ind. Eng. Chem. Res. 46, 29–34 (2007) 9. T. Phenrat, N. Saleh, K. Sirk, R.D. Tilton, G.V. Lowry, Aggregation and sedimentation of aqueous nanoscale zerovalent iron dispersions. Environ. Sci. Technol. 41, 284–290 (2007) 10. A. Tiraferri, R. Sethi, Enhanced transport of zerovalent iron nanoparticles in saturated porous media by guar gum. J. Nanopart. Res. 11, 635–645 (2009) 11. J.F. McCarthy, L.D. McKay, Colloid transport in the subsurface. Vadose Zone J. 3, 326–337 (2004) 12. B.W. Hydutsky, E.J. Mack, B.B. Beckerman, J.M. Skluzacek, T.E. Mallouk, Optimization of nanoand microiron transport through sand columns using polyelectrolyte mixtures. Environ. Sci. Technol. 41, 6418–6424 (2007) 13. T. Cosgrove, Colloid Science – Principles, Methods and Applications (Blackwell, Oxford, 2005) 14. D.H. Napper, Steric stabilization. J. Colloid Interface Sci. 58, 390–407 (1977) 15. S. Krajangpan, H. Kalita, B.J. Chisholm, A.N. Bezbaruah, Iron nanoparticles coated with amphiphilic polysiloxane graft copolymers: dispersibility and contaminant treatability. Environ. Sci. Technol. 46, 10130–10136 (2012) 16. T. Phenrat, F. Fagerlund, T. Illangasekare, G.V. Lowry, R.D. Tilton, Polymer-modified Fe0 nanoparticles target entrapped NAPL in two dimensional porous media: effect of particle concentration, NAPL saturation, and injection strategy. Environ. Sci. Technol. 45, 6102–6109 (2011) 17. S.R. Kanel, R.R. Goswami, T.P. Clement, M.O. Barnett, D. Zhao, Two dimensional transport characteristics of surface stabilized zero-valent iron nanoparticles in porous media. Environ. Sci. Technol. 42, 896–900 (2008) 18. Y.P. Sun, X.Q. Li, W.X. Zhang, A method for the preparation of stable dispersion of zero-valent iron nanoparticles. Colloids Surf. A Physicochem. Eng. Asp. 308, 60–66 (2007) 19. T. Phenrat, N. Saleh, K. Sirk, H.J. Kim, R.D. Tilton, G.V. Lowry, Stabilization of aqueous nanoscale zerovalent iron dispersions by anionic polyelectrolytes: adsorbed anionic polyelectrolyte layer properties and their effect on aggregation and sedimentation. J. Nanopart. Res. 10, 795–814 (2008) 20. Z. Xiong, D. Zhao, G. Pan, Rapid and complete destruction of perchlorate in water and ion-exchange brine using stabilized zero-valent iron nanoparticles. Water Res. 41, 3497–3505 (2007) 21. F. He, D. Zhao, C. Paul, Field assessment of carboxymethyl cellulose stabilized iron nanoparticles for in situ destruction of chlorinated solvents in source zones. Water Res. 44, 2360–2370 (2010) 22. I.C.P. Hoştuca, P. Filip, D. Humelnicu, I. Humelnicu, T.B. Scott, R.A. Crane, Removal of uranium (VI) from aqueous systems by nanoscale zero-valent iron particles suspended in carboxy-methyl cellulose. J. Nucl. Mater. (2013). doi:10.1016/j.jnucmat.2013.07.018 23. L.N. Shi, X. Zhang, Z.L. Chen, Removal of Chromium (VI) from wastewater using bentonitesupported nanoscale zero-valent iron. Water Res. 45, 886–892 (2011) 24. F. He, D. Zhao, Preparation and characterization of a new class of starch-stabilized bimetallic nanoparticles for degradation of chlorinated hydrocarbons in water. Environ. Sci. Technol. 39, 3314–3320 (2005) 25. A.N. Bezbaruah, S. Krajangpan, B.J. Chisholm, E. Khan, J.J. Bermudez, Entrapment of iron nanoparticles in calcium alginate beads for groundwater remediation applications. J. Hazard. Mater. 166, 1339–1343 (2009) 26. A. Tiraferri, K.L. Chen, R. Sethi, M. Elimelech, Reduced aggregation and sedimentation of zerovalent iron nanoparticles in the presence of guar gum. J. Colloid Interface Sci. 324, 71–79 (2008) Page 14 of 18

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27. E.D. Vecchia, M. Luna, R. Sethi, Transport in porous media of highly concentrated iron micro- and nanoparticles in the presence of xanthan gum. Environ. Sci. Technol. 43, 8942–8947 (2009) 28. A.K. Ibrahem, T.A. Moghny, Y.M. Mustafa, N.E. Maysour, F.M.S. El Dars, R.F. Hassan, Degradation of trichloroethylene contaminated soil by zero-valent iron nanoparticles. ISRN Soil Sci. 2012, 1–9 (2012) 29. S.R. Kanel, D. Nepal, B. Manning, H. Choi, Transport of surface-modified iron nanoparticle in porous media and application to arsenic(III) remediation. J. Nanopart. Res. 9, 725–735 (2007) 30. M. Zhang, F. He, D. Zhao, X. Hao, Degradation of soil-sorbed trichloroethylene by stabilized zero valent iron nanoparticles: effects of sorption, surfactants, and natural organic matter. Water Res. 45, 2401–2414 (2011) 31. G. Fan, L. Cang, W. Qin, C. Zhou, H.I. Gomes, D. Zhou, Surfactants-enhanced electrokinetic transport of xanthan gum stabilized nanoPd/Fe for the remediation of PCBs contaminated soils. Sep. Purif. Technol. 114, 64–72 (2013) 32. B.W. Zhu, T.T. Lim, J. Feng, Influences of amphiphiles on dechlorination of a trichlorobenzene by nanoscale Pd/Fe: adsorption, reaction kinetics, and interfacial interactions. Environ. Sci. Technol. 42, 4513–4519 (2008) 33. T. Long, C.A. Ramsburg, Encapsulation of nZVI particles using a Gum Arabic stabilized oil-in-water emulsion. J. Hazard. Mater. 189, 801–808 (2011) 34. N.D. Berge, C.A. Ramsburg, Oil-in-water emulsions for encapsulated delivery of reactive iron particles. Environ. Sci. Technol. 43, 5060–5066 (2009) 35. Z.X. Chen, X.Y. Jin, Z. Chen, M. Megharaj, Removal of methyl orange from aqueous solution using bentonite-supported nanoscale zero-valent iron. J. Colloid Interface Sci. 363, 601–607 (2011) 36. N. Horzum, M.M. Demir, M. Nairat, T. Shahwan, Chitosan fiber-supported zero-valent iron nanoparticles as a novel sorbent for sequestration of inorganic arsenic. RSC Adv. 3, 7828–7837 (2013) 37. B. Geng, Z. Jin, T. Li, X. Qi, Kinetics of hexavalent chromium removal from water by chitosan-Fe0 nanoparticles. Chemosphere 75, 825–830 (2009) 38. W. Wang, M. Zhou, Q. Mao, J. Yue, X. Wang, Novel NaY zeolite-supported nanoscale zero-valent iron as an efficient heterogeneous Fenton catalyst. Catal. Commun. 11, 937–941 (2010) 39. P. Zhang, X. Tao, Z. Li, R.S. Bowman, Enhanced perchloroethylene reduction in column systems using surfactant-modified zeolite/zero-valent iron pellets. Environ. Sci. Technol. 36, 3597–3603 (2002) 40. J. Wan, J. Wan, Y. Ma, M. Huang, Y. Wang, R. Ren, Reactivity characteristics of SiO2-coated zerovalent iron nanoparticles for 2,4-dichlorophenol degradation. Chem. Eng. J. 221, 300–307 (2013) 41. J. Zhan, T. Zheng, G. Piringer, C. Day, G.L. McPherson, Y. Lu, K. Papadopoulos, V.T. John, Transport characteristics of nanoscale functional zerovalent iron/silica composites for in situ remediation of trichloroethylene. Environ. Sci. Technol. 42, 8871–8876 (2008) 42. H. Choi, S. Agarwal, S.R. Al-Abed, Adsorption and simultaneous dechlorination of PCBs on GAC/Fe/Pd: mechanistic aspects and reactive capping barrier concept. Environ. Sci. Technol. 43, 488–493 (2009) 43. Y. Li, J. Li, Y. Zhang, Mechanism insights into enhanced Cr(VI) removal using nanoscale zerovalent iron supported on the pillared bentonite by macroscopic and spectroscopic studies. J. Hazard. Mater. 227, 211–218 (2012) 44. H.J. Kim, T. Phenrat, R.D. Tilton, G.V. Lowry, Fe0 nanoparticles remain mobile in porous media after aging due to slow desorption of polymeric surface modifiers. Environ. Sci. Technol. 43, 3824–3830 (2009)

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45. F. He, D. Zhao, Manipulating the size and dispersibility of zero-valent iron nanoparticles by use of carboxymethyl cellulose stabilizers. Environ. Sci. Technol. 41, 6216–6221 (2007) 46. J. Fatisson, S. Ghoshal, N. Tufenkji, Deposition of carboxymethylcellulose-coated zero-valent iron nanoparticles onto silica: roles of solution chemistry and organic molecules. Langmuir 26, 12832–12840 (2010) 47. T. Phenrat, Y. Liu, R.D. Tilton, G.V. Lowry, Adsorbed polyelectrolyte coatings decrease Fe0 nanoparticle reactivity with TCE in water: conceptual model and mechanisms. Environ. Sci. Technol. 43, 1507–1514 (2009) 48. R. Singh, V. Misra, M.K.R. Mudiam, L.K.S. Chauhan, R.P. Singh, Degradation of g-HCH spiked soil using stabilized Pd/Fe0 bimetallic nanoparticles: pathways, kinetics and effect of reaction conditions. J. Hazard. Mater. 237–238, 355–364 (2012) 49. Q. Wang, H. Qian, Y. Yang, Z. Zhang, C. Naman, X. Xu, Reduction of hexavalent chromium by carboxymethyl cellulose-stabilized zero-valent iron nanoparticles. J. Contam. Hydrol. 114, 35–42 (2010) 50. T. Dong, H. Luo, Y. Wang, B. Hu, C. Hua, Stabilization of Fe–Pd bimetallic nanoparticles with sodium carboxymethyl cellulose for catalytic reduction of para-nitrochlorobenzene in water. Desalination 271, 11–19 (2011) 51. L.B. Hoch, E.J. Mack, B.W. Hydutsky, J.M. Hershman, J.M. Skluzacek, T.E. Mallouk, Carbothermal synthesis of carbon-supported nanoscale zero-valent iron particles for the remediation of hexavalent chromium. Environ. Sci. Technol. 42, 2600–2605 (2008) 52. Y.-H. Lin, H.-H. Tseng, M.-Y. Wey, M.-D. Lin, Characteristics of two types of stabilized nano zerovalent iron and transport in porous media. Sci. Total Environ. 408, 2260–2267 (2010) 53. P. Jiemvarangkul, W.X. Zhang, H.L. Lien, Enhanced transport of polyelectrolyte stabilized nanoscale zero-valent iron (nZVI) in porous media. Chem. Eng. J. 170, 482–491 (2011) 54. N. Sakulchaicharoen, D.M. O’Carroll, J.E. Herrera, Enhanced stability and dechlorination activity of pre-synthesis stabilized nanoscale FePd particles. J. Contam. Hydrol. 118, 117–127 (2010) 55. E.J. Bishop, D.E. Fowler, J.M. Skluzacek, E. Seibel, T.E. Mallouk, Anionic homopolymers efficiently target zerovalent iron particles to hydrophobic contaminants in sand columns. Environ. Sci. Technol. 4, 9069–9074 (2010) 56. N. Saleh, T. Phenrat, K. Sirk, B. Dufour, J. Ok, T. Sarbu, K. Matyjaszewski, R.D. Tilton, G.V. Lowry, Adsorbed triblock copolymers deliver reactive iron nanoparticles to the oil/water interface. Nano Lett. 5, 2489–2494 (2005) 57. K.L. Chen, S.E. Mylon, M. Elimelech, Aggregation kinetics of alginate-coated hematite nanoparticles in monovalent and divalent electrolytes. Environ. Sci. Technol. 40, 1516–1523 (2006) 58. K.L. Chen, S.E. Mylon, M. Elimelech, Enhanced aggregation of alginate-coated iron oxide (hematite) nanoparticles in the presence of calcium, strontium, and barium cations. Langmuir 23, 5920–5928 (2007) 59. S. Comba, R. Sethi, Stabilization of highly concentrated suspensions of iron nanoparticles using shear-thinning gels of xanthan gum. Water Res. 43, 3717–3726 (2009) 60. M.J. Truex, V.R. Vermeul, D.P. Mendoza, B.G. Fritz, R.D. Mackley, M. Oostrom, T.W. Wietsma, T.W. Macbeth, Injection of zero-valent iron into an unconfined aquifer using shear thinning fluids. Ground Water Monit. Rem. 31, 50–58 (2011) 61. S. Comba, D. Dalmazzo, E. Santagata, R. Sethi, Rheological characterization of xanthan suspensions of nanoscale iron for injection in porous media. J. Hazard. Mater. 185, 598–605 (2011) 62. L. Zhong, J. Szecsody, M. Oostrom, M. Truex, X. Shen, X. Li, Enhanced remedial amendment delivery to subsurface using shear thinning fluid and aqueous foam. J. Hazard. Mater. 191, 249–257 (2011) Page 16 of 18

