Carbon Nanotubes for Targeted Drug Delivery [1st ed. 2019] 978-981-15-0909-4, 978-981-15-0910-0

Table of contents :
Front Matter ....Pages i-xiv
Background: Carbon Nanotubes for Targeted Drug Delivery (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 1-9
Classification of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 11-15
Synthesis of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 17-20
Functionalization of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 21-28
Characterization of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 29-31
Applications of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 33-36
Targeted Delivery with Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 37-50
Carbon Nanotubes in Controlled Drug Delivery (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 51-54
CNTs in Solubility Enhancement (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 55-57
Carbon Nanotubes as Quantum Dots for Therapeutic Purpose (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 59-64
Absorption and Transportation of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 65-68
Carbon Nanotubes in Vaccine Delivery (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 69-73
Carbon Nanotubes in Gene Delivery (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 75-87
Toxicity Consideration of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 89-101
Regulatory Considerations of Carbon Nanotubes (Md Saquib Hasnain, Amit Kumar Nayak)....Pages 103-106

Citation preview

SPRINGER BRIEFS IN APPLIED SCIENCES AND TECHNOLOGY

Md Saquib Hasnain Amit Kumar Nayak

Carbon Nanotubes for Targeted Drug Delivery 123

SpringerBriefs in Applied Sciences and Technology

SpringerBriefs present concise summaries of cutting-edge research and practical applications across a wide spectrum of fields. Featuring compact volumes of 50– 125 pages, the series covers a range of content from professional to academic. Typical publications can be: • A timely report of state-of-the art methods • An introduction to or a manual for the application of mathematical or computer techniques • A bridge between new research results, as published in journal articles • A snapshot of a hot or emerging topic • An in-depth case study • A presentation of core concepts that students must understand in order to make independent contributions SpringerBriefs are characterized by fast, global electronic dissemination, standard publishing contracts, standardized manuscript preparation and formatting guidelines, and expedited production schedules. On the one hand, SpringerBriefs in Applied Sciences and Technology are devoted to the publication of fundamentals and applications within the different classical engineering disciplines as well as in interdisciplinary fields that recently emerged between these areas. On the other hand, as the boundary separating fundamental research and applied technology is more and more dissolving, this series is particularly open to trans-disciplinary topics between fundamental science and engineering. Indexed by EI-Compendex, SCOPUS and Springerlink.

More information about this series at http://www.springer.com/series/8884

Md Saquib Hasnain Amit Kumar Nayak •

Carbon Nanotubes for Targeted Drug Delivery

123

Md Saquib Hasnain Department of Pharmacy Shri Venkateshwara University Amroha, Uttar Pradesh, India

Amit Kumar Nayak Department of Pharmaceutics Seemanta Institute of Pharmaceutical Science Mayurbhanj, Odisha, India

ISSN 2191-530X ISSN 2191-5318 (electronic) SpringerBriefs in Applied Sciences and Technology ISBN 978-981-15-0909-4 ISBN 978-981-15-0910-0 (eBook) https://doi.org/10.1007/978-981-15-0910-0 © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Synopsis: Short Abstract, Motivation for the Book

This book is targeted for the audience who is basically involved in the biological sciences like pharmacy, biotechnology, bioengineering, nanotechnology as well as for the bioscience studies to develop the targeted drug delivery systems by carbon nanotubes (CNTs). This book provides basics as well as advanced knowledge of CNTs for targeted drug delivery in a comprehensive manner. So, this work is very useful for health professionals like students, teachers, researchers as well as industrial professionals to explore the potential of CNTs for their application in biomedical sciences. This book covers all the topics of CNTs for targeted drug delivery in a concise way with the help of figures, tables and flowcharts for easy understanding of readers. This book contains the chapters on classification, preparation, characterization of carbon nanotubes. This book also contains chapters specifically on targeted drug delivery of CNTs. It also has chapters on CNTs for controlled drug delivery, CNTs for solubility enhancement, CNTs for vaccine delivery, CNTs for gene delivery and CNTs as quantum dots. This book also covers the absorption and transportation of CNTs, toxicity consideration and regulatory considerations of CNTs. Therefore, this book is fully dedicated for the biological scientists for better understanding of CNTs for targeted drug delivery and their biomedical applications. In a nutshell, this book is very concise, up to date and useful on Carbon nanotubes for targeted drug delivery for the professionals.

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Contents

1 1 6

1

Background: Carbon Nanotubes for Targeted Drug Delivery . . . . . 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

Classification of Carbon Nanotubes . . . . 2.1 Classification of CNTs . . . . . . . . . . 2.2 Differences in SWNTs and MWNTs References . . . . . . . . . . . . . . . . . . . . . . . .

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Synthesis of Carbon Nanotubes . . . . . . . . . . . . . . 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Method of Synthesis . . . . . . . . . . . . . . . . . . 3.2.1 Laser Ablation (LA) Technique . . . . 3.2.2 Chemical Vapor Deposition (CVD) . 3.2.3 Electric Arc Discharge (EAD) . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Functionalization of Carbon Nanotubes 4.1 Introduction . . . . . . . . . . . . . . . . . 4.2 Properties of Functionalized-CNTs . 4.2.1 Solubility . . . . . . . . . . . . . 4.2.2 Solution NMR . . . . . . . . . 4.2.3 Microscopy Analysis . . . . 4.3 Non-covalent Functionalization . . . 4.4 Covalent Functionalization . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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Characterization of Carbon Nanotubes . . . . . . . . . . . . . . . . . 5.1 Various Instrumentation Techniques for Characterization of CNTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Electron Microscopy for Characterization of CNTs . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contents

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Applications of Carbon Nanotubes . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 CNTs Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33 33 35

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Targeted Delivery with Carbon Nanotubes . 7.1 Introduction . . . . . . . . . . . . . . . . . . . . 7.2 CNTs in Cancer Targeting . . . . . . . . . . 7.3 CNTs in Brain Targeting . . . . . . . . . . . 7.4 CNTs in Lymphatic Targeting . . . . . . . 7.5 CNTs in Ocular Drug Targeting . . . . . 7.6 Nanotube-Based Antibody Therapy . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Carbon Nanotubes in Controlled Drug Delivery . 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Use of CNTs in Controlled Drug Delivery . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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CNTs in Solubility Enhancement . . . . . . . . . 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . 9.2 Use of CNTs in Solubility Enhancement References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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10 Carbon Nanotubes as Quantum Dots for Therapeutic Purpose 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 Structural Design of Q-dots . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11 Absorption and Transportation of Carbon Nanotubes . . . . . . . . . . 11.1 Absorption and Transportation of CNTs . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65 65 67

12 Carbon Nanotubes in Vaccine Delivery . 12.1 Introduction . . . . . . . . . . . . . . . . . 12.2 CNTs in Vaccine Delivery . . . . . . 12.3 Use of CNT as Vaccines, in Vivo . References . . . . . . . . . . . . . . . . . . . . . . .

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Carbon Nanotubes in Gene Delivery . . . . . . . . . . . . . . . . . . . . . 13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2 Advantages Offered by CNTs Over Other Non-viral Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3 CNT-Mediated Gene Therapeutics . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14 Toxicity Consideration of Carbon Nanotubes . . . . . . . 14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2 GIT and Its Interaction with Nanoparticles . . . . . . 14.3 Route of Nanoparticle Transport . . . . . . . . . . . . . 14.4 Toxicological Concerns with Nanoparticles . . . . . 14.5 Toxicity of Carbon Nanocarriers . . . . . . . . . . . . . 14.6 CNT Properties as the Determinant of Toxicity . . 14.6.1 Dimensions . . . . . . . . . . . . . . . . . . . . . . 14.6.2 Surface Properties and Functionalizations References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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15 Regulatory Considerations of Carbon Nanotubes 15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 15.2 Regulatory Considerations of CNTs . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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About the Authors

Dr. Md Saquib Hasnain, Ph.D. has over 8 years of research experience in the field of drug delivery and pharmaceutical formulation analyses, especially systematic development and characterization of diverse nanostructured drug delivery systems, controlled release drug delivery systems, bio-enhanced drug delivery systems, nanomaterials and nanocomposites employing ‘Quality by Design’ approaches as well as development and characterization of polymeric composites, formulation characterization and many more. Till date, he has authored over 35 publications in various high impact peer-reviewed journals, 40 book chapters, seven books and one Indian patent application to his credit. He is also serving as the reviewer of several prestigious journals. Overall, he has earned highly impressive publishing and cited record in Google Scholar (H-Index: 14). He has also participated and presented his research work at over ten conferences in India and abroad. He served as the member of various scientific societies. Dr. Amit Kumar Nayak, Ph.D. is currently working as Associate Professor at Seemanta Institute of Pharmaceutical Sciences, Odisha, India. He has earned his Ph.D. in Pharmaceutical Sciences from IFTM University, Moradabad, UP, India. He has over 11 years of research experience in the field of pharmaceutics, especially in the development and characterization of polymeric composites, polymeric gels, hydrogels, novel and nanostructured drug delivery systems. Till date, he has authored over 110 publications in various high impact peer-reviewed journals and 34 book chapters and six books to his credit. Overall, he has earned highly impressive publishing and cited record in Google Scholar (H-Index: 35, i10-Index: 87). He has been the permanent reviewer of many international journals of high repute. He also has participated and presented his research work at several conferences in India and is a life member of Association of Pharmaceutical Teachers of India (APTI).

