New Developments in Nanosensors for Pharmaceutical Analysis [1 ed.] 0128161442, 9780128161449

Table of contents :
Cover
NEW
DEVELOPMENTS IN
NANOSENSORS FOR
PHARMACEUTICAL
ANALYSIS
Copyright
Contributors
About the Authors
Preface
1
Introduction to Nanosensors
Introduction
Nanoparticles in Nanosensors and Their Broad Applications
Metal-Based Nanoparticles and Their Broad Applications
Metal-Based NPs as Gas Sensors
Metal-Based NPs as OLEDs
Magnetic Metal-Based NPs
Metal-Based NPs as Sunscreens
Metal-Based NPs in Virology and Bacteriology
Metal-Based NPs as Supercapacitors
Carbon-Based Nanomaterials
Carbon-Based Nanomaterials as Gas Sensors
Carbon-Based Nanomaterials as Electrochemical Sensors and in Fluorescence Quenching
Carbon Nanomaterials as High-Performance Energy Storage Devices
Molecularly Imprinted Polymer-Based Nanosensors
MIP-Functionalized SPE
MIPs Functionalized as Magnetic MIPs
MIPs Modified With Carbon Nanomaterials
MIPs as Sensors
Dendrimers
Dendrimer-Nanostructured Hybrid System
Dendrimers Conjugated to Carbon-Based Nanomaterials
Conclusions
References
Further Reading
2
Immobilization Techniques of Nanomaterials
Introduction
Nanomaterials Used in Biosensors for Pharmaceutical Detection
Carbon Nanomaterials
Carbon Nanotubes
Graphene
Fullerene
Quantum Dots
Metal Nanoparticles
Magnetic Nanoparticles
Modification Strategies for Nanomaterial-Based Biosensors
Drop Casting
Electrochemical Deposition
Electrochemical Polymerization
Molecularly Imprinted Polymer
Self-Assembly and Adsorption of Nanomaterials
Addition Nanomaterials in Carbon Paste Electrodes
Conclusion
References
3
The Effect of Nanomaterials on the Drug Analysis Performance of Nanosensors
Introduction
Nanomaterials Used for Sensor Development
Morphological and Structural Characterization Techniques for Nanomaterials
Techniques Used for the Characterization of the Sensor Effect of Electrodes Fabricated From Nanomaterials
Role of the Structure of Nanomaterials in Enhancing the Sensitivity and Selectivity of Sensors
The Shape Effect of Nanostructures on Drug Analyzer Nanosensors
Morphological Effect of Specific Nanomaterials-Based Sensors
Types of Nanostructures
Carbon Nanostructure-Based Sensors
Polymeric Nanostructures as Nanosensors
Transition Metal Nanostructures for Nanosensors
Sensors Fabricated From Nanocomposites, Nanohybrids, and Nanobimetallic Alloys
The Effect of Crystal Phases and Structural Units on Nanosensors
Selective and Simultaneous Detection of Drugs by a Specific Nanosensor in Analyte Samples
Conclusion and Future Perspectives
References
Further Reading
4
Optical Nanosensors for Pharmaceutical Detection
Introduction
Chemical and Bio-Based Optical Nanosensors
Surface-Enhanced Raman Spectroscopy
Localized Surface Plasmon Resonance-Based Optical Nanosensors
Fluorescence-Based Optical Biosensors
Chemical Modification of Nanosensors
Conclusion
References
5
Chemical Nanosensors in Pharmaceutical Analysis
Introduction to Chemical Nanosensors
Transducer Types in Chemical Nanosensors
Nanomaterials in Chemical Nanosensors
Carbon-Based Nanomaterials in Chemical Nanosensors
Metal-Based Nanomaterials in Chemical Nanosensors
Polymer-Based Chemical Nanosensors
Conclusion
References
Further Reading
6
Noble Metal Nanoparticles in Electrochemical Analysis of Drugs
Introduction
Noble Metals
Ruthenium
Rhodium
Palladium
Iridium
Platinum
Gold
Silver
Electrochemical Techniques
The Functions of Noble Metal Nanoparticles
Applications of Noble Metal Nanoparticles for Electrochemical Drug Analysis
Conclusion
References
Further Reading
7
Photoelectrochemical Nanosensors
Introduction
The Effect of the Morphology of Nanomaterials on the Detection Ability of Photoelectrochemical Sensors
Quantum Dots in Photoelectrochemical Sensors
Molecularly Imprinted Polymers in Photoelectrochemical Sensors
Photoelectrochemical Nanobiosensors: Fabrication Techniques and the Measurements
Recent Developments in Photoelectrochemical Nanosensors for the Determination of Pharmaceuticals, Chemicals, Cancer Bio ...
Conclusion
References
Further Reading
8
Molecularly Imprinted Polymer-Based Nanosensors for Pharmaceutical Analysis
Introduction
Molecularly Imprinted Polymers
Nanomaterials in molecularly imprinted polymers
Carbon Nanomaterials
Metal-based nanoparticles
Sensor Configurations
Conclusion
References
Further Reading
9
Nanomaterials for Drug Delivery Systems
Introduction
Drug Delivery Systems
Why Nanomaterials?
Types of Nanomaterials
Dendrimers
Liposomes
Solid Lipid Nanocarriers
Micelles
Polymeric Nanoparticles
Inorganic Nanoparticles
Metal Nanoparticles
Ceramic Nanoparticles
Silica Nanoparticles
Carbon-Based Nanomaterials
Fullerenes
Graphene
Carbon Nanotubes
Diamonds
Conclusion
References
10
Nanomaterials-Enriched Nucleic Acid-Based Biosensors
Introduction
Electrochemical Biosensors
Voltammetric Nucleic Acid Biosensors
Impedimetric-Based Nucleic Acid Biosensors
Amperometric-Based Nucleic Acid Biosensors
QCM Biosensors
Optical Nucleic Acid Biosensors
Colorimetric Nucleic Acid Biosensors
Fluorescence-Based Nucleic Acid Biosensors
Chemiluminescence-Based Nucleic Acid Biosensors
Electrochemiluminescence-Based Nucleic Acid Biosensors
Surface-enhanced Raman Spectroscopy (SERS)-Based Nucleic Acid Biosensors
SPR-Based Nucleic Acid Biosensors
Conclusion
Acknowledgments
References
11
Nanosensors in Biomarker Detection
Introduction
Biomarkers
Nanomaterials for Sensor Design
Carbon Nanotubes
Graphene
Metal Nanoparticles
Methods for Biomarker Detection and Determination
Electrochemical Methods
Optical Methods
Conclusion and Future Prospects
References
12
Nanomaterials-Based Enzyme Biosensors for Electrochemical Applications: Recent Trends and Future Prospects
Introduction
Electrochemical Enzyme Biosensors
Nanomaterials-Based Electrochemical Enzyme Biosensors
Carbon Nanotubes-Based Electrochemical Enzyme Biosensors
Graphene-Based Electrochemical Enzyme Biosensors
Nanoparticles-Based Electrochemical Enzyme Biosensors
Nanostructured Polymers-Based Electrochemical Enzyme Biosensors
Electrochemical Biosensors Based on Combinations of Different Nanomaterials
Conclusions and Prospects
Acknowledgments
References
Index
A
B
C
D
E
F
G
H
I
L
M
N
O
P
Q
R
S
T
V
W
X
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Back Cover