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63. D. Xue, R. Sethi, Viscoelastic gels of guar and xanthan gum mixtures provide long-term stabilization of iron micro- and nanoparticles. J. Nanopart. Res. 14, 1239–1252 (2012) 64. G.C.C. Yang, H.C. Tu, C.H. Hung, Stability of nanoiron slurries and their transport in the subsurface environment. Sep. Purif. Technol. 58, 166–172 (2007) 65. S. Pamukcu, L. Hannum, J.K. Wittle, Delivery and activation of nano-iron by DC electric field. J. Environ. Sci. Health A 43, 934–944 (2008) 66. K.R. Reddy, K. Darko-Kagya, C. Cameselle, Electrokinetic-enhanced transport of lactate-modified nanoscale iron particles for reduction of dinitrotoluene in clayey soils. Sep. Purif. Technol. 79, 230–237 (2011) 67. G.C.C. Yang, C.H. Hung, H.C. Tu, Electrokinetically enhanced removal and degradation of nitrate in the subsurface using nanosized Pd/Fe slurry. J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng. 43, 945–951 (2008) 68. T. Suzuki, Y. Oyama, M. Moribe, M. Niinae, An electrokinetic/Fe0 permeable reactive barrier system for the treatment of nitrate-contaminated subsurface soils. Water Res. 46, 772–778 (2012) 69. Z. Li, S. Yuan, J. Wan, H. Long, M. Tong, A combination of electrokinetics and Pd/Fe PRB for the remediation of pentachlorophenol-contaminated soil. J. Contam. Hydrol. 124, 99–107 (2011) 70. W. Stumm, J.J. Morgan, Aquatic Chemistry, 3rd edn. (Wiley, New York, 1996) 71. M. Elimelech, X. Jia, W.R. Gregory, Particle Deposition and Aggregation: Measurement, Modelling, and Simulation (Butterworth–Heinemann, Oxford, 1995) 72. P. Mayer, M.M. Fernqvist, P.S. Christensen, U. Karlson, S. Trapp, Enhanced diffusion of polycyclic aromatic hydrocarbons in artificial and natural aqueous solutions. Environ. Sci. Technol. 41, 6148–6155 (2007) 73. S.K. Park, A.R. Bielefeldt, Non-ionic surfactant flushing of pentachlorophenol from NAPLcontaminated soil. Water Res. 39, 1388–1396 (2005) 74. S.S. Chen, H.D. Hsu, C.W. Li, A new method to produce nanoscale iron for nitrate removal. J. Nanopart. Res. 6, 639–647 (2004) 75. C. Shin, H.D. Choi, D.H. Kim, K. Baek, Effect of surfactant on reductive dechlorination of trichloroethylene by zero-valent iron. Desalination 223, 299–307 (2008) 76. J. Quinn, C. Geiger, C. Clausen, K. Brooks, C. Coon, S. O’Hara, T. Krug, D. Major, W.S. Yoon, A. Gavaskar, T. Holdsworth, Field demonstration of DNAPL dehalogenation using emulsified zerovalent iron. Environ. Sci. Technol. 39, 1309–1318 (2005) 77. S. O’Hara, T. Krug, J. Quinn, C. Clausen, C. Geiger, Field and laboratory evaluation of the treatment of DNAPL source zones using emulsified zero-valent iron. Remediation 16, 35–56 (2006) 78. C. Wise, V. Warren, E. Bishop, M. Scalzi, A pilot-scale EZVI and ZVI treatment of unsaturated and saturated soil for TCE reduction, in Proceedings of the 10th International In Situ and On-Site Bioremediation Symposium, Baltimore, 5–8 May 2009 79. P. La Mori, Remediation of chlorinated VOC by emulsified zero-valent iron (EZVI) emplaced by large diameter auger soil mixing, in Proceedings of the 10th International In Situ and On-Site Bioremediation Symposium, Baltimore, 5–8 May 2009 80. C. Su, R. Puls, S. O’Hara, T. Krug, M. Watling, J. Quinn, N. Ruiz, Pilot field test of the treatment of source zone chlorinated solvents using emulsified zero-valent iron, in Proceeding of the International Environment Nanotechnology Conferences: Applications and Implications, vol. 1 (Chicago, 7–9 Oct 2008), pp. 101–106 81. G.C.C. Yang, Y.I. Chang, Integration of emulsified nano iron injection with the electrokinetic process for remediation of trichloroethylene in saturated soil. Sep. Purif. Technol. 7, 278–284 (2011) 82. C. Su, R.W. Puls, T.A. Krug, M.T. Watling, S.K. O’Hara, J.W. Quinn, N.E. Ruiz, A two and halfyear-performance evaluation of a field test on treatment of source zone tetrachloroethene and its Page 17 of 18

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83.

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chlorinated daughter products using emulsified zero valent iron nanoparticles. Water Res. 46, 5071–5084 (2012) L. Wu, M. Shamsuzzoha, S.M.C. Ritchie, Preparation of cellulose acetate supported zero-valent iron nanoparticles for the dechlorination of trichloroethylene in water. J. Nanopart. Res. 7, 469–476 (2005) S.M. Ponder, J.G. Darab, T.E. Mallouk, Remediation of Cr(VI) and Pb(II) aqueous solutions using supported, nanoscale zero-valent iron. Environ. Sci. Technol. 34, 2564–2569 (2000) Z. Li, H.K. Jones, P. Zhang, R.S. Bowman, Chromate transport through columns packed with surfactant-modified zeolite/zero valent iron pellets. Chemosphere 68, 1861–1866 (2007) C.C. Davis, H.W. Chen, M. Edwards, Modeling silica sorption to iron hydroxide. Environ. Sci. Technol. 36, 582–587 (2002) Y. Li, Z. Xiu, T. Li, Z. Jin, Stabilization of Fe0 nanoparticles with silica for enhanced transport and remediation of hexavalent chromium in groundwater, in Sustainable Nanotechnology and the Environment: Advances and Achievements. ACS symposium series, vol. 1124 (American Chemical Society, Washington, DC, 2013), pp. 307–326 G.K. Parshetti, R.A. Doong, Dechlorination of trichloroethylene by Ni/Fe nanoparticles immobilized in PEG/PVDF and PEG/nylon 66 membranes. Water Res. 43, 3089–3094 (2009) H. Park, Y.M. Park, K.M. Yoo, S.H. Lee, Reduction of nitrate by resin-supported nanoscale zerovalent iron. Water Sci. Technol. 59, 2153–2157 (2009) C. Chang, F. Lian, L. Zhu, Simultaneous adsorption and degradation of g-HCH by nZVI/Cu bimetallic nanoparticles with activated carbon support. Environ. Pollut. 159, 2507–2514 (2011) G.K. Parshetti, R.A. Doong, Dechlorination of chlorinated hydrocarbons by bimetallic Ni/Fe immobilized on polyethylene glycol-grafted microfiltration membranes under anoxic conditions. Chemosphere 86, 392–399 (2012) H. Jia, C. Wang, Comparative studies on montmorillonite-supported zero-valent iron nanoparticles produced by different methods: reactivity and stability. Environ. Technol. 34, 25–33 (2012) X. Zhang, S. Lin, Z. Chen, M. Megharaj, R. Naidu, Kaolinite-supported nanoscale zero-valent iron for removal of Pb2+ from aqueous solution: reactivity, characterization and mechanism. Water Res. 45, 3481–3488 (2011) Z. Chen, T. Wang, X. Jin, Z. Chen, M. Megharaj, R. Naidu, Multifunctional kaolinite-supported nanoscale zero-valent iron used for the adsorption and degradation of crystal violet in aqueous solution. J. Colloid Interface Sci. 398, 59–66 (2013) M.D. Fan, P. Yuan, T.H. Chen, H.P. He, A.H. Yuan, K.M. Chen, J.X. Zhu, D. Liu, Synthesis, characterization and size control of zerovalent iron nanoparticles anchored on montmorillonite. Chin. Sci. Bull. 55, 1092–1099 (2010)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

Advanced Engineering Approaches in the Development of PLGA-Based Nanomedicines Mazen M. El-Hammadia,b and José L. Ariasa* a Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja s/n, Granada, Spain b Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria

Abstract Drug molecules often display little affinity for nonhealthy tissues and/or cells, leading to inefficiency, and high incidence of severe side effects. To face the problem, numerous strategies have been postulated, i.e., chemical modifications to the drug molecule, and proper engineering of drug nanocarriers. In this line, the introduction of poly(D,L-lactide-co-glycolide) nanoparticles in the drug delivery arena has been hypothesized to optimize drug biodistribution and concentration into the targeted site, thus improving the therapeutic effect while reducing the associated drug toxicity. Recent advances in the field have been devoted to the optimization of the in vivo fate and effectiveness of poly(D,L-lactide-co-glycolide)-based drug nanocarriers, i.e., by passive targeting strategies based on the functionalization of the particle surface with special biomolecules, and/or active targeting stratagems thanks to modifications leading to stimuliresponsive nanoparticles. In this chapter, we analyze the current state of the art and future perspectives in the formulation of poly(D,L-lactide-co-glycolide)-based nanomedicines against severe diseases.