xi

Abbreviations

5-FU Ach AFM APA APCs BBB CNHs CNTs CO CVD DCs DLS DOX DWNTs EAD ECHA EDC EPA FA f-CNTs FR GIT He HRTEM IR KLH MWNTs NCF NEPA NH2-MSNTs

5-Fluorouracil Acetylcholine Atomic force microscope Alginate-poly-lysine-alginate Antigen-presenting cells Blood–brain barrier Carbon nanohorns Carbon nanotubes Carbon monoxide Chemical vapor deposition Dendritic cells Dynamic light dispersion Doxorubicin Double-walled nanotubes Electric arc discharge European Chemicals Agency 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Environmental Protection Agency Folate Functionalized carbon nanotubes Folate receptors Gastrointestinal tract Helium High-resolution transmission electron microscopy Infrared spectroscopy Keyhole limpet hemocyanin Multi-walled carbon nanotubes Non-covalent functionalization National Environmental Policy Act Amine-functional mesoporous silica nanotubes

xiii

xiv

NIOSH NMR PANI PEG PEI POSS-PCU PRTs SEM SiNx SPAN SPM STM SWNTs TEM TGA TJs TLP XPS XRD

Abbreviations

National Institute for Occupational Safety and Health Nuclear magnetic resonance Polyaniline Polyethylene glycol Polyethyleneimine Polyhedral oligomeric silsesquioxane–polycarbonate urethane Platinum thermometers Scanning electron microscopy Silicon nitride Sulfonated polyaniline Scanning probe microscopy Scanning tunneling microscopy Single-walled carbon nanotubes Transmission electron microscopy Thermogravimetric analysis Tight junctions Tumor lysate proteins X-ray photoemission spectroscopy X-ray diffraction

Chapter 1

Background: Carbon Nanotubes for Targeted Drug Delivery

1.1 Introduction Current researches and developments in the field of nanotechnology have been concentrated in the explorations and exploitations of different novel nanotechnological products or systems for numerous biomedical applications (Nayak et al. 2019; Nayak and Bera 2019; Rani et al. 2019; Ray et al. 2019). These newer nanotechnological products or systems comprise polymeric nanoparticles, inorganic or ceramic nanoparticles, nanocapsules, nanovesicles, nanocomposites, nanogels, nanofibers, nanotubes, nanorods, etc. (Das et al. 2017; Hasnain et al. 2016, 2019a, b, c, d; Jana et al. 2013, 2014, 2015; Malakar et al. 2012; Mazumder et al. 2019; Nanda et al. 2019; Nayak and Das 2018; Nayak and Dhara 2010; Pal and Nayak 2010; Waghule et al. 2019). Since past few decades, drug delivery researchers use the nanotechnology applications in various novel drug delivery system to improve site specificity and therapeutics (Nayak and Dhara 2010; Pal and Nayak 2010). The size of different dosage forms has an important uniqueness leading to the increased performance in terms of controlling rate of drug release and target-specificity (Nayak et al. 2018). The targeted and controlled drug delivery is desired necessity using a carrier that involves multidisciplinary targeted or site-specific approach (Hasnain and Nayak 2019c; Nayak 2011). The drug delivery system having nanoparticles is advantageous as it has enhanced efficacy, distribution and decreased toxicity having better patient compliance (Malakar et al. 2012). The pharmaceutical nanoparticles are basically having the structure of sub-nano size with a bioactive molecule or drug and made up of several hundreds of molecules or atoms having a size range between 5 and 300 nm and different morphology like crystalline, spherical, tubes, amorphous and needles. Until mid-1980s, pure solid carbon was believed to subsist in just two forms physically i.e., diamond as well as graphite (Hoffman et al. 2016). These two have distinct physical structures and characteristics, but covalently bonded networks as well as their atoms equally arranged. An important discovery was established in 1985 © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_1

1

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1 Background: Carbon Nanotubes for Targeted Drug Delivery

by a group of scientists led by Robert Curl and Richard Smalley of Rice University, Houston as well as Harry Kroto of Sussex University, England (Kroto et al. 1985). With a powerful pulse of laser light, they vaporized a graphite sample and used helium (He) gas flow to bring the vaporized carbon into a mass spectrometer. Spectra of mass spectroscopy indicated peaks analogous to carbon atom clusters, with a predominantly strapping peak analogous to C60 (60 carbon atoms), consisting of molecules. The veracity that clusters of C60 were created so readily and resulted in the group to suggest the discovery of a fresh carbon type or allotrope (Harris 2004). It was in spherical form and shaped like a 32-faced ball. Amongst these ball faces, 12 were like pentagons whereas 20 were just similar to a soccer ball and named after Buckminster Fuller, the architect who was accountable for designing the first geodome (Dresselhaus et al. 1996). In brief, the soccer ball formed C60 molecule has been called “buckerminster fullerene” or “buckyball” (Kroto et al. 1985). Different forms of carbon are presented in Fig. 1.1. Different allotropes of carbon: diamond, graphite, and fullerenes are presented in Fig. 1.2. In spite of the fact that newer fields to develop nanotechnology-based proficient drug delivery frameworks extend out into all therapeutics classes of pharmaceuticals, numerous helpful specialists have not been effective due to their constrained limitations to reach up to the desired target (Hasnain and Nayak 2019a, b; Hasnain et al. 2019a, b; Ray et al. 2018). Likewise, there is much-increased growth and development is predicted in the improvement of the delivery of drug molecule for the management and treatment of cancer and vaccines, but due to a shortcoming in safety

Fig. 1.1 Different forms of carbon

1.1 Introduction

3

Fig. 1.2 Different allotropes of carbon: diamond, graphite, and fullerenes

and efficacy of its conventional administration. Like in chemotherapy for cancer, the anticancerous medication affects and destroys both normal cells as well as cancerous cells (Sheikhpour et al. 2017). Therefore, a drug delivery system is needed which specifically target only particular cancerous cells and does not affect normal cells. With the emphasis on these necessities, the ongoing researches demonstrate that carbon nanotubes (CNTs) possess the property to deliver the drug at particular targeted tissue, which may be useful in the medication of cancer, DNA application, and gene transfer (Hasnain et al. 2019b). Functionalized carbon nanotubes (f-CNTs) are rising as a newer approach in the field of nanobiotechnology as well as in nanomedicine (Lay et al. 2011). Different nanotechnological approaches and nanomedicines are presented in Fig. 1.3. In the early 19th century, Iijima coined the term ‘carbon nanotubes’ or CNTs (Hoenlein et al. 2003; Iijima 1991). These are like needle tubes. It is composed of numerous graphite sheet layers (Ajayan 1999; Pan et al. 2005). Because of thermal characteristics, enhanced mechanical strength and good electronics (Dresselhaus et al. 2004; Ouyang et al. 2002; Thostenson et al. 2001; Troiani et al. 2003; Wan et al. 1998; Zare et al. 2013), CNTs are being potentially used in industries (Baughman et al. 2002; He et al. 2013; Paradise and Goswami 2007). In addition, it has a lightweight and huge surface area which provides its application in neuroengineering. Very large surface area is required for chemical surface modification of CNTs and to achieve therapeutic moiety. The multifunctional CNTs have enhanced effectiveness for targeted imaging of different parts, for particular cells and tissues respectively. As CNTs looks like needle tubes, it has an advantage in the delivery of a drug molecule. In the inner hollow space the drug is filled and on the external surface, the other molecules may be attached to provide biocompatible and dispersible for the purpose of targeted delivery of the drug to a specific site. Presently, a variety of therapeutic agents, like central nervous system disorders therapy drugs, anti-microbial drugs, anticancer drugs, and anti-inflammatory drugs have been effectively delivered using CNTs (Beg et al. 2011; Brandelli 2012; Liu et al. 2007; Luo et al. 2011; Vashist et al. 2011; Wong et al. 2013) by versatile strategies, signifying least toxicity and enhanced efficiency to cells or tissues. CNTs belong to fullerenes sub-family. These are 1-dimensional (pseudo) allotrope of carbon having a high surface area, aspect

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1 Background: Carbon Nanotubes for Targeted Drug Delivery

Fig. 1.3 Different nanotechnological approaches and nanomedicines

ratio and outstanding material characteristics e.g., mechanical strength, electrical as well as thermal conductivities (Lu et al. 2009). These carbon allotropes have a distinctive ratio of length-to-diameter as 28,000,000:1. Every CNT varies from one another in terms of the number of carbon atoms like C20 , C30 , C36 , C70, as well as C78 , and known as “Graphene”. CNTs are therefore graphenes that have an empty cylindrical tube-like framework, with sp2 hybridized carbon atoms prearranged in an explicit pattern forming hexagonal structural units (Beg et al. 2011). This leads to elevated C-C bond rigidity of the hexagonal network and produces increased tensile strength of nearly 150 Gpa and Young’s modulus nearly to 1. It is obtained in a variety of shapes like spherical, cylindrical, ellipsoidal or tube shape structures. CNTs can be synthesized chemically using graphite on exposure to a laser beam or electric arc (Awasthi et al. 2005). Structure of carbon nanotubes (CNTs) is presented in Fig. 1.4. Structures of fullerenes, single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) are presented in Fig. 1.5. CNTs are basically used as an ideal nanocarrier in delivery of drug molecules for therapeutic purpose. CNTs are broadly used as a novel device for delivery of drug molecules, siRNA, DNA as well as a peptide (Hasnain et al. 2019b). These applications are feasible because of its characteristic functionalization, unique morphological features, small dimensions and ability to penetrate drug molecules, antibodies, and peptides into cells (Lay et al. 2011). This offers various prospective for its application in pharmacology, molecular biology and particularly in the field of drug delivery. Among several applications of CNTs, the essential ones encompass targeted