Citation preview

NEW DEVELOPMENTS IN NANOSENSORS FOR PHARMACEUTICAL ANALYSIS

NEW DEVELOPMENTS IN NANOSENSORS FOR PHARMACEUTICAL ANALYSIS Edited by

Sibel A. Ozkan Afzal Shah

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2019 Sibel A. Ozkan and Afzal Shah. Published by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-816144-9 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre G. Wolff Acquisition Editor: Glyn Jones Editorial Project Manager: Tracy I. Tufaga Production Project Manager: Maria Bernard Cover Designer: Christian Bilbow Typeset by SPi Global, India

Contributors Saima Aftab  Department of Chemistry, Quaidi-Azam University, Islamabad, Pakistan

Sevinc Kurbanoglu Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey

Mohammad Salim Akhter Department of Chemistry, College of Science, University of Bahrain, Sakhir, Bahrain

Giovanna Marrazza  Department of Chemistry “Ugo Schiff”, Florence University, Florence, Italy

Elif Burcu Aydin  Tekirdag Namık Kemal University, Scientific and Technological Research Center, Tekirdag˘ , Turkey

Azeema Munir Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan Rafia Nimal  Department of Chemistry, Quaidi-Azam University, Islamabad, Pakistan

Muhammet Aydin  Tekirdag Namık Kemal University, Scientific and Technological Research Center, Tekirdag˘ , Turkey

Erum Nosheen Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan

Nurgul K. Bakirhan  Department of Chemistry, Faculty of Art and Science, Hitit University, Corum, Turkey