List of Abbreviations 17-AAG AEMA ALE anti-DR5 anti-EGFR anti-EpCAM anti-HER2 APO-1 Apt 7a-APTADD BBB BP bPEI BSA cLABL CLR CPP CPT cRGD

17-Allylamino-17-demethoxygeldanamycin 2-Aminoethyl methacrylamide Alendronate Anti-death receptor 5 Anti-epidermal growth factor receptor Anti-epithelial cell adhesion molecule Anti-human epidermal growth factor receptor 2 Apoptosis antigen 1 Aptamer 7a-(40 -Amino)phenylthio-1,4-androstadiene-3,17-dione Blood-brain barrier Bisphosphonate Branched poly(ethyleneimine) Bovine serum albumin cyclo(1,12)PenITDGEATDSGC C-type lectin receptor Cell-penetrating peptide Camptothecin Cyclic arginine-glycine-aspartic acid

*Email: [email protected] Page 1 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

DC DNA DOPE DOSPA DOX DSPE DTPA EDC EPR FA FDA FR G-rich gWiz-Luc HIV-1 HUVEC IC50 ICAM-1 ICG KC MAb MAN MDR1 Mw Neu5Ac NHS NIR NP OL OVA pDNA PE PEG pEGFP PEI P-gp PLGA PSMA PTX PVA RES RGD RNA SA siRNA STL

Dendritic cell Deoxyribonucleic acid 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine 2,3-Dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate Doxorubicin 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine Diethylenetriaminepentaacetic acid 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide Enhanced permeability and retention Folic acid Food and Drug Administration Far red Guanosine-rich Firefly luciferase reporter gene Human immunodeficiency virus type 1 Human umbilical vein endothelial cell Half maximum inhibitory concentration Intercellular adhesion molecule-1 Indocyanine green Kupffer cell Monoclonal antibody Mannan Multidrug resistance 1 Molecular weight N-Acetylneuraminic acid N-Hydroxysucinimide Near infrared Nanoparticle Odorranalectin Ovalbumin Plasmid deoxyribonucleic acid L-a-Phosphatidylethanolamine Poly(ethylene glycol) Plasmid enhanced green fluorescent protein Poly(ethyleneimine) P-glycoprotein Poly(D,L-lactide-co-glycolide) Prostate-specific membrane antigen Paclitaxel Polyvinyl alcohol Reticuloendothelial system Arginine-glycine-aspartic acid Ribonucleic acid Sialic acid Small interfering ribonucleic acid Solanum tuberosum lectin Page 2 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

TAT Tf Tg TNF VCR WGA z

Transactivating transcriptional activator Transferrin Glass transition temperature Tumor necrosis factor Vincristine Wheat germ agglutinin Zeta potential

Introduction Conventional methods of drug delivery are characterized by numerous drawbacks including poor drug solubility, unfavorable pharmacokinetics, limited bioavailability, poor accumulation at the diseased tissue, lack of selectivity, which all lead to inefficient therapy, and high incidence of severe adverse effects. To address these disadvantages a diversity of strategies have been speculated based either on the alteration of the physicochemical properties of the drug molecule using approaches, such as, prodrugs, solid dispersions, complexation, and salt formation, or on the proper engineering of tailored drug nanocarriers or nanomedicines. Nanomedicine is taken as the application of nanotechnology to medicine. This emerging field involves the use of nanoscale or nanostructured materials for the prevention, diagnosis, and treatment of diseases. These nanostructures exhibit unique characteristics in terms of physiochemical properties and physiological interactions, which could be exploited to improve drug efficacy, enhance delivery, and minimize toxicity. Nanomedicine is a broad term that encompasses a variety of nano-sized (submicron) structures manufactured using a wide range of materials. Materials used as drug nanocarriers must fulfill a number of requirements, i.e., low toxicity and biocompatibility, biodegradability, and ease of processing. Polymers are among the most studied nanomedicine-forming materials owing to their favorable biocompatibility and low toxicity. In particular, synthetic biodegradable polymers, whose shape (linear, branched, or globular) and size [molecular weight (Mw)] can be easily controlled, are of great potential as drug nanocarriers. Amongst these, the copolymer poly(D,L-lactide-co-glycolide) (PLGA), one of a few polymers approved by the United States Food and Drug Administration (FDA) for biomedical applications, has long been utilized as a biomaterial due to its excellent biocompatibility and biodegradability. The PLGA nanotechnology has received increasing attention in the last two decades (Table 1). A brief review of publications resulting from a Scopus and PubMed search of PLGA NPs for drug delivery applications displays a drastic increase from two in 1995 to around 300 articles in each year of 2012 and 2013 (Fig. 1). This chapter analyzes the current state of the art and future perspectives in the formulation of PLGAbased nanomedicines and their potential to cure severe diseases. Following a brief description of PLGA physicochemical and biodegradable characteristics, the chapter sheds the light on the several available types of PLGA-based nanoparticulate systems. The chapter will further focus on the recent advances in particle engineering (and surface functionalization) strategies of these nanocarriers.

Physicochemical Properties of Poly(D,L-Lactide-co-Glycolide) PLGA is a synthetic copolymer composed of lactic acid and glycolic acid. It is obtained by random ringopening copolymerization of two different monomers, the cyclic dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid (Fig. 2). The two acids are linked together by an ester linkage in a casual order during copolymerization, thus leading to aliphatic linear polyester [8]. The monomers’ ratio is usually Page 3 of 25

Biomedical use Cancer therapy

Micelle

Doxorubicin (DOX)

NP Micelle Polymersome NP

Gemcitabine Zeylenone S14G-humanin Rapamycin NP

NP

Docetaxel

Clodronate

NP

Camptothecin (CPT)

NP

Nanoplatform Nanoparticle (NP)

Drug Paclitaxel (PTX)

Block copolymer with PEG

– Block copolymer with PEG Block copolymer with PEG –

Block copolymer with PEG

Conjugation with lecithin and 1,2-distearoyl-sn-glycero-3phosphoethanolamineN-carboxyPEG (DSPE-PEG) –

Block copolymer with PEG Block copolymer with PEG, and conjugation with polyhistidine –

Structural modification – Combination with montmorillonite Block copolymer with poly (ethylene glycol) (PEG) Conjugation with lecithin and PEG –

Table 1 An overview of PLGA-based nanoparticulate systems for biomedical applications

Aravind et al. [3] Yu et al. [88]/Mattu et al. [55]/Mo and Lim [58, 59], Wang et al. [81]/Aravind et al. [4, 5]/Sahoo and Labhasetwar [68], Sahoo et al. [67], Shah et al. [72] Yoo and Park [87]/Jin et al. [40] Jia et al. [39]

MUC1 Apt/herceptin (monoclonal antibody, MAb)/ wheat germ agglutinin (WGA)/ AS1411 Apt/transferrin (Tf) FA/HAb18 F(ab')(2) –

Conatumumab/peripheral antibodies directed toward apoptosis antigen 1 (APO-1) Trastuzumab/herceptin/A10 ribonucleic acid (RNA) Apt – – Lactoferrin Anti-epidermal growth factor receptor (anti-EGFR) LyP-1 cyclic tumor-homing peptide

Sharma et al. [73]

Koopaei et al. [46]/Liu et al. [49]/Gu et al. [32] Martín-Banderas et al. [53] Hu et al. [37] Yu et al. [89] Acharya et al. [1]

Fay et al. [26]/McCarron et al. [56]

Kong et al. [45]

Pignatello et al. [62, 63], Cenni et al. [11]/ Chittasupho et al. [17]

[64]/Guo et al. [33]

Folic acid (FA)/AS1411 aptamer (Apt) AS1411 Apt

Alendronate (ALE)/cyclo (1,12)PenITDGEATDSGC (cLABL) peptide –

References He et al. [35] Sun et al. [76]

Surface functionalization – Trastuzumab

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

Page 4 of 25

Gene delivery

Inflammation therapy Oral delivery of protein drugs Drug delivery to the brain Block copolymer with PEG – Block copolymer with branched poly(ethyleneimine) (bPEI)

NP NP NP NP Micelle

NP NP Micelle

NP NP

NP

Docetaxel and PTX Tariquidar and PTX DOX and PTX Interferon-g

Bovine serum albumin (BSA) and streptavidin

Urocortin peptide Loperamide

Plasmid deoxyribonucleic acid (pDNA) encoded with the firefly luciferase reporter gene (gWiz-Luc) pDNA Small interfering ribonucleic acid (siRNA) for silencing the multidrug resistance 1 (MDR1) gene, and PTX Plasmid enhanced green fluorescent protein (pEGFP)

Block copolymer with PEG and 2-aminoethyl methacrylamide (AEMA) Block copolymer with PEG Block copolymer with PEG – Block copolymer with PEG

Micelle

Seo et al. [71] Patil et al. [61]

– Biotin

Mannan (MAN) and La-phosphatidylethanolamine (PE)

Block copolymer with bPEI Block copolymer with PEG

–

[44, 86]

Mishra et al. [57]

Koyamatsu et al. [47]

–

Wen et al. [84, 85] Tosi et al. [79]

Cheng et al. [16] [60] Cui et al. [18] Zhang et al. [91]

(continued)

Khoee and Rahmatolahzadeh [41]

A10 RNA Apt Biotin Tf cLABL peptide

FA

Zheng et al. [92]

Dhar et al. [21]

Chen et al. [15]

Saxena et al. [69]

Chen et al. [14]

Odorranalectin Similopioid peptide and sialic acid –

Block copolymer with PEG

Lipid coated NP

Block copolymer with PEG

NP

NP

–

NP

7a-(40 -amino)phenylthio-1,4androstadiene-3,17-dione (7a-APTADD) Quercetin

Platinum(IV) (cisplatin prodrug)

Solanum tuberosum lectin (STL) A10 prostate-specific membrane antigen (PSMA) Apt Tf

Block copolymer with PEG

NP

17-Allylamino-17demethoxygeldanamycin (17-AAG) Coumarin 6

FA and R7 cell penetrating peptide FA

Block copolymer with PEG

NP

Vincristine sulfate

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

Page 5 of 25

Theranosis

Indocyanine green (ICG)

Imaging

CPT and quantum dots DOX and superparamagnetic iron oxide PTX and superparamagnetic iron oxide

Gold NP Far red/near infrared (FR/NIR) emissive conjugated polymer and lipidcoated iron oxides IR5 and IR26 (NIR dyes) Technetium

Drug Ovalbumin

Biomedical use Vaccination

Table 1 (continued)

NP

NP NP

NP NP

NP Nanocomposite NP

Lipid NP

Nanoplatform NP NP

– Conjugated with diethylenetriaminepentaacetic acid (DTPA) – PEGylated lipid to form a coating shell –

Combined with soybean lecithin and lipid-PEG conjugates Block copolymer with PEG Block copolymer with PEG Block copolymer with PEG

Structural modification – Block copolymer with PEG

Deepagan et al. [20] Wang et al. [82] Schleich et al. [70]

–

Kohl et al. [43] Subramanian et al. [75]

Ma et al. [52] Geng et al. [29] Li et al. [48]

Zheng et al. [93]

References Hamdy et al. [34] Garinot et al. [28]

Cetuximab FA

– –

FA FA FA

Surface functionalization MAN Arginine-glycine-aspartic acid (RGD) peptide FA

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

Page 6 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015 350 Pubmed Number of publications

300 Scopus 250 200 150 100 50

9 19 6 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13

19

19

95

0

Year

Fig. 1 Research studies on PLGA-based drug nanocarriers identified in Scopus and PubMed databases from 1995 to 2013

Fig. 2 Chemical synthesis of PLGA by random ring-opening copolymerization of the cyclic dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid (x: number of lactic acid units; y: number of glycolic acid units)

used to identify the polymer’s form. For example, PLGA 50:50, which is widely used for drug delivery applications, refers to a PLGA whose composition is 50 % lactic acid and 50 % glycolic acid. PLGA physical characteristics, such as, degree of crystallinity, Mw, and melting point, influence its mechanical strength and ability to be fabricated as a drug nanocarrier as well as its stability. One important property is the crystallinity of the polymer which has a direct effect on its mechanical strength, swelling behavior, capacity to undergo hydrolysis, and, consequently, the biodegradation rate [22]. PLGA crystallinity is related to the type and the molar ratio of the individual monomer components (glycolic acid and lactic acid) in the copolymer chain [22]. PLGAs manufactured from poly(L-lactide) and poly(glycolide) are crystalline, whereas those from poly(D,L-lactide) and poly(glycolide) are amorphous in nature. Moreover, copolymers with less than 70 % of poly(glycolide) are amorphous. Lactide-rich PLGAs are less hydrophilic, because lactic acid is more hydrophobic than glycolic acid. In addition, the polymer becomes less hydrophobic with decreasing Mw, and it is water soluble at 1,100 Da [27]. PLGA copolymers have a glass transition temperature (Tg) in the range of 45–55  C which is above the physiological temperature (37  C), thus they are normally glassy in nature mechanical, with sufficient strength for formulation development. It has been demonstrated that the Tg of a PLGA copolymer decreases with Mw and lactide content [22]. Table 2 compiles the most significant aspects of PLGA composition defining the physical chemistry of this copolymer.