1.1 Introduction

5

Fig. 1.4 Structure of carbon nanotubes (CNTs)

Fig. 1.5 Structures of fullerenes, single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs)

drug delivery and controlled drug delivery to particular sites e.g., cancerous tissues, brain, ocular system, and lymphatic system (Lay et al. 2011). In addition, CNTs have application in the delivery of biotechnological preparations such as genes, enzymes, hormones, as well as vaccines. As from latest research findings, it has been proven that nanotubes are being used as an excipient for the increment of the solubility of drugs which are poorly soluble in water and also has numerous for pharmaceutical applications (Beg et al. 2011; Bekyarova et al. 2005; Bianco et al. 2005a; Jung et al. 2011; Klingeler and Sim 2011; Sinha and Yeow 2005; Vardharajula et al. 2012).

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1 Background: Carbon Nanotubes for Targeted Drug Delivery

The uptake of CNTs in cells has been proven and shown by numerous studies, yet the mechanism of penetration of CNTs in cells is still unknown. CNTs may pierce inside side the cell membrane and goes inside the cellular component without affecting the cell may be due to the needle-like shape of CNTs (Cai et al. 2005; Kam et al. 2005; Klumpp et al. 2006; Pantarotto et al. 2004a; Pantarotto et al. 2004b). Chen et al. (2007) developed CNTs nano-injector for the in vitro system by use of functionalized MWNTs and atomic force microscope (AFM) tip which is attached via disulfide link to a model cargo compound. The MWNTs nanoinjector effectively transports inside the cell by breaking of a disulfide bond, ensuing in the release of the compound, cargo within the cytosol. The nanotubes penetrate inside the cell membrane at a 90 angle, which means that CNTs diffuse into the cells at the same position without affecting/causing the death of the cell (Bianco et al. 2005b). It was reported by Kam et al. that SWNTs-biotin and fluoreceinated protein, when are in contact with other was found to be in the endosomes, which signify that by the process of endocytosis the uptake of nanotubes might have occurred (Shi Kam et al. 2004). By the use of confocal microscopy and epifluorescence, the labeled functionalized CNTs having fluorescent agent penetrates inside the cell into the cytoplasm or into the fibroblast of the nucleus (Pantarotto et al. 2004a). In a different study, it has been shown that the mechanism involved in the uptake of MWNTs depends on the length of the nanotube. The length of nanotubes less than one micrometer easily penetrates inside the cell and the cellular uptake was not by endocytosis (Raffa et al. 2008).

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S. Ray, P. Sinha, B. Laha, S. Maiti, U.K. Bhattacharyya, A,K, Nayak, Polysorbate 80 coated crosslinked chitosan nanoparticles of ropinirole hydrochloride for brain targeting. J. Drug Deliv. Sci. Technol. 48, 21–29 (2018) P. Rani, D. Pal, M.N. Hoda, T.J. Ara, S. Beg, M.S. Hasnain, A.K. Nayak, Dental pulp capping nanocomposites, in Applications of Nanocomposite Materials in Dentistry (Elsevier, 2019), pp. 65–91 P. Ray, M.S. Hasnain, A. Koley, A.K. Nayak, Bone-implantable devices for drug delivery applications, in Bioelectronics and Medical Devices (Elsevier, 2019), pp. 355–392 M. Sheikhpour, A. Golbabaie, A. Kasaeian, Carbon nanotubes: a review of novel strategies for cancer diagnosis and treatment. Mater. Sci. Eng. C 76, 1289–1304 (2017) N.W. Shi Kam, T.C. Jessop, P.A. Wender, H. Dai, Nanotube molecular transporters: internalization of carbon nanotube—protein conjugates into mammalian cells. J. Am. Chem. Soc. 126, 6850–6851 (2004) N. Sinha, J.-W. Yeow, Carbon nanotubes for biomedical applications. IEEE Trans. Nanobiosci. 4, 180–195 (2005) E.T. Thostenson, Z. Ren, T.-W. Chou, Advances in the science and technology of carbon nanotubes and their composites: a review. Compos. Sci. Technol. 61, 1899–1912 (2001) H. Troiani, M. Miki-Yoshida, G. Camacho-Bragado, M. Marques, A. Rubio, J. Ascencio, M. JoseYacaman, Direct observation of the mechanical properties of single-walled carbon nanotubes and their junctions at the atomic level. Nano Lett. 3, 751–755 (2003) S. Vardharajula, S.Z. Ali, P.M. Tiwari, E. Ero˘glu, K. Vig, V.A. Dennis, S.R. Singh, Functionalized carbon nanotubes: biomedical applications. Int. J. Nanomed. 7, 5361 (2012) S.K. Vashist, D. Zheng, G. Pastorin, K. Al-Rubeaan, J.H. Luong, F.-S. Sheu, Delivery of drugs and biomolecules using carbon nanotubes. Carbon 49, 4077–4097 (2011) T. Waghule, V.K. Rapalli, G. Singhvi, P. Manchanda, N. Hans, S.K. Dubey, M.S. Hasnain, A.K. Nayak, Voriconazole loaded nanostructured lipid carriers based topical delivery system: QbD based designing, characterization, in-vitro and ex-vivo evaluation. J. Drug Deliv. Sci. Technol. 52, 303–315 (2019) X. Wan, J. Dong, D. Xing, Optical properties of carbon nanotubes. Phys. Rev. B 58, 6756 (1998) B.S. Wong, S.L. Yoong, A. Jagusiak, T. Panczyk, H.K. Ho, W.H. Ang, G. Pastorin, Carbon nanotubes for delivery of small molecule drugs. Adv. Drug Deliv. Rev. 65, 1964–2015 (2013) K. Zare, F. Najafi, H. Sadegh, Studies of ab initio and Monte Carlo simulation on interaction of fluorouracil anticancer drug with carbon nanotube. J. Nanostruct. Chem. 3, 71 (2013)

Chapter 2

Classification of Carbon Nanotubes

2.1 Classification of CNTs Based on the structure of the wall, carbon nanotubes (CNTs) are of following two types (Balasubramanian and Burghard 2005; Foldvari and Bagonluri 2008a, b). These are Single-walled carbon nanotubes (SWNTs) and Multi-walled carbon nanotubes (MWNTs). Classifications of CNTs are described in Fig. 2.1. No more than one sheet of graphene is designed to offer a one-atom-thick cylindrical framework in SWNTs with a radius of up to one nanometer. During the synthesis, the SWNTs are closed with cap-like structures at the ends of both side and the ring shape finishes with C–C bonds (Joselevich 2004) whereas MWNTs made up of a small number of graph sheet layers (two to ten) and are over and above one atom thick with an internal diameter of more than ten nanometers. Single-walled carbon nanotubes (SWNTs) comprise of a solitary graphene cylinder. In this only single graphene sheet is arranged, which imparts cylindrical arrangement to it and at both ends, it is closed by cap-like structure (Chen et al. 1998; Kataura et al. 1999; Salvetat et al. 1999; Yu et al. 2000). Multi-walled carbon nanotubes (MWNTs) consist of numerous concentric graphene cylinders. These are formed by rolling of around nearly 3–5 sheets of single-walled nanotube over one another (Kwon and Tománek 1998; Liu et al. 2004; Odom et al. 1998). Further, MWCNTs vary from each other in the arrangement pattern of graphitic sheets. Structurally, SWCNTs differ from MWNTs, as SWNTs possess varying basic arrangement of carbon atoms, providing three dissimilar structural configurations such as zig-zag arrangement, where the tube is characterized to have a V-shape structure, is at right angles to the axis of tube; arm-chair arrangement, the chiral vector is characterized by chair structure, is perpendicular to the axis of tube. The chirality degree for CNTs is a measure of its electrical plus conductive characteristics, which helps in designing a broad variety of nanoelectronic instruments. In addition, chirality also determines the nanotubes ‘ diameter and its elastic or semi-metallic properties (Thakare et al.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_2

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Fig. 2.1 Classifications of CNTs