Sibel A. Ozkan  Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey

Haluk Bingol  Ege University, Graduate School of Natural and Applied Science, Materials Science and Engineering Department, Izmir; Necmettin Erbakan University, Faculty of A. K. Education, Chemistry Department, Konya, Turkey

Yalcin Ozkan  University of Health Sciences, Department of Pharmaceutical Technology, Gulhane Campus, Ankara, Turkey Ayhan Savaser  University of Health Sciences, Department of Pharmaceutical Technology, Gulhane Campus, Ankara, Turkey

Burcin Bozal-Palabiyik  Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey

Frieder W. Scheller  University of Potsdam, Institute of Biochemistry and Biology, Potsdam, Germany

Arzum Erdem  Ege University, Faculty of Pharmacy, Analytical Chemistry Department; Ege University, Graduate School of Natural and Applied Science, Materials Science and Engineering Department, Izmir, Turkey

Mustafa Kemal Sezginturk Bioengineering Department, Çanakkale Onsekiz Mart ­University, Faculty of Engineering, Çanakkale, Turkey

Ozgur Esim  University of Health Sciences, Department of Pharmaceutical Technology, Gulhane Campus, Ankara, Turkey

Afzal Shah  Department of Chemistry, Quaid-iAzam University, Islamabad, Pakistan; Department of Chemistry, College of Science, University of Bahrain, Sakhir, Bahrain

Faiza Jan Iftikhar  Department of Chemistry, Quaid-i-Azam University; NUTECH School of Applied Sciences and Humanities, National University of Technology, Islamabad, Pakistan

Selen Soyalp  Ege University, Faculty of Pharmacy, Analytical Chemistry Department; Ege University, Graduate School of Natural and Applied Science, Materials Science and Engineering Department, Izmir, Turkey

Tayyaba Kokab Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan Filiz Kuralay  Department of Chemistry, Faculty of Arts and Sciences, Ordu University, Ordu, Turkey



Sundas Sultan Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan

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CONTRIBUTORS

Bengi Uslu  Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey Aysu Yarman  University of Potsdam, Institute of Biochemistry and Biology, Potsdam, Germany Muhammad Abid Zia  University of Education Attock Campus, Attock, Pakistan

Erhan Zor Necmettin Erbakan University, Faculty of A. K. Education, Science Education Department, Konya, Turkey

About the Authors Academy of Pharmacy Science Award of the Turkish Pharmaceutical Association in 2008, and The Best PhD Thesis in Turkey Award 2017 (Health Sciences), High Council of Education of Turkey. She is the Regional Editor of Current Pharmaceutical Analysis (2015) and the Section Editor of the Turkish Journal of Chemistry (2018). She is an Editorial Board Member of many journals, such as the Journal of Pharmaceutical and Biomedical Analysis, Talanta, Chromatographia, Current Drug Therapy, Journal of Turkish Pharmaceutical Sciences, and others. Afzal Shah is an Associate Professor of Physical Chemistry at the University of Bahrain. His PhD is from Quaid-i-Azam University, Islamabad, Pakistan and his postdoctorate is from the University of Toronto, Canada. He has supervised the theses of 8 PhD and 30 MS students. He is the recipient of fellowships/awards from the American Chemical Society, TUBITAK, and the Pakistan Council of Science and Technology. He has published more than 150 research articles in peer-refereed Scopus-indexed journals. His research is focused on the development of electrochemical nanosensors for drugs analysis and the detection of water toxins.

Sibel A. Ozkan is presently working as a Full Professor of Analytical Chemistry at Ankara University, Faculty of Pharmacy. She became a full professor in 2003. She has been involved in several analytical chemistry projects related to electroanalytical chemistry and separation techniques for drug active compounds, nanosensor development, and DNA-drug interactions. Her research interests include the analysis of pharmaceuticals using separation techniques, especially with liquid chromatography, method development and validation, electroanalytical techniques, novel electrode materials, nanostructured materials, ­surface-modified electrodes, the fabrication of biosensors and nanosensors, and the analysis of pharmaceuticals from their dosage forms and biological samples. She has published more than 250 (SSCI) original and review papers, more than 20 chapters in various books, and 4 scientific books, namely, “Electroanalytical methods in pharmaceutical analysis and their validation” (HNB Publishing 2012), “Electroanalysis in biomedical and pharmaceutical sciences” (Springer 2015), “Recent Advances in Analytical Techniques” Book Series Volume 1, 2017 and Volume 2, 2018, Bentham Science Publishers. She received the Ankara University Scientific Support Award in 2003, the