Page 7 of 25

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_45-1 # Springer International Publishing Switzerland 2015

Table 2 Effects of PLGA composition on the copolymer characteristics Polymer composition Lactide segment: poly(L-lactide) Lactide segment: poly(D,L-lactide) 1. However, its parameters were determined within a narrow temperature range, and thus, it is valid only in a very narrow domain. On the other hand, the CMD correlation is designed quite sensibly and, as shown above, fits several limiting asymptotic values. For this reason, it could be used to develop a more general correlation, applicable within a wide temperature range. In order to make correlation (8) applicable within a wide temperature range, it has been modified as follows [46] Page 12 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015

Fig. 12 Diffusion coefficient of nanoparticles in uranium hexafluoride versus nanoparticle radius

Dk ¼ kT =gk ,

gk ¼ 6p  R½1 þ A Kn þ Q Knexpð
b=KnÞ
1

so that its parameters become functions of temperature, A ¼ AðT =295Þj ,

Q ¼ QðT =295Þj

where the j parameter is given by the following correlation h i
1 j ¼ 1:03 þ 0:57 1 þ 10ð2:703dp
10:45Þ : Now it would like to note another interesting property of nanoparticle diffusion. Equation 9 differs radically from the Einstein relation (6). The diffusion of Brownian particles (Eq. 6) depends only on their size and the viscosity of the carrier medium. Meanwhile, in accordance with (9), the diffusion of nanoparticles should also be determined by the mass ratio of the particle to the molecule and by the particle–molecule interaction parameters, i.e., ultimately by the nanoparticle material. Calculations [48] have shown that this is indeed so. The calculations were performed for the diffusion of lithium, zinc, and uranium nanoparticles in hydrogen, neon, and uranium hexafluoride over a wide range of nanoparticle radii R = 0.5  50 nm and gas temperature T = 200  1000 K. A typical calculation of the dependence of the diffusion coefficients (cm2/s) of these nanoparticles on their radius (Å) in neon at a fixed temperature T = 300 K is shown in Fig. 12. In this figure, lines 1, 2, and 3 correspond to nanoparticles of lithium, zinc, and uranium, respectively. For small nanoparticles, the diffusion coefficient depends substantially on the particle material, but this dependence becomes negligibly small for particles with a diameter greater than 7–10 nm.

Thermal Diffusion of Nanoparticles in Gases Thermal diffusion is one of the most interesting and subtle transport processes. Usually, the thermal diffusion coefficient is much smaller than the concentration diffusion coefficient. However, thermal diffusion has practical applications. It is used to separate components of gas mixtures, especially isotopes, and is a valuable tool for studying intermolecular forces. Thermal diffusion may prove to be an additional factor of mixing processes in microchannels. Page 13 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015

Thermal diffusion of nanoparticles is often confused with thermophoresis, a process typical of larger aerosol particles (e.g., see a review by M€adler and Friedlender [38]). Strictly speaking, thermophoresis is the motion due to nonuniform heating of the particle surface. However, the nanoparticle size is of the order of the hydrodynamic infinitesimal scale of the carrier gas (if the gas is not too rarefied); i.e., it can be considered a material point in the metric of the carrier gas, and, hence, it makes no sense to speak of nonuniform heating. For the same reason, this nonuniformity cannot arise for physically reasonable temperature gradients. Thus, nanoparticle motion in a nonuniform temperature field is nothing thermophoresis but thermal diffusion. A rigorous expression for the thermal diffusion coefficient can be derived from kinetic theory based on the Boltzmann equations for gas mixtures. In particular, for a binary mixture, the thermal diffusion coefficient DT is linked to the diffusion coefficient D by the thermal diffusion relation kT: DT ¼ k T D [49], where kT is determined by the mole fractions xi of components 1 and 2 and by the so-called thermal diffusion factor aT: k T ¼ aT x1 x2 , which is given by
 aT ¼ 6C 12
5 S1 ¼

Q1 x21

S 1 x1
S 2 x2 ; þ Q2 x22 þ Q12 x1 x2

(10)

m1 þ m2 l12 15 m2
m1 m1 þ m2 l12 15 m1
m2

1, S 2 ¼

1; 2m2 l1 4A12 2m1 2m1 l2 4A12 2m2

        l12 m2 5 6  m1 8  l12 m1 5 6  m2 8 
B
B Q1 ¼ 3 þ þ A , Q2 ¼ 3 þ þ A ; 2 5 12 m2 5 12 2 5 12 m1 5 12 l1 m1 l2 m2 Q12

    16 ðm1 þ m2 Þ2  l212 12  15 ðm1
m2 Þ2 12  ¼ A12 þ 11
B12 þ  5
B12 ; 5 5 8A12 5 4m1 m2 l1 l2 m1 m2

Aij ¼

ð2, 2Þ

Oij

ð1, 1Þ Oij

, Bij ¼

ð1, 2Þ

5Oij

Oij sffiffiffiffiffiffiffiffiffi 3 1 1 2kT Dij ¼ ; ð 1 , 1 Þ 2 16 n s O pmij ij

ð1, 3Þ


4Oij ð1, 1Þ

pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2pmij kT 3k 25 , C ij ¼ ð1, 1Þ , lij ¼ , 32 ps2 Oð2, 2Þ 4mij Oij ij ij ð1, 2Þ

Oij

ij


 where mi is the mass of the i-th molecule, mij ¼ mi mj = mi þ mj is the reduced mass, and O(k,l)* are the ij O-integrals. The sign of the thermal diffusion factor aT and the direction of thermal diffusion are determined mainly by the factors S and Q in Eq. 10, which, in turn, depend on the mass ratio of the molecules and their ð1, sÞ ). The following typical cases can be distinguished. For not effective scattering cross sections (s2ij Oij
  too low temperatures, the factor 6C 12
5 in formula (10) is positive, and the nature of thermal diffusion is determined by the mass ratio and size ratio of the molecules. If the molecular masses are different, e.g., m1 > m2, then aT > 0, and heavier molecules tend to migrate to cooler areas. If the molecular masses are similar, larger molecules tend to migrate to cooler areas. If the heavier-gas molecules are larger than the lighter-gas molecules, the thermal diffusion factor increases only slightly or even decreases. Moreover, in such cases, the thermal diffusion factor can become negative. Typically, textbooks and reference books on kinetic theory (e.g., [49]) state that the thermal diffusion factor depends weakly on the mixture composition. Generally, this is not so. Indeed, in the case of a Page 14 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015

Fig. 13 Thermal diffusion coefficient DT (cm2/s) of various nanoparticles in Ne versus their radius R (nm). The solid, dash, and dot-and-dash curves correspond to U, Li, and Zn nanoparticles, respectively, T = 300 K

mixture of heavy isotopes, the thermal diffusion factor is almost independent on the concentration of the components. For instance, for a U238F6–U235F6 mixture, the thermal diffusion factor changes by 0.4 % as the mole fraction of U238F6 varies from 0.01 to 0.99. The same is observed for the dependence of the thermal diffusion factor on the mole fraction of Xe132 in a Xe132–Xe129 mixture. This is also true for the thermal diffusion factor of a H2–He mixture. On the other hand, the thermal diffusion ratio for rarefied gas mixtures with significantly different masses of molecules is very sensitive to the mole fractions of components. For an example, the thermal diffusion factor of a Xe–Ne mixture varies by more than a factor of two. A similar situation is observed for an Ar–He mixture. Here the thermal diffusion factor of the mixture is positive and increases by almost a factor of three with increasing mole fraction of the lighter gas [50]. Although the dependence of the thermal diffusion factor on the mixture composition seems too complex and non-universal, the reciprocal of the thermal diffusion factor a
1 T for so-called “normal” systems was found to be linear [51]. Its linearity has been confirmed by experiments, as reported by several authors. Exceptions are the so-called anomalous systems in which the sign of aT varies as a function of the mole fraction of one of the components. This phenomenon is called the temperature inversion of the thermal diffusion factor. Detection of temperature inversion in computations depends strongly on the intermolecular potential used. Such a subtle dependence of the thermal diffusion factor on the parameters of the potential is a useful tool for determining whether these parameters are obtained correctly. For instance, the hard-sphere potential does not describe this temperature inversion. This inversion has been confirmed by experiments. Studies of mixtures of inert gases and nitrogen [52] have shown that the observed dependences of aT agree with those computed using the Lennard-Jones 6–12 potential or the exp-6 potential, both qualitatively and quantitatively. A characteristic feature of nanoparticle thermal diffusion by which it differs from the thermal diffusion of gas molecules is the dependence of the thermal diffusion coefficient and other parameters on the nanoparticle size. Naturally, the thermal diffusion coefficient decreases with increasing nanoparticle size. In addition, the thermal diffusion coefficient (just as the thermal diffusion ratio kT) depends strongly on the nature of nanoparticles and carrier gas. As an example, Fig. 13 shows the thermal diffusion coefficients for Zn, Li, and U nanoparticles in Ne as functions of their radius for a fixed volume fraction of nanoparticles ’ ¼ 0:001. Small particles have significantly different values of the thermal diffusion coefficient. At the same time, even for particle sizes larger than 3 nm, these values are almost identical. Another important feature that distinguishes thermal diffusion of molecules from that of nanoparticles is the absence of inversion of the thermal diffusion factor. Finally, the thermal diffusion coefficient of Page 15 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015 aT 1

1·103 100

2 10 1

3

0.1 0

2·10 −4

4·10 −4

6·10 −4

8·10 −4

f

Fig. 14 Thermal diffusion factor aT as a function of the volume fraction ’ of nanoparticles for U–Ne gas nanosuspensions, R ¼ 20 nm (curve 1) and R ¼ 1 nm (curve 2) and Xe–Ne gas mixtures (curve 3)

nanoparticles and other parameters depend on the volume concentration of nanoparticles. Figure 14 shows typical curves of the thermal diffusion factor versus volume fraction of nanoparticles (or molecules of a heavier component) at a fixed temperature T ¼ 300 K for U–Ne gas nanosuspensions (R ¼ 20 nm and R ¼ 1 nm), and Xe–Ne gas mixtures [50]. One can see that the thermal diffusion factors of different media differ by several orders of magnitude, increasing with increasing ratios of the masses and radii of the heavy and light components.