2010). Apart from differences in structural form, the CNTs vary from each other in respect to dimensions also. Various features of single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) are described in Fig. 2.2. The structural features of SWNTs are generally illustrated by means of a (n, m) vector that describes the chirality and diameter (Meng et al. 2012). There are three SWNTs: (a) Armchair (10, 10), (b) Chiral (13, 6), and (c) Zigzag (14, 0). The archetypal structures of these three SWNTs are shown in Fig. 2.3. In contrast to different MWNTs, SWNTs have a tendency to display better electrical as well as optical characteristics (Carlson and Krauss 2008). There are a number of considerable characteristics of SWNTs that can be exploited for the uses in various biomedical applications. Besides targeting by means of the EPR effect, SWNTs are simply internalized by the cell-openings and the option for their applications in the delivery of numerous therapeutic payloads for improved therapeutics and diagnosis (Ji et al. 2010). By means of sp2-hybridized carbon surfaces and a larger surface area (i.e., 1300 m2 /g, theoretically), SWNTs encompass a high-powered capability for loading of therapeutic agents or specific targeting biomolecules inside the tubestructure (Meng et al. 2012). During past few decades, numerous specific targeting biomolecules are being integrated onto the SWNT-surface via either non-covalent or covalent interactions (Foldvari and Bagonluri 2008a, b). Besides this, there is an additional form of SWNT-like nanotube which is acknowledged as double-walled nanotubes (DWNTs), with structural resemblance to SWNTs and are of significant concern in pharmaceutical sector (Danailov et al. 2002). It comprises of concentric graphene cylinders having coaxial structure, enhanced thermal as well as chemical stability as compared to SWNTs. Besides this, there are numerous variants of CNT are known, such as nanotorus, nanobuds and carbon nanohorns (CNHs). They have broad application in the delivery of drug molecule because of its distinctive modified

2.1 Classification of CNTs

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Fig. 2.2 Various features of single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs)

Fig. 2.3 Three archetypal SWNTs: a Armchair (10, 10), b chiral (13, 6), and c zigzag (14, 0) functionalizations. Meng et al. (2012); Copyright @ 2011, Elsevier Ltd.

structure suited for drug delivery. Structurally, CNHs is similar to CNTs is being prepared by the laser ablation method using graphite’s (Iijima et al. 1999; Zhu and Xu 2010). SWNTs are made up of graphene sheets having a diameter of 2–3 nm and have 5-member ring cap at the tip. CNHs are cone-shaped, the horn-like structure having a narrow open end and one broad open end. As CNHs resembles dahlia flower petals, thus they are called as ‘dahlia-like’ aggregates. It has a feature that its diameter changes as there is an increase in its length. It has numerous applications

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in the drug delivery to targeted sites, like in cancer (Ajima et al. 2005; Murakami et al. 2008; Nasibulin et al. 2007; Shiba et al. 2006). Theoretically, nanotorous are CNTs, which are twisted in the form of a doughnut or torus-shaped structure (Liu et al. 2002). On the other hand, carbon nanobuds are recently discovered, is made up of fullerenes and CNTs and have the intermediate features of both (i.e., fullerenes and CNTs). Structurally, it resembles CNTs and difference lies only in its external growth.

2.2 Differences in SWNTs and MWNTs Structurally, SWNTs differs from MWNTs is in having varying basic arrangement of carbon atoms, providing three dissimilar structural configurations such as zig-zag arrangement, in this the tube is characterized to have a V-shape structure, is perpendicular to the axis of tube; arm-chair arrangement, the chiral vector is characterized by chair structure, is perpendicular to the axis of tube. The degree of chirality for CNTs is a measure of its electrical as well as conductive properties, which helps in designing a broad variety of nanoelectronic instruments. Besides, chirality also determines the diameter of nanotubes, and its metallic or semi-metallic characteristics (Thakare et al. 2010). Apart from differences in structural form, the CNTs vary from each other in respect to dimensions also.

References K. Ajima, M. Yudasaka, T. Murakami, A. Maigné, K. Shiba, S. Iijima, Carbon nanohorns as anticancer drug carriers. Mol. Pharm. 2, 475–480 (2005) K. Balasubramanian, M. Burghard, Chemically functionalized carbon nanotubes. Small 1, 180–192 (2005) L.J. Carlson, T.D. Krauss, Photophysics of individual single-walled carbon nanotubes. Acc. Chem. Res. 41, 235–243 (2008) J. Chen, M.A. Hamon, H. Hu, Y. Chen, A.M. Rao, P.C. Eklund, R.C. Haddon, Solution properties of single-walled carbon nanotubes. Science 282, 95–98 (1998) D. Danailov, P. Keblinski, S. Nayak, P. Ajayan, Bending properties of carbon nanotubes encapsulating solid nanowires. J. Nanosci. Nanotechnol. 2, 503–507 (2002) M. Foldvari, M. Bagonluri, Carbon nanotubes as functional excipients for nanomedicines: I. Pharmaceutical properties. Nanomed.: Nanotechnol. Biol. Med. 4, 173–182 (2008a) M. Foldvari, M. Bagonluri, Carbon nanotubes as functional excipients for nanomedicines: II. Drug delivery and biocompatibility issues. Nanomed.: Nanotechnol. Biol. Med. 4, 183–200 (2008b) S. Iijima, M. Yudasaka, R. Yamada, S. Bandow, K. Suenaga, F. Kokai, K. Takahashi, Nanoaggregates of single-walled graphitic carbon nano-horns. Chem. Phys. Lett. 309, 165–170 (1999) S.-R. Ji, C. Liu, B. Zhang, F. Yang, J. Xu, J. Long, C. Jin C, D.-l. Fu, Q.-X. Ni, X.-J. Yu, Carbon nanotubes in cancer diagnosis and therapy. Biochimica et Biophysica Acta (BBA) Rev. Cancer 1806:29–35 (2010) E. Joselevich, Electronic structure and chemical reactivity of carbon nanotubes: a chemist’s view. ChemPhysChem 5, 619–624 (2004)

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H. Kataura, Y. Kumazawa, Y. Maniwa, I. Umezu, S. Suzuki, Y. Ohtsuka, Y. Achiba, Optical properties of single-wall carbon nanotubes. Synth. Met. 103, 2555–2558 (1999) Y.-K. Kwon, D. Tománek, Electronic and structural properties of multiwall carbon nanotubes. Phys. Rev. B 58, R16001 (1998) L. Liu, G. Guo, C. Jayanthi, S. Wu, Colossal paramagnetic moments in metallic carbon nanotori. Phys. Rev. Lett. 88, 217206 (2002) T. Liu, I.Y. Phang, L. Shen, S.Y. Chow, W.-D. Zhang, Morphology and mechanical properties of multiwalled carbon nanotubes reinforced nylon-6 composites. Macromolecules 37, 7214–7222 (2004) L. Meng, X. Zhang, Q. Lu, Z. Fei, P.J. Dyson, Single walled carbon nanotubes as drug delivery vehicles: targeting doxorubicin to tumors. Biomaterials 33, 1689–1698 (2012) T. Murakami, H. Sawada, G. Tamura, M. Yudasaka, S. Iijima, K. Tsuchida, Water-dispersed singlewall carbon nanohorns as drug carriers for local cancer chemotherapy (2008) A.G. Nasibulin, P.V. Pikhitsa, H. Jiang, D.P. Brown, A.V. Krasheninnikov, A.S. Anisimov, P. Queipo, A. Moisala, D. Gonzalez, G. Lientschnig, A novel hybrid carbon material. Nat. Nanotechnol. 2, 156 (2007) T.W. Odom, J.-L. Huang, P. Kim, C.M. Lieber, Atomic structure and electronic properties of singlewalled carbon nanotubes. Nature 391, 62 (1998) J.-P. Salvetat, J.-M. Bonard, N. Thomson, A. Kulik, L. Forro, W. Benoit, L. Zuppiroli, Mechanical properties of carbon nanotubes. Appl. Phys. A 69, 255–260 (1999) K. Shiba, M. Yudasaka, S. Iijima, Carbon nanohorns as a novel drug carrier. Nihon Rinsho Jpn. J. Clin. Med. 64, 239–246 (2006) V.S. Thakare, M. Das, A.K. Jain, S. Patil, S. Jain, Carbon nanotubes in cancer theragnosis. Nanomedicine 5, 1277–1301 (2010) M.-F. Yu, B.S. Files, S. Arepalli, R.S. Ruoff, Tensile loading of ropes of single wall carbon nanotubes and their mechanical properties. Phys. Rev. Lett. 84, 5552 (2000) S. Zhu, G. Xu, Single-walled carbon nanohorns and their applications. Nanoscale 2, 2538–2549 (2010)

Chapter 3

Synthesis of Carbon Nanotubes

3.1 Introduction The synthesis of CNTs is achieved naturally by using graphites and carbon black in a controlled setting (Iijima 1991). The synthesized CNTs using this technique are generally uneven in their shape, size, mechanical strength, purity as well as in quality due to the irrepressible natural environment. The CNTs which are prepared by using the technique of synthetically developed methods are of significant importance for the pharmaceutical scientists (Awasthi et al. 2005).

3.2 Method of Synthesis There are two methods for the syntheses of CNTs are: laser ablation (LA) technique, chemical vapor deposition (CVD) and electric arc discharge (EAD) (Fig. 3.1).

3.2.1 Laser Ablation (LA) Technique In this process, nanotubes are formed by using a particular spectrum of the laser beam which strikes to the target (graphite) by means of transition metal (catalyst). It forms both kinds of nanotubes i.e., SWNTs as well as MWNTs. In this method, the two dissimilar laser sources are used, 1° and 2° laser beam. The 1° laser beam is used for the initialization of bombardment followed by the 2° laser beam resulting in the formation of high-quality CNTs (Arepalli 2004). It is advantageous as it produces the CNTs for a particular specific application. Although it has a drawback, it is costly and time-consuming.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_3

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Fig. 3.1 Various methods for syntheses of CNTs

3.2.2 Chemical Vapor Deposition (CVD) The substratum used in this method is a blended vapor phase (it is a form of vaporized carbon and inert gas) (Kumar and Ando 2010). It is passed onto a hot furnace and decomposes to produce CNTs and deposits over the substrate surface. The substrate is composed by embedding cobalt or nano-sized nickel particles, or its combination as a catalyst on the substrate surface. The temperature of the furnace is nearly 700 °C. The diameter and tensile strength of the nanotubes rely on the metal particles size. It may only be controlled via masking the deposition of metal by the technique of annealing or plasma etching of a metal layer. Commercially, the metal particles of nano-size are blended with magnesium oxide or aluminum oxide for large-scale production to improve catalytic assistance and greater yield surface area. Various important features of CVD technique for syntheses of CNTs are presented in Fig. 3.2.

3.2.3 Electric Arc Discharge (EAD) In EAD technique, the two electrodes (i.e. anode and cathode) are used. In this method, at the anode, the CNTs are being produced and comprises of graphite (pure). It needs electrons beams of higher voltage (about 100 amps) by the arc that bombards

3.2 Method of Synthesis

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Fig. 3.2 Various important features of CVD technique for syntheses of CNTs

the graphite surface. The electrical arc used is a collection of CNT plasmons that results in the creation of CNTs on the substratum (Awasthi et al. 2005). In addition, numerous newer techniques, such as thermal CVD, plasma-increased CVD, high-pressure CVD, laser-assisted CVD, high-pressure carbon monoxide (HiPCO) disproportionation process and cobalt-molybdenum catalytic (CoMoCat) process are developed for the producing CNTs of good quality (Beg et al. 2011). Using carbon feedstock, carbon monoxide (CO) and Fe having catalytic precursor of Fe(CO)5 (iron pentacarbonyl) in a continuous-flow gas phase, the HiPCO technique is used to catalyze single-wall nanotubes. By controlling the pressure of CO, the diameter and size distribution of the nanotubes can easily be selected. This technique is advantageous for the production of CNTs in bulk. CNTs are prepared using various methods having different mechanical and physical and properties. Usually, the method differs from each other during the production of CNTs. The purity quality, solubility, and mechanical properties also differ in each method. The comparative features (summary, strengths, weaknesses and yields) of various methods for syntheses of CNTs are enlisted in Fig. 3.3.

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Fig. 3.3 Comparative features (summary, strengths, weaknesses and yields) of various methods for syntheses of CNTs

References S. Arepalli, Laser ablation process for single-walled carbon nanotube production. J. Nanosci. Nanotechnol. 4, 317–325 (2004) K. Awasthi, A. Srivastava, O. Srivastava, Synthesis of carbon nanotubes. J. Nanosci. Nanotechnol. 5, 1616–1636 (2005) S. Beg, M. Rizwan, A.M. Sheikh, M.S. Hasnain, K. Anwer, K. Kohli, Advancement in carbon nanotubes: basics, biomedical applications and toxicity. J. Pharm. Pharmacol. 63, 141–163 (2011) S. Iijima, Helical microtubules of graphitic carbon. Nature 354, 56 (1991) M. Kumar, Y. Ando, Chemical vapor deposition of carbon nanotubes: a review on growth mechanism and mass production. J. Nanosci. Nanotechnol. 10, 3739–3758 (2010)

Chapter 4

Functionalization of Carbon Nanotubes

4.1 Introduction Functionalization is defined as the modification of carbon nanotubes (CNTs) in which the preferred functional group drug molecule where the desired drug molecule or a functional group is introduced over the CNTs wall for several applications (Lay et al. 2011). The functionalized CNTs (f-CNTs) may be used for improved biocompatibility in the body, increased tendency of encapsulation, solubility, and multimodal delivery of drug and imaging (Liu et al. 2009). Numerous investigations on the outcome of nanotubes in the body indicates that f-CNTs laden with molecules of the drug may pass without any difficulty into the cells and subsequently into the nucleus of the cells, thus achieving targeted drug delivery at cellular as well as nuclear levels. There may be two kinds of functionalization: (i) non-covalent functionalizations and (ii) covalent functionalizations (Fig. 4.1) (Mahajan et al. 2018).

4.2 Properties of Functionalized-CNTs 4.2.1 Solubility The addition of comparatively bulky functional groups to the nanotubes is essential for the solubilization of CNTs. There are several polymeric as well as oligomeric compounds which have been used in functionalization of CNTs for its solubility in organic solvents. Due to the process of functionalization, a bundles of nanotube break, which is necessary for its solubility. There are several functionalized CNTs for which proof of direct microscopy exists for casing the nanotubes individually by the polymer (Czerw et al. 2001; Lin et al. 2003; Zhu and Xu 2010). Hence, the cased nanotubes with polymer are much more soluble. For the CNTs having the same functionality, the solubility depends on the route of reaction. For example, the © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_4

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Fig. 4.1 Two methods of functionalization of the CNT-surface: (i) covalent functionalizations and (ii) non-covalent functionalizations Mahajan et al. (2018); Copyright @ 2018, Elsevier B.V.

functional group having amino substitute during amidation, the samples produced from acyl chloride are much soluble as compared to samples produced from diimide activated coupling reaction (Hill et al. 2002; Huang et al. 2002; Lin et al. 2002).

4.2.2 Solution NMR CNTs solubilization provides a chance to study the NMR solution of CNTs. However, contrary to the successful characterization of the 13 C NMR of pristine CNT, there was no significant detection of any carbon signal in the 13 C NMR solution for estimation of solubilized CNT (including samples enriched with 13 C). 1H NMR and 13C NMR both provide significant data on the functional groups included in the SWNT and MWNT samples. For example, for IPEG, 1 H NMR creates wide signals when attached to CNTs by esterifying carboxylic acids linked to a nanotube (Sun et al. 2001). The understanding of the consequence of NMR nuclei spin-lattice (T1) and spin-spin (T2) relaxation times demonstrates that the extended electron signals are related to the diamagnetic property with reduced mobility of nanotube-attached IPEG molecules (Sun et al. 2001).

4.2 Properties of Functionalized-CNTs

23

4.2.3 Microscopy Analysis For a variety of microscopy analysis, the CNTs that are functionalized in the solution can be deposited directly across the surface. The findings acquired after the analyzing provide immediate proof that CNTs are present in the soluble samples. The transmission electron microscopy (TEM) analysis of f-CNTs is particularly helpful in providing a thorough evaluation at greater resolution and reduced magnification. Because of its relatively big dimensions (diameters), the functionalized MWNTs imaging is simple (Fu et al. 2002b). Because of its larger size (diameters), TEM analyses of functionalized SWNTs assessment is much more difficult. Atomic force microscopy (AFM) was commonly used for the characterization of functional CNTs. The benefit of characterization using atomic AFM is that owing to the concentrated beam of electrons, there is no harm to the sample that happened in the TEM assessment (Niyogi et al. 2001; Zhao et al. 2001). The results of this study show that nanoscopic unbundling/bundling information may be obtained from image height in particular areas. The AFM technique may be used to test the binding of large polymer species to CNTs, like functionalization with natural proteins of SWNTs and MWNTs (Fu et al. 2002a).

4.3 Non-covalent Functionalization The benefit of non-covalent functionalization (NCF) is that it does not obliterate the conjugated structure of CNT-sidewall and thus, does not influence the material’s final structural characteristics (Bilalis et al. 2014; Hu et al. 2009; Lee et al. 2007). NCF is an alternative way of tuning nanotubes’ interfacial characteristics. The CNTs are functionalized by polymers, surfactants, and aromatic compounds in a non-covalent manner, most of which employ stacking or hydrophobic interactions. Non-covalent changes of CNTs can do a great deal to maintain their required characteristics whilst significantly enhancing their solubility. It will summarize the following: aromatic absorption of tiny molecules, wrapping of polymers, surfactants, biopolymers, and endohedral technique. CNTs-based non-covalent interaction functionalization methods can be performed without the destruction of the nanotube sidewall’s inherent sp2-hybrid structure in order to preserve the initial electronic structure and characteristics of CNTs. The NCF of CNTs could be accomplished through interactions between CNTs graphitic sidewall and conjugated molecules. Pyrene moiety compounds, e.g., N-succinimidyl-1-pyrenebutanoate, could irreversibly be adsorbed on the surface of SWCNT through the contact between π–π bond (Chen et al. 2001; Zare et al. 2015). Different important features of non-covalent functionalizations of CNTs are presented in Fig. 4.2. The biomolecules, such as, protein and DNA (Besteman et al. 2003; Taft et al. 2004; Xin and Woolley 2003) and gold nanoparticles (Gupta et al. 2016; Liu et al.