Diffusion of Nanoparticles in Dense Gases and Liquids Nanoparticle diffusion in liquids has not been sufficiently studied experimentally. This is partly due to the widespread belief that it is described by the Einstein–Stokes equation (6). However, the few existing experimental data indicate that this law is not valid for at least sufficiently small nanoparticles [53–57]. There have been attempts to explain this discrepancy by the use of slip boundary conditions to describe the forces acting on a nanoparticle [53, 56]. This is, of course, a misunderstanding. The motion of a nanoparticle in a liquid cannot be described hydrodynamically since in the metric of the carrier fluid (continuum), it is a material point. Can the slip condition be applied to a point? This approach has not given a clear answer as to the force acting on the nanoparticle. Therefore, it has been [53, 57] proposed to describe experimental data by the correlation D ¼ A=p ; where the parameters A and p should be chosen for given particle radius and fluid temperature. Attempts have also been made to determine the adequacy of the Einstein–Stokes law (6) for nanoparticles using the molecular dynamics (MD) method [58, 59]. The main conclusion of these studies was that the law does not generally describe the diffusion of nanoparticles. Later, a systematic modeling of the diffusion of small nanoparticles with a diameter of 1–2 nm was performed [60]. Nanoparticles and molecules were modeled by a system of hard spheres of different diameters. The density of the pffifficarrier ffi
 3 fluid was described by the parameter a ¼ V
V p =V 0 (V is the volume of the cell, V 0 ¼ N r =8 2 is the volume of close packed molecules of radius r, V p ¼ 4pR3 =3 is the volume of the nanoparticle), and a ranged from 2 to 75. The obtained data are shown in Fig. 15. The dependence of the diffusion coefficient of the nanoparticles on density differs from the dependence derived from the law (6). As already mentioned, the diffusion of sufficiently small nanoparticles depends greatly on their material. Figure 16 shows the dependence of the diffusion coefficient of lithium and aluminum nanoparticles 1–4 nm in diameter in argon at a temperature of 322.5 K and a density of argon eV ¼ 0:707 [61] (see also [26]). For small nanoparticles, the differences from formula (6) reach fifty Page 16 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015

25 D 20 15 10 5 0 0

20

40

60

α

Fig. 15 Diffusion coefficient versus density of nanoparticles. The solid curve was obtained by molecular dynamics simulation, and the dotted curve corresponds to Einstein law (6)

D·105 4

3

2

1

0

0.5

1

1.5

2 R

Fig. 16 Dependence of the diffusion coefficient D (cm2/s) on the radius R (nm). The dashed line and squares correspond to Li, the dash-dot line and circles to Al, and the solid line corresponds to the Einstein formula

percent, and the difference between the diffusion coefficients of aluminum and lithium nanoparticles reaches 20–30 %. Furthermore, according to Einstein's theory, the diffusion coefficient of a particle is inversely proportional to its radius. In general, the dependence of the diffusion coefficient on nanoparticle radius is described by the power-law function: D ¼ aR
k , whose exponent also depends on the nanoparticle material, but k is always larger than unity. For lithium nanoparticles, kLi = 1.37, and for aluminum nanoparticles, kAl = 1.59. The dependence of the diffusion coefficient on the fluid temperature becomes completely different. As for Brownian particles, this dependence is described by the power-law function D  T n , but the exponent n is not universal and depends on the nanoparticle material and size. As an example Fig. 17 shows the temperature dependence of the diffusion coefficient of lithium nanoparticles 2 nm in diameter in argon (eV ¼ 0:707). Here the symbols correspond to molecular dynamics calculations [61], and the dashed line is its approximation by the indicated power-law dependence with an exponent n = 1.1. The corresponding dependence defined by Einstein’s formula (solid curve) gives a much slower growth. This difference increases with increasing temperature.

Page 17 of 21

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_54-1 # Springer International Publishing Switzerland 2015

D·105

2

1.5

1

200

300

400

T

Fig. 17 Dependence of the diffusion coefficient D (см2/c) of nanoparticles on fluid temperature T (К)

Conclusion In conclusion, it is necessary to note two important facts. First, the set of experimental and theoretical data, including those obtained by the molecular dynamics method, indicates that the classical theoretical models describing the diffusion of nanoparticles in gases and liquids are inapplicable or working in a narrow range of parameters. This is particularly important for the diffusion of sufficiently small nanoparticles. Large nanoparticles, of course, can be described by the relations obtained for Brownian particles. Thus, the size of nanoparticles is the most important factor determining their diffusion. The second important factor is the shape of nanoparticles. The deviation of the shape of nanoparticles from a spherical shape can significantly change the mechanisms of diffusion. This is particularly important in the presence of external fields. For magnetic particles, this can be a magnetic field, and for conventional particles, shear flow. Under these conditions, the diffusion of nanoparticles is not isotropic. On the other hand, if the longitudinal and transverse dimensions of a nanoparticle are significantly different, this will cause rotation of the nanoparticles. In this situation, it is possible to introduce an effective nanoparticle diameter and consider the nanoparticles to be quasispherical. At the same time, however, the added mass effect needs to be considered. The size and shape of nanoparticles is an important factor that determines not only their diffusion and also the viscosity and thermal conductivity of nanofluids (see, e.g., [62–66].) In particular, it has been reliably established that the viscosity of nanofluids for a given concentration of nanoparticles is the larger the smaller their size.

References 1. S. Choi, Enhancing thermal conductivity of fluids with nanoparticles, in Developments Applications of Non-Newtonian Flows, FED-vol. 231/MD-vol. 66., ed. by D. A. Siginer, H. P. Wang, (ASME, New York, 1995), pp. 99–105 2. V.Y. Rudyak, S.L. Krasnolutskii, On kinetic theory of diffusion of nanoparticles in a rarefied gas. Atm. Oceanic Opt. 16(5–6), 468–471 (2003) 3. V.Y. Rudyak, A.A. Belkin, Mechanisms of collective nanoparticles interaction with condensed solvent. Thermophys. Aeromech. 11(2), 54–63 (2004)

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4. V.Y. Rudyak, Kinetic theory and modern aerohydromechanics. Siberian J. Ind. Math. 8(3), 120–148 (2005) 5. V.Y. Rudyak, A.A. Belkin, S.L. Krasnolutskii, Statistical theory of nanoparticle transport processes in gases and liquids. Thermophys. Aeromech. 12(4), 506–516 (2005) 6. I.S. Grigoriev, E.Z. Meilikhov (ed.), Physical Values. Handbook (Energy & Atom Press, Moscow, 1991) 7. H. Masuda et al., Alteration of thermal conductivity and viscosity of liquid by dispersing ultra-fine particles (dispersions of g-Al2O3, SiO2, and TiO2 ultra-fine particles). Netsu Bussei (Japan) 4, 227–239 (1993) 8. J.A. Eastman, U.S. Choi, S. Li, G. Soyez, L.J. Thompson, R.J. DiMelfi, Novel thermal properties of nanostructured materials. Inv. paper to Int. Symp. on Metastable Mechanically Alloyed, and Nanocrystalline Materials, December 7–12, 1998, Wollongong, Australia 9. X. Wang, X. Xu, S.U.S. Choi, Thermal conductivity of nanoparticle–fluid mixture. J. Thermophys. Heat Trans. 13(4), 474–480 (1999) 10. R. Saidur, K.Y. Leong, H.A. Mohammad, A review on applications and challenges of nanofluids. Renew. Sustain. Energy Rev. 15(3), 1646–1668 (2011) 11. A.M. Baklanov, S.N. Dubtsov, An experimental set-up for aerosol spectrometers calibration. J. Aerosol. Sci. 24(Suppl. 1), S237–S238 (1993) 12. V.Y. Rudyak, S.N. Dubtsov, A.M. Baklanov, Temperature dependence of the diffusion coefficient of nano-particles. Tech. Phys. Lett. 34, 519–521 (2008) 13. V.Y. Rudyak, S.N. Dubtsov, A.M. Baklanov, Measurements of the temperature dependent diffusion coefficient of nanoparticles in the range of 295–600 K at atmospheric pressure. J. Aerosol. Sci. 40, 833–843 (2009) 14. H. Akoh, Y. Tsukasaki, S. Yatsuya, A. Tasaki, Magnetic properties of ferromagnetic ultrafine particles prepared by vacuum evaporation on running oil substrate. J. Crystal Growth. 45, 495–500 (1978) 15. C.-H. Lo, T.-T. Tsung, L.-C. Chen, Shape-controlled synthesis of Cu based nanofluid using submerged arc nanoparticle synthesis system (SANSS). J. Crystal Growth. 277(1–4), 636–642 (2005) 16. M. Wagener, B.S. Murty, B. Gunther, Preparation of metal nanosuspensions by high-pressure DC-sputtering on running liquids, in Nanocrystalline and Nanocomposite Materials II, ed. by S. Komarnenl, J.C. Parker, H.J. Wollenberger, vol. 457 (Materials Research Society, Pittsburgh, 1997), pp. 149–154 17. H.T. Zhu, Y.S. Lin, Y.S. Yin, A novel one-step chemical method for preparation of copper nanofluids. J. Colloid Interface Sci. 277, 100–103 (2004) 18. E. Goharshadi, Y. Ding, M. Jorabchi, P. Nancarrow, Ultrasound-assisted green synthesis of nanocrystalline ZnO in the ionic liquid. Ultrason. Sonochem. 16(1), 120–123 (2009) 19. D. Wen, Y. Ding, Formulation of nanofluids for natural convective heat transfer applications. Int. J. Heat Fluid Flow. 26(6), 855–864 (2005) 20. L. Fedele, L. Colla, S. Bobbo, S. Barison, F. Agresti, Experimental stability analysis of different water-based nanofluids. Nanoscale Res. Lett. 6(1), 1–8 (2011) 21. Y. Hwang et al., Production and dispersion stability of nanoparticles in nanofluids. Powder Technol. 186(2), 145–153 (2008) 22. K.V. Chuistov, V.G. Trubachev, A.E. Perekos, V.C. Luk’yanov, V.D. Koval, Structure and properties of high dispersed particles obtained at ultrahigh velocity cooling. Metallofizika 10(1), 118–120 (1988) 23. V.Y. Rudyak, S.V. Dimov, V.V. Kuznetsov, S.P. Bardahanov, Measurement of the viscosity coefficient of an ethylene glycol–based nanofluid with silicon dioxide particles. Dokl. Phys. 58(5), 173–176 (2013) Page 19 of 21

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24. D.N. Zubarev, Nonequilibrium Statistical Thermodynamics (Consultants Bureau, New York, 1974) 25. V.Y. Rudyak, A.A. Belkin, D.A. Ivanov, V.V. Egorov, The simulation of transport processes using the method of molecular dynamics self-diffusion coefficient. High Temp. 46(1), 30–39 (2008) 26. V.Y. Rudyak, Statistical Aerohydromechanics of Homogeneous and Heterogeneous Media. Hydromechanics. Civil Engineering, vol. 2 (University Press, Novosibirsk, 2005) 27. B.J. Alder, T.E. Wainwright, Decay of the velocity autocorrelation function. Phys. Rev. A 1, 18–21 (1970) 28. V.Y. Rudyak, A.A. Belkin, D.A. Ivanov, V.V. Egorov, On the nonclassical diffusion of molecules of liquid and dense gases. Dokl. Phys. 52, 115–118 (2007) 29. V.Y. Rudyak, A.A. Belkin, Noclassical properties of molecular diffusion in liquids and dense gases. Defect Diffus. Forum 273–276, 560–565 (2008) 30. A. Einstein, A new determination of molecular sizes. Ann. Phys. 19, 289–306 (1906) 31. V.Y. Rudyak, A.A. Belkin, Nanoparticle velocity relaxation in condensed carrying medium. Tech. Phys. Lett. 29, 560–562 (2003) 32. V.Y. Rudyak, G.V. Kharlamov, A.A. Belkin, The velocity autocorrelation function of nanoparticles in hard-sphere molecular system. Tech. Phys. Lett. 26, 553–556 (2000) 33. V.Y. Rudyak, G.V. Kharlamov, A.A. Belkin, Diffusion of nanoparticles and macromolecules in dense gases and liquids. High Temp. 39, 264–271 (2001) 34. F. Ould-Kaddour, D. Levesque, Diffusion of nanoparticles in dense fluids. J. Chem. Phys. 127, 154514 (2007) 35. S.K. Friedlander, Smoke, Dust, Haze. Fundamentals of Aerosol Dynamics (Oxford University Press, New York/Oxford, 2000) 36. E.O. Knutson, History of diffusion batteries in aerosol measurements. Aerosol Sci. Technol. 31, 83–128 (1999) 37. H.S. Epstein, In the resistance experienced by spheres in their motion through gases. Phys. Rev. 23, 710–733 (1924) 38. L. M€adler, S.K. Friedlender, Transport of nanoparticles in gases: overview and recent advances. Aerosol Air Qual. Res. 7, 304–342 (2007) 39. W.F. Phillips, Drug on a small sphere moving through a gas. Phys. Fluids 18, 1089–1093 (1975) 40. V.Y. Rudyak, S.L. Krasnolutskii, Kinetic description of nanoparticles diffusion in rarefied gases. Russian Phys. Dokl. (USA) 46, 1336–1339 (2001) 41. V.Y. Rudyak, S.L. Krasnolutsky, Diffusion of nanoparticles in a rarefied gas. Tech. Phys. 47(7), 807–813 (2002) 42. S. Chapman, T.G. Cowling, The Mathematical Theory of Non-Uniform Gases (Cambridge University Press, Cambridge, 1952) 43. V.Ya. Rudyak, S.L. Krasnolutskii, The interaction potential of carrier gas molecules with dispersed particles, in Rarefied Gas Dynamics XXI. Proc. 21st Int. Symp. on RGD. Toulouse, Ge´padue´sÉditions, vol. 1, 1999, pp. 263–270 44. V.Y. Rudyak, S.L. Krasnolutskii, A.G. Nasibulin, E.I. Kauppinen, About measurement methods of nanoparticles sizes and diffusion coefficient. Doklady Phys. 47, 758–761 (2002) 45. V.Y. Rudyak, S.N. Dubtsov, A.M. Baklanov, Temperature dependence of the diffusion coefficient of nano-particles. Tech. Phys. Lett. 34, 519–521 (2008) 46. V.Y. Rudyak, S.N. Dubtsov, A.M. Baklanov, Measurements of the temperature dependent diffusion coefficient of nanoparticles in the range of 295–600 K at atmospheric pressure. J. Aerosol Sci. 40, 833–843 (2009) 47. P.A. Baron, K. Willeke (eds.), Aerosol Measurement: Principles, Techniques, and Applications (Wiley, New York, 2001) Page 20 of 21