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Fig. 4.2 Different important features of non-covalent functionalizations of CNTs

2003) were also associated with the CNTs using a comparable approach. The selective interaction between porphyrin derivatives and CNTs was also discovered (Ago et al. 1999). To incorporate this new form of material with living systems, it is definitely more suitable to solubilize CNTs with biological elements. The biomacromolecules included proteins for non-covalent CNTs (Chen et al. 2001), saccharides and polysaccharides (Barone and Strano 2006; Chambers et al. 2003; Ikeda et al. 2007; Star and Stoddart 2002). For NCF of CNTs phospholipid-dextran (Goodwin et al. 2008), η-cyclodextrin (Dodziuk et al. 2003), pullulan (Kim et al. 2003), γcyclodextrin (Chambers et al. 2003) and chitosan (Yan et al. 2008) has been used. The non-covalent functionalization of CNTs with biomaterials like proteins, nucleic acids, etc., to design bionanohybrid system for the use in nanobiotechnology is described in Fig. 4.3.

4.4 Covalent Functionalization

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Fig. 4.3 The non-covalent functionalization of CNTs with biomaterials like proteins, nucleic acids, etc., to design bionanohybrid system for the use in nanobiotechnology

4.4 Covalent Functionalization Covalent functionality increases the safety of drugs or functional groups (Balasubramanian and Burghard 2005). With strong acids, CNTs can be oxidized to accomplish this sort of functionalization, leading to a decrease in their length whilst producing –COOH groups, thereby improving their dispersibility in aqueous solutions (Khabashesku 2011; Pennetreau et al. 2015; Qi et al. 2007). Conversely, hydrophilic group responses to the internal walls and tips of the CNTs can also render them water-soluble. Chemical responses such as 1,3-cycloaddition can be used to accomplish such sort of functionalization with therapeutic molecules such as methotrexate. However, absolute control over these chemo/or region-selective based additions are rather difficult to obtain because it includes specific groups e.g., halogens, arynes, carbenes or cyclic compounds. In addition, such responses often involve tremendous covalent bonding circumstances. In addition, it is also very hard to characterize these functionalized nanotubes to examine the accurate place of functionality and mode of addition. Different important features of covalent functionalizations of CNTs are presented in Fig. 4.4. Functionalizations of CNTs are being carried out to persuade a number of demands. For this reason, different functionalizations or conjugations of for CNTs are being done with the PEG, chitosan, peptide, folic acid, aptamer, antibody, etc. (Mahajan et al. 2018). Various strategies for the functionalizations of CNTs are presented in Fig. 4.5.

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Fig. 4.4 Different important features of covalent functionalizations of CNTs

Fig. 4.5 Possible functionalizations/conjugations reported for CNTs Mahajan et al. (2018); Copyright @ 2018, Elsevier B.V.

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J.U. Lee, J. Huh, K.H. Kim, C. Park, W.H. Jo, Aqueous suspension of carbon nanotubes via noncovalent functionalization with oligothiophene-terminated poly (ethylene glycol). Carbon 45, 1051–1057 (2007) Y. Lin, D.E. Hill, J. Bentley, L.F. Allard, Y.-P. Sun, Characterization of functionalized single-walled carbon nanotubes at individual nanotube-thin bundle level. J. Phys. Chem. B 107, 10453–10457 (2003) Y. Lin, A.M. Rao, B. Sadanadan, E.A. Kenik, Y.-P. Sun, Functionalizing multiple-walled carbon nanotubes with aminopolymers. J. Phys. Chem. B 106, 1294–1298 (2002) L. Liu, T. Wang, J. Li, Z.-X. Guo, L. Dai, D. Zhang, D. Zhu, Self-assembly of gold nanoparticles to carbon nanotubes using a thiol-terminated pyrene as interlinker. Chem. Phys. Lett. 367, 747–752 (2003) Z. Liu, S. Tabakman, K. Welsher, H. Dai, Carbon nanotubes in biology and medicine: in vitro and in vivo detection, imaging and drug delivery. Nano Res. 2, 85–120 (2009) S. Mahajan, A. Patharkar, K. Kuche, R. Maheshwari, P.K. Deb, K. Kalia, R.K. Tekade, Functionalized carbon nanotubes as emerging delivery system for the treatment of cancer. Int. J. Pharm. 548, 540–558 (2018) S. Niyogi, H. Hu, M. Hamon, P. Bhowmik, B. Zhao, S. Rozenzhak, J. Chen, M. Itkis, M. Meier, R. Haddon, Chromatographic purification of soluble single-walled carbon nanotubes (s-SWNTs). J. Am. Chem. Soc. 123, 733–734 (2001) F. Pennetreau, C. Vriamont, B. Vanhorenbeke, O. Riant, S. Hermans, Covalent functionalization of carbon nanotubes with xanthates and peroxides. Eur. J. Org. Chem. 2015, 1804–1810 (2015) X. Qi, W. Pinghua, S. Zhichun, Covalent functionalization of carbon nanotubes. Prog. Chem. Beijing 19, 101 (2007) A. Star, J.F. Stoddart, Dispersion and solubilization of single-walled carbon nanotubes with a hyperbranched polymer. Macromolecules 35, 7516–7520 (2002) Y.-P. Sun, W. Huang, Y. Lin, K. Fu, A. Kitaygorodskiy, L.A. Riddle, Y.J. Yu, D.L. Carroll, Soluble dendron-functionalized carbon nanotubes: preparation, characterization, and properties. Chem. Mater. 13, 2864–2869 (2001) B.J. Taft, A.D. Lazareck, G.D. Withey, A. Yin, J. Xu, S.O. Kelley, Site-specific assembly of DNA and appended cargo on arrayed carbon nanotubes. J. Am. Chem. Soc. 126, 12750–12751 (2004) H. Xin, A.T. Woolley, DNA-templated nanotube localization. J. Am. Chem. Soc. 125, 8710–8711 (2003) L.Y. Yan, Y.F. Poon, M. Chan-Park, Y. Chen, Q. Zhang, Individually dispersing single-walled carbon nanotubes with novel neutral pH water-soluble chitosan derivatives. J. Phys. Chem. C 112, 7579–7587 (2008) K. Zare, V.K. Gupta, O. Moradi, A.S.H. Makhlouf, M. Sillanpää, M.N. Nadagouda, H. Sadegh, R. Shahryari-Ghoshekandi, A. Pal, Z-j Wang, A comparative study on the basis of adsorption capacity between CNTs and activated carbon as adsorbents for removal of noxious synthetic dyes: a review. J. Nanostruct. Chem. 5, 227–236 (2015) B. Zhao, H. Hu, S. Niyogi, M.E. Itkis, M.A. Hamon, P. Bhowmik, M.S. Meier, R.C. Haddon, Chromatographic purification and properties of soluble single-walled carbon nanotubes. J. Am. Chem. Soc. 123, 11673–11677 (2001) S. Zhu, G. Xu, Single-walled carbon nanohorns and their applications. Nanoscale 2, 2538–2549 (2010)

Chapter 5

Characterization of Carbon Nanotubes

5.1 Various Instrumentation Techniques for Characterization of CNTs To determine their basic characteristics, CNTs employed in pharmaceutical applications entail to be characterized widely. Purity, size, diameter, shape, solubility, electromechanical characteristics plus thermal conductivity are the characteristic properties (Foldvari and Bagonluri 2008). Several instrumental and analytical techniques are being used to characterize CNTs e.g., scanning electron microscopy (SEM), atomic force microscopy (AFM), TEM, thermogravimetric analysis (TGA), infrared spectroscopy (IR), nuclear magnetic resonance (NMR), Raman spectroscopy as well as dynamic light dispersion (DLS). Each of the methods has possessed exceptionality as well as benefits that assist to determine the features of the CNTs. A limited number of techniques could be employed to probe the morphological and structural uniqueness of CNTs. However, only a few techniques like scanning tunneling microscopy (STM) and TEM can characterize CNTs individually. X-ray photoelectron spectroscopy is useful in analyzing the nanotubes chemical structure whereas neutron diffraction, X-ray diffraction (XRD), X-ray photoemission spectroscopy (XPS), grazing incidence small angles X-ray scattering, X-ray absorption near-edge structure spectroscopy, IR and Raman spectroscopy are more often used methods worldwide for the characterization of various CNTs. There has been a wide variety of methods and strategies used to evaluate CNTs over the last century (Belin and Epron 2005; Hassellöv et al. 2008; Lehman et al. 2011; Thostenson et al. 2001).

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_5

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5.2 Electron Microscopy for Characterization of CNTs Electron microscopy is a method of imaging that utilizes an electron beam to test material. Since an electron’s wavelength is much lower than visible light’s wavelength, diffraction impacts happen at physical sizes that are much lower. The microscope was the first instrument by which matters confined to be seen with the nude eye could be made into true research. It has been created into a tool since its rudimentary start some 300 years ago, which is a tribute to the ingenious and analytical capacity of those who have worked on this. A contemporary microscope is a tool that advances the “theoretical limitation” of its efficiency; the data that might be obtained as of high-resolution transmission electron microscopy (HRTEM) is not simple as the preparation of transmission electron microscopy (TEM) specimens may mask a few observations regarding the structures of CNTs. A wide range of experimentations were carried out cautiously to offer the atoms, molecules, electrons, protons, considered to be the component of matter. The restriction of a microscope’s efficiency is determined by its solving strength. For the completion of electron microscopy research, additional characterization instruments are enviable particularly those that are not damaging to the samples. For CNTs characterization and dimensional analysis, various non-destructive imaging and microscopic methods were used: Various kinds of electron microscopy such as SEM and TEM. The other kinds of scanning probe microscopy (SPM) like AFM and STM. Microscopic methods are frequently employed instruments to probe the morphology at a confined level whereas diffraction methods are used to achieve an average sample morphology depiction. SEM and TEM are eminent methods commonly used to study inorganic, organic and biological species ultrastructure. SEM generates pictures by means of scanning the samples with a concentrated electron beam that interacts with CNT atoms. Usually, this technique is used to study nanotubes morphology and length (Chiang et al. 2001; Rinzler et al. 1998) for assessing the quality of as-prepared CNTs and checking the occurrence of functionalization responses in certain cases (Jimeno et al. 2009). In instances where the measurements needed exceed SEM resolution (1–20 nm), TEM is employed (Gommes et al. 2003; Täschner et al. 2003). In this higher energy electrons (up to 300 keV) are used to acquire a sample picture based on CNTs transmission of the electron. Through highresolution TEM pictures, minor sizes e.g., diameter, amount of layers and distance between layers in MWNT might be obtained (Kiang et al. 1998). In addition, when the functionalization of CNTs by means of various organic plus inorganic functional groups evidently alters the nanotubes surface, TEM was also employed to assess the processes of functionalization (Sun et al. 2002; Wepasnick et al. 2010). Both SEM and TEM were employed to examine the CNTs structural integrity and the functionalizations of the plant surface generated by acidic and natural oxidations to produce oxygen-containing groups e.g., hydroxyl (–OH), carbonyl (–CO) and –COOH groups (Datsyuk et al. 2008).

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References T. Belin, F. Epron, Characterization methods of carbon nanotubes: a review. Mater. Sci. Eng. B 119, 105–118 (2005) I. Chiang, B. Brinson, A. Huang, P. Willis, M. Bronikowski, J. Margrave, R. Smalley, R. Hauge, Purification and characterization of single-wall carbon nanotubes (SWNTs) obtained from the gas-phase decomposition of CO (HiPco process). J. Phys. Chem. B 105, 8297–8301 (2001) V. Datsyuk, M. Kalyva, K. Papagelis, J. Parthenios, D. Tasis, A. Siokou, I. Kallitsis, C. Galiotis, Chemical oxidation of multiwalled carbon nanotubes. Carbon 46, 833–840 (2008) M. Foldvari, M. Bagonluri, Carbon nanotubes as functional excipients for nanomedicines: I. Pharmaceutical properties. Nanomed.: Nanotechnol. Biol. Med. 4, 173–182 (2008) C. Gommes, S. Blacher, K. Masenelli-Varlot, C. Bossuot, E. McRae, A. Fonseca, J.-B. Nagy, J.-P. Pirard, Image analysis characterization of multi-walled carbon nanotubes. Carbon 41, 2561–2572 (2003) M. Hassellöv, J.W. Readman, J.F. Ranville, K. Tiede, Nanoparticle analysis and characterization methodologies in environmental risk assessment of engineered nanoparticles. Ecotoxicology 17, 344–361 (2008) A. Jimeno, S. Goyanes, A. Eceiza, G. Kortaberria, I. Mondragon, M. Corcuera, Effects of amine molecular structure on carbon nanotubes functionalization. J. Nanosci. Nanotechnol. 9, 6222–6227 (2009) C.-H. Kiang, M. Endo, P. Ajayan, G. Dresselhaus, M. Dresselhaus, Size effects in carbon nanotubes. Phys. Rev. Lett. 81, 1869 (1998) J.H. Lehman, M. Terrones, E. Mansfield, K.E. Hurst, V. Meunier, Evaluating the characteristics of multiwall carbon nanotubes. Carbon 49, 2581–2602 (2011) A. Rinzler, J. Liu, H. Dai, P. Nikolaev, C. Huffman, F. Rodriguez-Macias, P. Boul, A.H. Lu, D. Heymann, D. Colbert, Large-scale purification of single-wall carbon nanotubes: process, product, and characterization. Appl. Phys. A Mater. Sci. Process. 67, 29–37 (1998) Y.-P. Sun, K. Fu, Y. Lin, W. Huang, Functionalized carbon nanotubes: properties and applications. Acc. Chem. Res. 35, 1096–1104 (2002) C. Täschner, F. Pacal, A. Leonhardt, P. Spatenka, K. Bartsch, A. Graff, R. Kaltofen, Synthesis of aligned carbon nanotubes by DC plasma-enhanced hot filament CVD. Surf. Coat. Technol. 174, 81–87 (2003) E.T. Thostenson, Z. Ren, T.-W. Chou, Advances in the science and technology of carbon nanotubes and their composites: a review. Compos. Sci. Technol. 61, 1899–1912 (2001) K.A. Wepasnick, B.A. Smith, J.L. Bitter, D.H. Fairbrother, Chemical and structural characterization of carbon nanotube surfaces. Anal. Bioanal. Chem. 396, 1003–1014 (2010)

Chapter 6

Applications of Carbon Nanotubes

6.1 CNTs Application The unique characteristic of carbon combines with the molecular integrity of CNTs to provide it with outstanding substance characteristics like elevated electrical and thermal conductivity, rigidity, strength as well as hardness (Aqel et al. 2012). No element throughout the periodic table bonds with the intensity of the carbon bond in an enhanced network. In the first known molecule, the delocalized pi-electron donated by each atom is free to move around the whole structure instead of staying with its donor atom, resulting in electrical conductivity of the metallic type. Furthermore, carbon-carbon bond high-frequency vibrations provide greater inherent heat conductivity than even diamond. However, due to structural defects, the real material characteristics observed in most plastics (strength, electrical conductivity, etc.) is significantly degraded (Aqel et al. 2012). The high-strength steel, for instance, normally fails at just about one percent of its theoretical braking power. Though, due to their molecular perfection of structure, CNTs attain values very close to their theoretical boundaries. This element is part of CNTs. CNTs are very helpful molecules that might be chemically and physically manipulated, which open up a range of incredible applications in the science of materials, electronics, energy management, chemical processing, and several other areas (Vashist and Venkatesh 2012). The properties of CNTs make these as the most effective and multifunctional candidates for different biomedical applications. Additionally, the increased surface area of CNT-structure helps to manipulate the dimensions of CNTs, which offers various superior prospective advantages as an improved nanomaterial group (Alshehri et al. 2016). CNTs offer a better prospective for the biomedical applications because of their chemical, mechanical, thermal, and electrical characteristics (Aqel et al. 2012). The exclusive biomedical characteristics of CNTs are being exploited for different vital uses since past few decades. These are now being used in both therapeutic as well as diagnostic purposes (Hasnain et al. 2019). CNTs have appeared recently in the drug delivery arena as efficient carriers. For the particular release of several © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_6

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active pharmaceutical ingredients, CNTs are commonly used as drug carriers. Such materials have also been studied for their targeted drug delivery systems because of their simple transportation through cell membranes. High tensile strength and very lightweight CNTs have increased transport conductivity. There is also excellent heat and chemical stability (Liu et al. 2009; Smart et al. 2006). Large-scale CNTs are appropriate for the preparing of conjugates with various biological molecules, such as proteins, certain drugs, nucleic acid enzymes, etc. However, the development of new drug delivery systems relies strongly on drug carriers ‘capacity to effectively cross the cell barrier and release the drug molecule readily (Wong Shi Kam and Dai 2006). CNTs were an emerging target and a new system for the delivery of drugs. As drug delivery carriers, CNTs with exceptional physicochemical features and unique composition are a helpful choice. CNTs play a role in the delivery of nanocarrier drug molecules. A large number of molecules, ionic species or metallic species that can be inserted into the CNT wall surface can also be used to functionalize CNTs. Because of their hydrophobic interactions, fullerenes, porphyrins, and metals were identified as inserted molecules in CNT’s interior space. When drug delivery systems interact with the cancerous cells, these possibly will distinguish the cancer-specific receptors on the cell-surface and subsequently, provoke the receptor-mediated endocytosis. It is believed that the complex is taken up competently and exclusively by the cancerous cells with the ensuing intracellular releasing of different chemotherapeutical molecules (Fig. 6.1). Recently, f-CNTs have been extensively researched for therapeutic and diagnostic applications. Most functional groups (e.g. carboxylates and amines) are further modified to produce CNT conjugates in these types of conjugates with certain therapeutic agents with some kind of pharmacological activity (Khlobystov et al. 2005). CNTs also used as an alternative and effective tool for the delivery and transportation of therapeutic molecules. With certain bioactive peptides, certain proteins, and nucleic acid, many CNTs have been functionalized that can be used to bring cargo to cells and organs. It has been found that functionalized CNTs are non-immunogenic and less toxic. In the field of nanomedicine and nanotechnology, these technologies have potential utility. Because CNTs tend to agglomerate, it is necessary to solve dispersion issues. The chemical functionalization of CNTs is of basic significance to recognize the many prospective applications that CNTs can offer. The introduction of functional groups, like –COOH and –NH2 , not only increases the solubility of CNTs in various solvents, as well as uses other chemical compounds, such as inorganic compounds (Banerjee et al. 2005). Self-assembly of polymers, biomolecules and CNTs into device structures (Klinke et al. 2006). Different functional groups can be attached to CNTs through concentrated acid cycloaddition (Tagmatarchis and Prato 2004), oxidation (Avilés et al. 2009), diazonium salt chemistry (Amiri et al. 2011; Bahr and Tour 2001; Ellison and Gasda 2008), arylation (Stephenson et al. 2006), and other reactions (Yook et al. 2010). All future applications of CNTs as electronic structures require the nanotubes to be expanded to make them processable and to adjust their properties (Hirsch and Vostrowsky 2005).