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48. V.Y. Rudyak, S.L. Krasnolutskii, E.N. Ivashchenko, Influence of the physical properties of the material of nanoparticles on their diffusion in rarefied gases. J. Eng. Phys. Thermophys. 81, 520–524 (2008) 49. J.H. Ferziger, H.G. Kaper, Mathematical Theory of Transport Processes in Gases (North-Holland, Amsterdam/London, 1972) 50. V.Y. Rudyak, S.L. Krasnolutskii, On thermal diffusion of nanoparticles in gases. Tech. Phys. 55(8), 1124–1127 (2010) 51. E.A. Mason, R.J. Munn, F.J. Smith, Thermal diffusion in gases, in Advances in Atomic and Molecular Physics, ed. by D.R. Bates (Academic, New York, 1966), p. 484 52. K.E. Grew, J.N. Mundy, Thermal diffusion in some mixtures of inert gases. Phys. Fluids 4, 1325–1332 (1961) 53. D.F. Evans, T. Tominaga, H.T. Davis, Tracer diffusion in polyatomic liquids. J. Chem. Phys. 74, 1298–1306 (1981) 54. T. Kato, K. Kikuchi, Y.J. Achiba, Measurement of the self-diffusion coefficient of C60 in benzene-D6 using 13C pulsed-gradient spin echo. Phys. Chem. 97, 10251–10253 (1993) 55. R. Haselmeyer et al., Translational diffusion in C60 and C70 fullerene solutions. Ber. Bunsenger Phys. Chem. 98, 878–881 (1994) 56. W.P. Wuelfing et al., Taylor dispersion measurements of monolayer protected clusters: a physicochemical determination of nanoparticle size. Anal. Chem. 71, 4069–4074 (1999) 57. R.W. Kowert et al., Size-dependent diffusion in cycloalkanes. Mol. Phys. 102, 1489–1497 (2004) 58. M.J. Nuevo, J.J. Morales, D.M. Heyes, Hydrodynamic behaviour of a solute particle by molecular dynamics. Mol. Phys. 91, 769–774 (1997) 59. F. Ould-Caddour, D. Levesque, Molecular-dynamics investigation of tracer diffusion in a simple liquid: test of the Stokes-Einstein law. Phys. Rev. E. 63, 011205 (2000) 60. V.Ya. Rudyak, G.V. Kharlamov, and A.A. Belkin, Direct numerical simulation of transport processes in heterogeneous media. II. Diffusion of nanoparticles and macromolecules in dense gases and liquids (NGASU, Novosibirsk, 2000). (Preprint No. 1(13)-2000, Novosibirsk State University of Architecture and Civil Engineering) 61. V.Y. Rudyak, S.L. Krasnolutskii, D.A. Ivanov, Molecular dynamics simulation of nanoparticle diffusion in dense fluids. Microfluid. Nanofluid. 11(4), 501–506 (2011) 62. I.M. Mahbubul, R. Saidur, M.A. Amalina, Latest developments on the viscosity of nanofluids. Int. J. Heat Mass Transfer. 55, 874–885 (2012) 63. E.V. Timofeeva, D.S. Smith, W. Yu, D.M. France, D. Singh, J.L. Routbo, Particle size and interfacial effects on thermo-physical and heat transfer characteristics of water-based a-SiC nanofluids. Nanotechnology 21, 215703 (2010). doi:10.1088/0957-4484/21/21/215703 64. V.Y. Rudyak, S.V. Dimov, V.V. Kuznetsov, S.P. Bardakhanov, Measurement of the viscosity coefficient of an ethylene glycol–based nanofluid with silicon dioxide particles. Doklady Phys. 58(5), 173–176 (2013) 65. V.Y. Rudyak, S.V. Dimov, V.V. Kuznetsov, About dependence of the nanofluid viscosity coefficient on the temperature and size of the particles. Tech. Phys. Lett. 39(17), 53–59 (2013) 66. V.Y. Rudyak, Viscosity of nanofluids. Why it is not described by the classical theories. Adv. Nanopart. 2(3), 266–279 (2013)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Application of Nanoparticles in Manufacturing Qin Hu*, Christopher Tuck, Ricky Wildman and Richard Hague Faculty of Engineering, EPSRC Centre for Innovative Manufacturing in Additive Manufacturing, The University of Nottingham, Nottingham, UK

Abstract With the development of nanoscience and nanotechnology, manufacturing is undergoing revolutionary changes. Nanoparticles, due to their novel and often enhanced properties, are now more and more used in manufacturing. In this chapter, the state-of-the-art application of nanoparticles in manufacturing is reviewed. The contents include five parts: (a) role of nanoparticles in manufacturing, (b) manufacturing methods, (c) applications, (d) challenges, and (e) conclusions. The roles of nanoparticles are divided into three categories: (i) building blocks, being the major component of a manufactured product by solid-state or colloidal nanoparticle consolidation; (ii) functional filler, as an addition for functionality, such as property improver, catalyst, stimuli-responsive, sensing, imaging, and carrier; and (iii) nanocomposites for multifunctionality. Various manufacturing methods and novel trends are summarized in this chapter, including top-down and bottom-up, from 2D to 3D, from cleanroom to desktop, 3D printing, and bio-assisted methods, such as DNA origami. Direct applications in areas of flexible electronics, molecular electronics, solar cells, construction industry, water treatment, and biomedical devices are presented. The associated challenges including nanoparticle safety issue, sustainable manufacturing, economic issue, and scale-up are discussed.

Role of Nanoparticles in Manufacturing With the development of nanoscience and nanotechnology, manufacturing is undergoing revolutionary changes. Nanoparticles, due to their novel and often enhanced properties, have more and more been used in various manufacturing applications. Their role can generally be divided into three categories: (a) building blocks, (b) functional filler, and (c) nanocomposites for multifunctionality, which is summarized in Table 1.

Building Block Nanoparticles sometimes act like the bricks in a house-building process to be the main component of a manufactured product. They can be consolidated via solid- and liquid-based methods. Solid-State Nanoparticle Consolidation Solid-state metallic, ceramic, amorphous, and compound particles can be thermomechanically processed to form bulk 2D/3D structures with desired strength and level of densification (even full densification is possible). Reported methods include powder compact forging/extrusion, equal channel angular extrusion/ pressing, and hot pressing/sinter forging combined with conventional heating, laser sintering, microwave sintering, electric discharge sintering, or spark plasma sintering [33, 255, 278, 306, 425, 426, 476, 492]. Particles with a narrow size distribution and spherical shape are desired to achieve low pore-to*Email: [email protected] *Email: [email protected] Page 1 of 53

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Table 1 Summary of the role of nanoparticles in manufacturing Role of NPs Building blocks As a major component of manufactured product – Like bricks in housing building

Functional filler As an addition for a special functionality

Property improver

Catalyst

General remarks Solid-state NPs consolidation – by heat and pressure: Powder compact forging/ extrusion Equal channel angular extrusion/ pressing Hot pressing/sinter forging Combined with conventional heating, laser sintering, microwave sintering, electric discharge sintering, or spark plasma sintering Need high pressure Sintering temperature is often lower than their bulk counterparts Colloidal NPs consolidation – by liquid-based techniques: Inkjet printing Screen printing Stamp printing Electro-spinning Spin coating Self-assembly Sintering is often followed to remove the protective layer around NPs Due to NPs intrinsic properties (e.g., size, shape, and surface treatment) and the newly formed bonds/structures with surrounding matrix Properties that can be improved include: Mechanical properties: Young’s modulus, tensile strength and dimensional stability Thermal stability Tribology Electrical conductivity Chemical resistance Flame resistance Optical properties Antimicrobials and biostability Due to high surface-to-volume ratios, tailorable selectivity and activity, easy separation, and recovery May serve as heterogeneous catalysts or catalyst supports in both gas and liquid phase Performance depends on individual properties of catalytic particles and

Nanoparticles Metals (e.g., Ag, Cu, Al, Fe, Ni, Ti, Pt, and Pd), alloys, oxides, carbides, nitrides, silicides, composites

References [33, 107, 114, 255, 278, 306, 333, 376, 425–427, 476, 492]

Metals (e.g., Ag, and Au), SiO2, SiC, metal oxides (e.g., Al2O3, Fe2O3, and TiO2), quantum dots (e.g., CdS and PbS)

[66, 125, 147, 213, 242, 339, 394, 436, 459]

Metals (e.g., Au, Ag, Cu, Pd, Pt, and Ni), Oxides (e.g., TiO2), quantum dots

[13, 71, 262, 267, 287, 297, 328, 344, 346]

(continued) Page 2 of 53

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Table 1 (continued) Role of NPs

General remarks

Stimuliresponsive

Sensing

Imaging

their supports (e.g., size, shape, structure, composition, and stability), as well as their collective properties (e.g., their relative spatial location and interaction between the particles and the supports) Works by receiving external signals (physical or chemical), changing their properties or experiencing chemical reactions, and then transducing the changes into a macro-/microscopically significant event Format: Photo-responsive Magneto-responsive Electro-responsive Thermo-responsive Chemical-responsive Aqua-responsive Applications include micro-reactor, smart products for personal care, diagnostics in medicine, intelligent drug delivery, intelligent catalyst, etc. Due to NPs novel characteristics (e.g., high reactivity, high surfaceto-volume ratio, surface tunability, size control, and chemical stabilities) Advantages: rapid response, high sensitivity, high selectivity, and high accuracy Format: Optical sensing Electrical/electrochemical sensing Magnetic sensing Applications include sensors for explosive chemicals, gas detection, biomedical diagnostics and analytics, food industry, etc. As contrast enhancement agents and molecular probes Advantages: Magnetic particles: suitable for magnetic resonance imaging (MRI) Quantum dots: size tunable, broad absorption spectra, efficient light absorption, narrow light

Nanoparticles

References

Nobel metals (e.g., Au and Ag), magnetic particles, composites

[158, 181, 265, 275, 358, 367, 381, 401, 440]

Nobel metals (e.g., Au, Ag), quantum dots, transition metals, magnetic particles, composites

[59, 68, 79, 82, 90, 196, 336, 397, 405]

Magnetic particles (e.g., Fe3O4, g-Fe2O3, and MnFe2O4), quantum dots (e.g., CdS, CdSe and CdTe), noble metals (e.g., Au), silica, carbon, composites

[86, 169, 210, 321, 409, 412, 429, 448, 500]

(continued)

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Table 1 (continued) Role of NPs

General remarks

Carrier

Nanocomposites for multifunctionality

emission, multiple signals simultaneous detection, long fluorescent lifetime, high resistance to photobleaching, and super bright Au: unique optical and electrical properties, e.g., surface plasmon resonance Typical application: biomedical diagnostics and analytics As cargo carrier due to its high surface-to-volume ratio, controllable surface functionality, and ability to cross physiological barriers and reach different tissues in a controllable style Performance depends on size, shape, rigidity, surface charge, and ligand density Typical application: drug/gene delivery, biomarker, and agrochemical delivery in plants Combined properties from individual component and new properties based on the hierarchically organized multicompartment at different length scale Popular architecture: Particle-brush structure Hybrid core-shell structure Applications include smart products, bio-imaging, diagnostics, and therapeutics

Nanoparticles

References

Quantum dots, noble metals, magnetics, silica, polymer, lipid, micelles, dendrimers, composites

[90, 101, 205, 300, 327, 343, 383, 467, 485]

Integration of different nanostructured materials

[54, 155, 162, 173, 180, 275, 380]

particle-size ratio and homogeneous density [45]. Owing to their extremely small size and high surface area, the sintering temperature of nanoparticles is much lower than that of their micrometer or bulk counterparts [107]. High applied pressures are associated with nanoparticle rearrangement and sliding, plastic deformation, and pore shrinkage [45]. Colloidal Nanoparticle Consolidation Colloidal nanoparticles can be consolidated by various liquid-based techniques, e.g., inkjet printing, screen printing, stamp printing, electrospinning, spin coating, and self-assembly [114, 376, 427]. A popular application of metal nanoparticles is to act as conducting tracks/layers in printed electronic devices [4, 150]. As nanoparticles are capped by organic ligands to prevent agglomeration, sintering is recommended to make the printed features conductive [273, 333]. By applying a special 3D coalescence process, sintering even at room temperature is possible – inkjet-printed Ag nanoparticle electrodes prepared in this way achieved 20 % of the conductivity of bulk Ag [243]. Metallic nanoparticles (e.g., Ag, Au, Pt, and Pd) can also self-assemble into plastic and moldable metals by a two-step method – they first self-assemble into spherical deformable aggregates and then glue together against arbitrarily shaped Page 4 of 53

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Fig. 1 (a) Left: Illustration of metal nanoparticles self-assembly into deformable spherical aggregates (“supraspheres”) triggered by ultraviolet (UV) light. Right: SEM image of a typical suprasphere on a silicon surface. The diameter of the nanoparticles is ~5 nm, and the self-assembled superasphere is 50 ~ 300 nm. The superaspheres are highly deformable upon contact with a substrate or other spheres. (b) Illustration of the molding process of forming arbitrary structures using the selfassembled supraspheres. (c) Left and middle: SEM images of molded microlens and microgear using the supraspheres. Right: Magnified SEM image showing the individual supraspheres. (d) Polypropylene miniature before (left) and after (right) coating with supraspheres (From Ref. [192]. Reprinted with permission from AAAS)

masters into desired macrostructures, as illustrated in Fig. 1 [192]. The synthesized material can also be thermally hardened into polycrystalline metal structures with controllable porosity [192]. This method can also be applied for a mixture of different nanoparticles.

Functional Filler In a manufacturing process, a small amount of nanoparticles are sometimes added for various functionalities, e.g., improving a material’s existing properties, being a catalyst to promote some reaction, being a medium to transduce external signals into a macro-/microscopically significant event, helping neighbors to be detected or imaged, or carrying cargos to desired locations. The role played by nanoparticles could be passively achieved by particles themselves or be actively achieved by functionalization (e.g., surface modification) [14, 36, 259, 280, 377]. Property Improver A material’s various properties can often be improved by the addition of nanoparticles due to particles’ intrinsic properties or the newly formed bonds or structures with the surrounding matrix by the relevant

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

interfacial forces such as van der Waals force, electrostatic force, and capillary force [125]. Properties that can be improved include: • Mechanical properties, e.g., Young’s modulus, tensile strength, and dimensional stability. Nylon6 infused with 5 wt% 50 nm SiO2 nanoparticles shows an increase in tensile strength by 15 %, strain-tofailure by 150 %, Young’s modulus by 23 %, and impact strength by 78 % [307]. Dental composite resins with SiO2 nanoparticles also show significantly improved flexural strength, fracture toughness, and hardness when compared with the conventional composite [147]. • Thermal stability: The thermal degradation temperature of hydroxypropyl methylcellulose edible films with chitosan nanoparticles increased from 232  C (without nanoparticles) to 271  C (with nanoparticles) [73]. Pyrolytic shrinkage of SiCN ceramic microstructure after two-photon lithography can be significantly minimized with the addition of 40 wt% of SiO2 nanoparticles [339]. • Tribology: In a NH3/H2O binary nanofluidic system, the heat transfer rate and absorption rate show 29 % and 18 % increase with the addition of 0.02 vol% Al2O3 nanoparticles [213]. The wear resistance of PTFE can be improved by 600 times with the addition of 20 wt% 40 nm Al2O3 particles [379]. • Electrical conductivity: Ag nanoparticles decorated carbon nanotubes can improve the electrical conductivity of carbon nanotube-polymer composites by four times [242]. • Chemical resistance: Epoxy-coated steel with Fe2O3 nanoparticles and halloysite clay nanoparticles in the coating exhibits significantly enhanced corrosion resistance after immersion in NaCl solution for 28 days [394]. • Flame resistance: TiO2 nanoparticles can improve fire resistance of conventional flame-retardant coatings [436]. • Optical properties: Inkjet-printed ZnO thin films achieved three orders of magnitude enhancement in UV photoresponse by capped CdS nanoparticles [459]. • Antimicrobials and biostability: e.g., Ag nanoparticles [66, 131, 353]. The popular nanoparticles used for the above applications include metals (e.g., Ag and Au), SiO2, SiC, metal oxides (e.g., TiO2, Al2O3, Fe2O3), and quantum dots (e.g., PbS and CdS). However, not just any particle addition brings an enhanced effect. The addition of untreated, as-received Al2O3 leads the fracture toughness of unsaturated polyester to decrease by 15 %, due to the poor particle-matrix bonding [482]. The particles’ surface treatment, size and shape, matrix ductility, and the formed nanostructure all have an effect on the performance of the composites [38, 457]. For example, concrete with smaller SiO2 particle addition (12 nm compared to 150 nm) shows accelerated cement hydration, reduced pore size, increased pozzolanic activity, and improved interfacial bonding [479]. In addition, such benefits do not follow a regime of the more the better. The flexural strength of self-compacting concrete can be improved by adding up to 4 wt% SiO2 nanoparticles; however, the strength is reduced when the addition is over this amount [288]. The anticorrosion performance of epoxy-coated mild steel can be improved by the addition of 2 wt% SiO2 nanoparticles; however, when the addition is over this amount, the number of pores in the coating is increased, thus having a negative impact on corrosion inhibition [223]. In addition, the function of nanoparticles can be multiple. Ag nanoparticles can enhance mechanical properties, thermal properties, and biostability of polyurethane [66]. Biphasic calcium phosphate scaffolds with 40 wt% bioactive glass nanoparticles exhibit 44 times increased compressive strength, three times increased modulus, better bioactivity, and faster degradation rates [364]. Transparent organic coatings with SiO2 nanoparticles exhibit improved modulus, hardness, and wear resistance; however, the optical properties such as transmittance, haze, and gloss are slightly decreased [486].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Fig. 2 A series of photos showing the shape transition of composites (Fe3O4 nanoparticles embedded in polymer matrix) activated by an external electromagnetic field. The size of the sample is about 15  2  0.5 mm (Reproduced from Ref. [381] with permission from John Wiley and Sons)

Catalyst Nanoparticles have emerged as a sustained alternative to conventional catalysts, due to their high surfaceto-volume ratios (thereby hugely enhancing the contact between the reactants and the catalyst), tailorable selectivity and activity, easy separation, and recovery [13, 344]. They may serve as robust heterogeneous catalysts and catalyst supports in both the gas and liquid phase. The popular nanoparticles used for this purpose include Au, Ag, Cu, Pd, Pt, Ni, and TiO2 [71, 83, 262, 267, 328]. In addition, graphene quantum dots are reported as excellent metal-free catalysts for oxygen reduction reactions [224, 393]. Support materials include porous SiO2, metal oxides (e.g., Al2O3 and ZrO2), magnetics, carbons, carbides, and organic polymers [115, 262, 344, 497]. A core-shell structure has been introduced in recent years with improved activity compared to traditionally used porous structures, in which the noble metal nanoparticle acts as the core and the support material as the shell [438, 449, 477]. The performance of the nano-catalysis is controlled by the individual properties of catalytic particles and their supports (e.g., size, shape, structure, composition, and stability) as well as the collective properties (e.g., their relative spatial location and interaction between the particles and the supports) [62, 281, 287, 297, 318, 346]. Nano-catalysis has various applications, including selective oxidation reaction and selective reduction reaction. One practical example is to use supported iron nanoparticles as catalysts for sustainable production of lower olefins, which are key integrations in polymer, drug, and cosmetics manufacturing [112]. Solar-driven photocatalysis has practical applications in energy-efficient and environmentally benign applications, such as wastewater treatment, air purification, energy-efficient buildings, and solar-to-hydrogen energy conversion. Plasmonic photocatalysis has enhanced photocatalytic efficiency [148, 238, 488, 494]. The current challenges of nano-catalysts include (i) improving the efficiency and selectivity of the reactions; (ii) improving the lifetime, recovery, and recyclability of the catalytic materials; and (iii) synthesizing and processing following “green chemistry” principles [478]. Stimuli-Responsive Stimuli-responsive nanoparticles work by receiving external signals (physical or chemical), changing their properties or experiencing chemical reactions, and then transducing the changes into a macro-/ microscopically significant event [275, 367, 401]. They can be photoactive, magneto-active, electroactive, thermo-active, chemical-active, and aqua-active [265, 440]. A popular use is for magnetic or metal nanoparticles, which are exposed to magnetic fields or light, that generate heat or force. Polymer networks incorporating magnetic nanoparticles can experience complex shape transitions when exposed to remotely controlled electromagnetic fields, as shown in Fig. 2 [381]. Temperature-sensitive ion channels can be triggered by the bio-conjugated nanoparticles and thereby activate cellular signals [158]. The local thermal activation can also be used to kill bacteria or cells in cancer and other disease treatment [181, 358]. Black carbon nanoparticles stimulated by femtosecond laser pulses can generate locally controlled shock