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Fig. 6.1 CNT-based tumor-targeted drug delivery system (DDS): CNTs, drug and tumor-targeting ligands. When drug delivery systems are administered, it can recognize specific receptor on the surface of cancer cells and cross the cell membrane by endocytosis. Ji et al. (2010); Copyright @ 2018, Elsevier B.V.

References R. Alshehri, A.M. Ilyas, A. Hasan, A. Arnaout, F. Ahmed, A. Memic, Carbon nanotubes in biomedical applications: factors, mechanisms, and remedies of toxicity: miniperspective. J. Med. Chem. 59, 8149–8167 (2016) A. Amiri, M. Maghrebi, M. Baniadam, S.Z. Heris, One-pot, efficient functionalization of multiwalled carbon nanotubes with diamines by microwave method. Appl. Surf. Sci. 257, 10261–10266 (2011) A. Aqel, K.M.A. El-Nour, R.A. Ammar, A. Al-Warthan, Carbon nanotubes, science and technology part (I) structure, synthesis and characterisation. Arab. J. Chem. 5, 1–23 (2012) F. Avilés, J. Cauich-Rodríguez, L. Moo-Tah, A. May-Pat, R. Vargas-Coronado, Evaluation of mild acid oxidation treatments for MWCNT functionalization. Carbon 47, 2970–2975 (2009) J.L. Bahr, J.M. Tour, Highly functionalized carbon nanotubes using in situ generated diazonium compounds. Chem. Mater. 13, 3823–3824 (2001) S. Banerjee, T. Hemraj-Benny, S.S. Wong, Covalent surface chemistry of single-walled carbon nanotubes. Adv. Mater. 17, 17–29 (2005) M.D. Ellison, P.J. Gasda, Functionalization of single-walled carbon nanotubes with 1,4benzenediamine using a diazonium reaction. J. Phys. Chem. C 112, 738–740 (2008) M.S. Hasnain, S.A. Ahmad, M.N. Hoda, S. Rishishwar, P. Rishishwar, A.K. Nayak, Stimuliresponsive carbon nanotubes for targeted drug delivery, in Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications (Elsevier, 2019), pp. 321–344 A. Hirsch, O. Vostrowsky, Functionalization of carbon nanotubes, in Functional Molecular Nanostructures (Springer, 2005), pp. 193–237

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S. Ji, C. Liu, B. Zhang, F. Yang, J. Xu, J. Long, C. Jin, D. Fu, Q. Ni, X. Yu, Carbon nanotubes in cancer diagnosis and therapy. Biochim. Biophys. Acta - Rev. Cancer 1806, 29–35 (2010) A.N. Khlobystov, D.A. Britz, G.A.D. Briggs, Molecules in carbon nanotubes. Acc. Chem. Res. 38, 901–909 (2005) C. Klinke, J.B. Hannon, A. Afzali, P. Avouris, Field-effect transistors assembled from functionalized carbon nanotubes. Nano Lett. 6, 906–910 (2006) Z. Liu, S. Tabakman, K. Welsher, H. Dai, Carbon nanotubes in biology and medicine: in vitro and in vivo detection, imaging and drug delivery. Nano Res. 2, 85–120 (2009) S. Smart, A. Cassady, G. Lu, D. Martin, The biocompatibility of carbon nanotubes. Carbon 44, 1034–1047 (2006) J.J. Stephenson, A.K. Sadana, A.L. Higginbotham, J.M. Tour, Highly functionalized and soluble multiwalled carbon nanotubes by reductive alkylation and arylation: the billups reaction. Chem. Mater. 18, 4658–4661 (2006) N. Tagmatarchis, M. Prato, Functionalization of carbon nanotubes via 1,3-dipolar cycloadditions. J. Mater. Chem. 14, 437–439 (2004) S. Vashist, A. Venkatesh, Carbon nanotubes-based electrochemica l sensors and drug delivery systems: prospects and challenges. J. Nanome d Nanotechol. 3, e121 (2012) N. Wong Shi Kam, Single walled carbon nanotubes for transport and delivery of biological cargos. Physica Status Solidi (b) 243, 3561–3566 (2006) J.Y. Yook, J. Jun, S. Kwak, Amino functionalization of carbon nanotube surfaces with NH3 plasma treatment. Appl. Surf. Sci. 256, 6941–6944 (2010)

Chapter 7

Targeted Delivery with Carbon Nanotubes

7.1 Introduction Functionalized nanotubes have been frequently used to provide their corresponding areas of action with drugs, proteins, antibodies, nucleic acids other therapeutic agents. CNTs are primarily used in the therapy of malignant diseases like Burkitt’s lymphoma, choriocarcinoma, breast cancer, cervical carcinoma and testicular tumors (Thakare et al. 2010). These have been encapsulated as drug-charged functional CNTs experience issues in releasing the drug material into new membrane microcapsules consisting of an alginate-poly-lysine-alginate (APA) membrane. Either the nanotubes are built into the core or linked to the alginate capsule surface. Due to the protection given to the nanotubes by the polymeric layer from the hostile external setting, these indicate prospective drug release profile, safety, and efficacy. The cells are connected to the sidewalls of the nanotubes when functionalization of chitosan is done on the CNTs surface, resulting in the required targeted release to the cells and increased drug absorptions (Mahajan et al. 2018; Prakash et al. 2011).

7.2 CNTs in Cancer Targeting Cancers are the most difficult form of the disease to treat, and also most patients with cancer definitely die even if they are cured with sophisticated medicinal techniques (Aggarwal 2010). Surgery might eradicate cancer focuses but couldn’t do the same for micro-focuses as well as can’t eradicate freely emerging cancerous cells. Chemotherapy against cancer is the primary auxiliary therapy but sometimes fails to owe to its unendurable toxic and side effects on patients. The cancer biology sector has advanced at a phenomenal pace over the previous few decades (Javan et al. 2015). However, these findings have not been converted into similar improvements in hospitals despite incredible developments in basic cancer biology. Cancer therapy © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019 M. S. Hasnain and A. K. Nayak, Carbon Nanotubes for Targeted Drug Delivery, SpringerBriefs in Applied Sciences and Technology, https://doi.org/10.1007/978-981-15-0910-0_7

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discrepancies are primarily due to meagerness in the capability to administer high therapeutic selectivity agents and minimal side effects (Javan et al. 2015). Therefore, significant efforts are aimed towards such type of drug delivery system which selectively targets the cancer tissue outside the focus of cancer with negligible harm to ordinary tissue. The majority of the researches are still in the preclinical stage, however, and there is still a remote dream of effective clinical implementation. The design of such a scheme depends not only on the recognition of unique biomarkers for neoplastic diseases though also on the construction of a biomarker-oriented delivery scheme for therapeutic agents that prevent entry into ordinary tissues (Ferrari 2005). With the growth of nanotechnology, a small number of nanomaterial-based formulations have demonstrated pledge in cancer therapy and many nanoparticles, liposomes, and polymer conjugates have been accepted for clinical trials. The criteria for novel drug delivery techniques to enhance pharmacological characteristics while reducing the toxicological impacts of the drugs also deemed CNTs as one of the probable carriers for the treatment of cancers (Hormozi 2015). CNTs belong to a cylindrical family of fullerene allotropes. The characteristic physicochemical characteristics in this exciting industry (Cui et al. 2010; Huang et al. 2010). Simply modified surface CNTs resulted in an increase in the number of publications. Besides their use in nanomedicine with diagnostic consequences in cellular imaging (Bao et al. 2010; Hormozi 2015). CNTs are potential drug carriers for cancer therapies in the targeted drug delivery systems. In contrast to other nanocarriers appeared in 1960s, like micelles/liposomes and nanoparticles/dendrimers appeared in 1980s, CNTs have appeared as targeted drug carriers for no more than 20 years. Treating or eradicating malignant cells from the body to ordinary cells without spillover is very hard. In more than 99% of cases, chemotherapy kills cancer cells together with normal cells, causing grave side effects. CNTs make a significant contribution to the safe therapy of cancer cells in this regard. Chemotherapy agents provided with CNTs help to enhance the absorption of malignant cells without influencing the tissues of the collateral. As a consequence, nanotubes decrease the dose of the drug by placing only its distribution at the site of the tumor (Mahajan et al. 2018; Prakash et al. 2011). By using an antibody molecule to functionalize the drug-containing CNTs and target it to the antigen of cancer cells, this can be further strengthened. Recently it has been disclosed that the CNTs also show their own features of cancer treatment. It’s especially true if the CNTs are subjected to an IR light source, heating them in few secs up to 70–160 °C (