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

waves which can facilitate the delivery of small molecules, proteins, and DNA efficiently through plasma membranes into cells, while still maintaining high cell viability [46]. The current trend is to develop smart nanoparticles that can respond to multiple signals and generate multiple responses. Sensing Nanoparticles’s novel characteristics such as high surface-to-volume ratio, surface tunability, high reactivity, size control, and chemical stabilities offer them as excellent sensors, with rapid response, high sensitivity, high selectivity, and high accuracy [90, 405]. For example, the high surface-to-volume ratio and surface tunability enable nanoparticles to have a large surface area and to be individually functionalized, to detect different biomarkers using a very small amount of sample. The demonstrated sensitivity can reach pico- (p, 10 12), femto- (f, 10 15), atto- (a, 10 18), and even zepto- (z, 10 21) scales [405]. The popular nanoparticles used for sensing include noble metals (especially Au) [98, 169, 372, 382], quantum dots (both traditional semiconductor quantum dots and new emerging graphene quantum dots) [196, 259, 393, 456, 462, 500], transition metals [96, 234], and magnetic particles [390, 434]. The sensing can be categorized according to signals into optical, electrical/electrochemical, and magnetic type [336, 405]. The popular optical methods include light absorption, light scattering, localized surface plasmon resonance, surface-enhanced Raman scattering, surface chemistry and ligands, colorimetric, and fluorescence [170, 372, 405, 443]. Novel metal nanoparticle-based localized surface plasmon resonance (LSPR) sensing has experienced signification progress in recent years [254, 452]. It has additional advantages of small sensing volumes, wavelength tunability, and low-cost instrumentation [452]. The sensitivity is size, shape, composition, and local environment dependent [170, 254, 452]. In addition, single-particle-based sensing offers a unique tool for probing individual behavior and processes, and even single molecule detection is possible [8, 10]. A well-known commercial product based on LSPR is pregnancy testing kits. Optical sensing has the advantages of high speed, signal immunity to electrical or magnetic interferences, and the potential for large information content; however, it may suffer from the high cost of some instrumentation [82]. The electrical/electrochemical method is relatively simple and of low cost and works by monitoring the changes of the current, the ohmic response, and the potential when nanoparticles bind with targets [336, 372, 405]. The magnetic method offers a robust in vivo detection using magnetic particles [134, 434]. Nanoparticle sensors have been widely used in various areas. Explosive chemicals such as nitroaromatic derivatives can be monitored by Au and Ru nanoparticles, which can be used for military and homeland security [59, 362]. Nanocomposites such as Ag/ZnO, Co3O4/ZnO, and CuO/TiO2/Au are especially useful for flammable gas detection [23, 31, 397]. Humidity sensors using CdS show three orders of change in resistance when the relative humidity varies between 17 % and 85 % [79]. Toxic metal ions (e.g., Hg2+, Pb2+, Cd2+, Cu2+) in both environmental and biological samples can be quickly monitored by Au/Ag nanoparticles or quantum dots in fluorescent and colorimetric way [95, 190, 229]. Au nanoparticles have also been used in the food industry for detection of aromas and melamine [68, 444]. The size-based spectral tuning and light absorption of metal nanoparticles and quantum dots have promoted their use for photon detection in imaging, spectroscopy, and fiberoptic communications [196]. The most significant advancement in recent years is for biological applications, such as biomarker/ cell detecting and disease diagnostics [173, 197, 336, 405]. To further promote its applications, work in the following directions needs to be focused: (i) developing chemical and physical methods to promote nanoparticle efficient binding and clearance, (ii) minimizing both nanoparticle and molecule leaking out of chemical/biosensor to avoid contamination, and (iii) developing robust, high-precision, low-cost, and high-throughput fabrication methods [10, 82].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Imaging Nanoparticles often serve as contrast enhancement agents and molecular probes for imaging technologies which have been dramatically used in biomedical diagnostics and analytics [86, 321, 412, 448]. Magnetic particles, including Fe3O4, g-Fe2O3, and MnFe2O4, are probably the most extensively explored nanomaterials, especially in magnetic resonance imaging (MRI) for cancer imaging, cardiovascular disease imaging, and molecule imaging [108, 210, 404]. MRI’s contrast effect depends on particle size, composition, doping, assembly, and surface properties [210]. Semiconductor quantum dots, such as CdS, CdSe, and CdTe, are widely used for fluorescent optical imaging [259, 432, 442, 456, 500]. Compared to traditionally used fluorophores, quantum dots exhibit many supreme advantages, such as being size tunable and super bright and having broad absorption spectra, efficient light absorption, narrow light emission, multiple signals simultaneous detection, long fluorescent lifetime, and high resistance to photobleaching [500]. Thus, they are excellent candidates for cell tracking [412]. Noble metal nanoparticles, especially Au nanoparticles, with unique optical and electrical properties, such as surface plasmon resonance, are widely used for light scattering imaging, two-photon fluorescence imaging, photoacoustic imaging, photothermal imaging, X-ray computed tomography (CT), and sample labeling [40, 90, 169, 279, 314]. The scattered light by Au nanoparticle at its plasmon wavelength could be five orders stronger than that of the emission from a fluorescing dye [168]. The other reported nanomaterials include silica nanoparticles [429], carbon nanoparticles [285], nano-diamonds [268, 335], and composite nanoparticles [222, 323, 409]. To serve as contrast agents, nanoparticles need to have the following properties: (i) forming stable colloidal solutions, (ii) maintaining chemical stability under different conditions, (iii) with high sensitivity and selectivity to the target, (iv) exhibiting limited nonspecific binding, (v) with programmable clearance mechanisms, and (vi) having good image contrast [429]. For in vivo observation, nanoparticles can be delivered via mechanical or nonmechanical methods into living cells, such as microinjection, nanotube-assisted injection, and endosome-mediated cell penetration [500]. To assist the translation from laboratory to clinic, further work needs to improve nanoparticles’ additional functionalities, biocompatibility, targeting efficiency (including the ability to track individual cells), and biodegradability [429, 448]. Carrier Nanoparticles are often served as cargo carriers due to the high surface-to-volume ratio and controllable surface functionality. A major application is in the biomedical area as a carrier for drug/gene delivery [300, 327, 343, 485], biomarkers [205], and agrochemicals in plants [383], as nanoparticles can often cross physiological barriers and reach different tissues in a controllable style. Various particles have been reported, including polymeric [101], silica [365, 410], magnetic [236, 295, 404], noble metal (especially Au nanoparticles) [12, 90], quantum dots [347], lipid [7, 29, 230], micelles [189], dendrimers [313], hybrid structures [143, 144], and even the new emerging nano-diamond [268]. The particle’s size, shape, rigidity, surface charge, and ligand density all have an effect on particle-cellular uptake [419, 467]. The reported cargo loading methods include partitioning, surface complexation, attachment to capping agents, layer-by-layer assembly, or loading inside the nanoparticles [90]. Using stimuli-responsive materials to engineer cargo carriers can help to achieve controllable delivery [61, 253, 282, 338]. Engineered carriers must be carefully chosen based on their loading capacity, targeting ability, cargo release ability, physical and functional stability, solubility, biocompatibility, and immune toxicity [72, 199, 233, 300, 338]. For clinical practice, particle’s specificity, functionality, and efficiency need to be improved.

Nanocomposites for Multifunctionality Nanocomposites are the integration of more than one nanostructured materials and have been developed rapidly in recent years [21, 94, 144, 180, 283]. They combine properties from their individual components Page 9 of 53

Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

a Nanoparticle

Polymer Brush Topology linear cyclic star Composition

graft

(hyper) network branched

homopolymer block copolymer

gradient

periodic

statistical

Functionality macromonomer end-functional

multi functional side functional telechelic

Molecular Weight & Molecular Weight Distribution

p h olo

in C h arac

Particle Brush

Chain Morphology Semi-Crystallinity Liquid Crystallinity Microphase Separation

M or

ha

Chain Composition/Topology

Electric, Magnetic Mechanical, Thermal

gy

C

vs

External Fields

t. Arc

Graft Density

hit e c t u

re

Directional Interactions

Graft Uniformity

b Biosensing:

Polymer gap:

ultrathin (~ 2-4 nm)

1): Prevent direct contact of the core/shell; 2): Tune LSPR response to NIR region;

Enzymatic Ag/Au Ns

Au Shell

LSPR shift Multimodal imaging:

Core

“solid/soft”:

Plasmonic Sensing Gox

Darkfield MRI

mmPA

PAT

semiconductor Qdot; superparamagnetic NP; cargo-loaded liposome; ---

(MNP/Au)

mmPA imaging

Controlled release: Multifunctional plasmonic hybrid AuNS

NIR

(overall size:~ 15-60 nm)

Liposome/AuNS

Rupture/ Cargo release

Fig. 3 Illustration of two popular architecture of multifunctional nanocomposite: (a) particle-brush structure, and (b) coreshell structure ((a) Adapted with permission from Ref [162]. Copyright 2014 American Chemical Society. (b) Reprinted with permission from Ref [173]. Copyright 2014 American Chemical Society)

and may also combine with new properties based on the hierarchically organized multi-compartment at different length scales [180]. Due to these reasons, nanocomposites could be multifunctional. A simple example is the particle-brush structure, which is illustrated in Fig. 3a [162]. Parameters that could influence the composite’s functionality include the polymer brush’s composition, topology and functionality, connectivity with particle, particle’s surface morphology, spatial distribution of brushes on the particle, as well as potential coupling to external fields [162]. Another popular architecture is the hybrid core-shell structure [54, 144, 155, 275, 414]. Figure 3b shows a hybrid structure composed of a plasmonic Au shell and non-plasmonic core [173]. The material of the core could be semiconductor quantum dots, magnetic nanoparticles, and even cargo-loaded liposome. The optical property of the hybrid could be tuned by the Au shell-induced localized surface plasmon resonance in the near-infrared region. Methods to synthesize nanocomposites include self-assembly, heterogeneous polymerization, layer-by-layer assembly, and surface modification from pre-synthesized polymers and particles [21, 54, 155, 275, 378, 401].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Fig. 4 Illustration of elastomeric polymer opal film with reversible light-, thermo-, and mechanical-responses. The film is made by colloidal RhBMA-labeled nanocomposite consolidation via compression molding. (a): Optical images of (right) a patterned elastomeric film after exposing to UV light and (left) pattern erasing after heating. (b): Optical images of the film viewing from different angles. (c) TEM image of the film showing the hexagonally ordered 111 plane. (d) Optical images of the film at different strains e (Reprinted with permission from Ref. [380]. Copyright 2013 American Chemical Society)

However, synthesizing with well-controlled combination, architecture, and functionality in a robust and simple route is a big challenge. The formed composite may later serve as building blocks of macro-devices while at the same time still maintaining their functionality [180]. As shown in Fig. 4, large-scale robust elastomeric opal films, made by colloidal nanocomposite consolidation through compression molding, exhibit triple reversible stimuli responses to light, temperature, and strain [380]. A rapidly developing area is to use nanocomposite for bio-imaging, diagnostics, and therapeutics [36, 144, 214, 298, 351, 500].

Manufacturing Methods Common Methods Top-Down and Bottom-Up A variety of techniques have been developed in the last two decades for material micro-/nanopatterning and device fabrication. Generally they can be divided into two major categories: top-down and bottom-up [37, 114, 226, 474]. The top-down approach uses various physical or chemical methods such as lithographic tools to produce nanostructures by deconstructing larger materials, while bottom-up approach uses the chemical properties of single molecules to cause molecular or atomic components to assemble into complex features. The resolution, merits, demerits, and general remarks of some methods are summarized in Table 2 [37]. From 2D to 3D General application normally requires the product being three dimensional (3D); however, most demonstrated micro-/nanofabrication techniques are intrinsically two dimensional (2D). The traditional approach from 2D to 3D is via layer-by-layer assembly, which offers an easy, inexpensive, versatile, and flexible process for multilayer formation and multi-material integration [11, 48, 91, 166, 228, 496]. However, multistep processing also means long time consumption. Another popular route is via origami, in which self-folding is achieved using stimuli-responsive materials [159, 165, 219, 356]. A variety of structures, such as boxes, tubes, rings, coils, and wrinkles, have been demonstrated [26, 216, 260, 261].

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Handbook of Nanoparticles DOI 10.1007/978-3-319-13188-7_55-1 # Springer International Publishing Switzerland 2015

Table 2 Summary of selected top-down and bottom-up methods (Modified from Ref. [37] with permission from Elsevier) Methods Top-down Optical lithography

Resolution

Merits

Demerits

General remarks

~50 nm

Long-standing, established micro-/nanofabrication tool especially for chip production, sufficient level of resolution at high throughputs

Tradeoff between resist process sensitivity and resolution, involves stateof-the-art expensive clean room-based complex operations

E-beam lithography

~10 nm

Popular in research environments, an extremely accurate method and effective nanofabrication tool for