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Preface Nanosensors are emerging as promising tools for the analysis of pharmaceuticals and biological molecules. Nanosensing devices are bestowed with superior qualities of selectivity, sensitivity, affordability, and fast detection ability. They are preferred in diverse fields, such as the environmental, agricultural, forensic, medical, and industrial sectors. Compared to other old-fashioned sensors, nanosensors possess several advantageous features, such as ultrasensitivity, portability, real-time detectability, and user friendliness. In the literature, many techniques, including top-down lithography, self-assembled layers, and bottom-up assembly have been reported for the fabrication of nanosensors. By adopting smart strategies, materials can be ordered into nanotubes, nanowires, nanofibers, graphenes, fullerenes, nanorods, nanocomposites, metal nanoparticles, and nanostructured polymers for use in the development of nanosensors. All these nanomaterials have high surface area/volume ratio and display excellent catalytic activities. Moreover, they are associated with high mechanical strength and attractive electrical and chemical features. Biological molecules, such as proteins and nucleic acids, can be detected by nanosensors as linked receptors on sensor surfaces. Thus, the development of nanosensors is very important for the analysis of pharmaceuticals, biological molecules, and disease biomarkers. The aim of this book is to introduce recent progress in the fabrication of nanosensors for the sensitive and selective detection of drug active compounds. The interaction of pharmaceuticals and nucleic acid has been dis-



cussed in detail. This book contains twelve contemporary chapters, which have been shared with readers, researchers, and students. All chapters emphasize recent nanosensor developments in different fields. In the first chapter, an overview of nanomaterials is presented to situate electrochemical methods in their analytical context. The following chapter includes the immobilization techniques of nanomaterials. Chapter 3 contains the mechanism effect of nanomaterials on the structure. In Chapter 4, optical nanosensors for pharmaceutical detection are described in detail. Subsequent chapters are summarized as chemical nanosensors in pharmaceutical analysis (Chapter  5), noble metal nanoparticles in electroanalytical studies of drugs (Chapter  6), ­photoelectrochemical-based nanosensors (Chapter  7), and molecularly imprinted polymer-based nanosensors for pharmaceuticals (Chapter  8). Recent developments in the field of nanomaterials for drug delivery systems are summarized in Chapter 9. In Chapters 10 and 11, details of nanomaterials-enriched nucleic acid-based biosensors and nanosensors in biomarker detection are presented. The last chapter (Chapter  12) offers valuable information about nanomaterials-based enzyme biosensors for electrochemical applications. We believe that this book will be very useful for researchers working in the areas of chemistry, pharmacy, nanomaterials, and biochemistry. New, fast, portable, and easyto-use devices that involve nanosensors can be modified according to the information presented in this book. Readers from various fields will likely find new ideas and

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PREFACE

approaches to solve typical nanosensor and nanomaterial problems. Moreover, it will be helpful in the development of environmental sensors and agricultural and food sensors as modern techniques. The completion of this book could not have been possible without help, inspiration, and encouragement from many people. Last, but not the least, we warmly acknowledge the gracious support of our families, and we are very grateful to them for their assistance throughout the entire process of writing and editing. We would like to specially thank Dr. Glyn Jones, our project manager, Tracy Tufaga,

and our publisher Elsevier, for their support during the publishing of this book. Finally, we would like to express our sincere gratitude to the leading authors, who accepted our invitation to join us and dedicated their valuable time and efforts to guarantee the success of this book. Sibel A. Ozkan* Afzal Shah† *Ankara University, Ankara, Turkey †

University of Bahrain, Sakhir, Bahrain

C H A P T E R

1 Introduction to Nanosensors Faiza Jan Iftikhar⁎,†, Afzal Shah⁎,‡, Mohammad Salim Akhter‡, Sevinc Kurbanoglu§, Sibel A. Ozkan§ ⁎

Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan †NUTECH School of Applied Sciences and Humanities, National University of Technology, Islamabad, Pakistan ‡ Department of Chemistry, College of Science, University of Bahrain, Sakhir, Bahrain §Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey

1 INTRODUCTION Improving nano-sensing technology is at the heart of electrochemical detection strategies that offer effective, economical, time-saving, on-site monitoring amongst a large pool of analytes, such as heavy metal ions, food contaminants, such as melamine and aflatoxin, clinical toxins, such as cholera toxin and dopamine, and cancer and other disease markers, to name just a few cases with promising results. Nanostructured materials have at least one dimension of single or multiple phase that is less than 100 nm in size. Sensors based on nanoparticles rely on focusing on nanoscale dimensions, thus enhancing the optical and electronic properties due to a significant increase in the number of atoms at the surface of the material rather than the bulk. Hence, the interesting and unexpected properties are due to a large surface area, which translates into manipulating the material at the molecular or atomic level, in order to deploy it in different applications, ranging from heath diagnostics and cancer treatment to environmental analysis to clean energy. Due to their small size, nanoparticles can confine electrons to produce quantum effects and display an exquisite array of optical colors. Other size-dependent properties may include super paramagnetism in magnetic materials and surface plasmon resonances in noble metal particles. This property was utilized by artists in medieval times, who were unaware at that time of the existence of nanoparticles and their chemistry, for sculptures and churches. Nanoparticles found use in red wine glass in mosaics, with the color arising from AuNPs of 20 nm size. Orange glass got its color from 80 nm AuNPs, while Ag and Pt had their own unique colors depending on the size of the nanoparticles (Cullum, Griffin, & Vo-Dinh, 2002; De Castro Bueno, Garcia, Steffens, Deda, & Leite, 2017; Horikoshi & Serpone, 2013; Pérez-López & Merkoçi, 2011; Zhu, Yang, Li, Du, & Lin, 2014).

New Developments in Nanosensors for Pharmaceutical Analysis https://doi.org/10.1016/B978-0-12-816144-9.00001-8

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Copyright © 2019 Sibel A. Ozkan and Afzal Shah. Published by Elsevier Inc. All rights reserved.

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1.  Introduction to Nanosensors

The application of nanotechnology provides a formidable toolbox and it can only be deployed effectively once we understand what each tool stands for. Signal amplification by electrochemical sensors and biosensors based on functional materials, such as nanosensors, can greatly improve their sensitivity and selectivity. The choice of appropriate electrode material for electrochemical detection is important in developing high-performance sensing platforms. These functional nanomaterials are not only responsible for synergism to enhance signal transduction for catalytic activity and biocompatibility but also to amplify recognition events, leading to many applications for devices based on electrochemical methods. Moreover, these functional nanostructured materials provide effective sites for immobilization at the surface of matrices. In this chapter, the unique and inherent features of nanomaterials coupled with electrochemical methods for improved sensing response and disease diagnosis are highlighted (Cullum et al., 2002; De Castro Bueno et al., 2017; Pérez-López & Merkoçi, 2011; Zhu et al., 2014).

2  NANOPARTICLES IN NANOSENSORS AND THEIR BROAD APPLICATIONS Nanoparticles, which are ultimately released into the environment, may be divided into natural, engineered, and incidental NPs based on their dimensions. Natural NPs may originate from biotic and abiotic factors and may include organic matter, volcanic dust, minerals from weathering, clays, microbial actions, and metal oxides (Morales-Díaz et al., 2017), while engineered NPs have a specific shape, size, and surface morphology designed for specific applications. These include TiO2, SiO2, and FeOx and are used in a wide variety of consumer applications (Piccinno, Gottschalk, Seeger, & Nowack, 2012). Anthropogenic incidental involuntary production of NPs as a by-product of the combustion of fuels and other combustion activities, from production and manufacturing facilities, and from agricultural practices are classified as incidental NPs and have far-reaching and even drastic effects on the environment and health (Zumwalde & Hodson, 2009). In addition to size and type, the shape of nanoparticles can be engineered and controlled. Besides, the shape of the nanoparticles can be determined by the ratio of the metal salt, appropriate solvent, and reducing agent during the synthesis step. Generally, a high ratio of, for example, Au, in comparison with other ingredients will result in larger nanoparticles. Moreover, by changing the conditions during synthesis, such as the temperature and pressure, other shapes can be formed, such as nanorods or other complex structures. The variety of NP shapes is used in a broad range of applications in areas in which NPs have desirable optical properties and suitable pore structures to potentially hold drugs for targeted drug delivery. An important aspect in nanoparticles is to encapsulate nanoparticles or to modify the surface of nanoparticles with a wide variety of molecular ligands, including alkyl-based molecular linkers, akanethiolates, arenethiolates, sugars, phospholipids, DNA, and dialkyl disulfides. Encapsulation is extremely important to protect nanoparticles from agglomeration and to avoid losing the special features of NPs, as well as to provide surface protection that helps in achieving specific properties; for example, by using a longer protecting ligand, the distance between the NPs can be larger, which affects the amount of analyte absorbed in sensing applications (Gupta & Gupta, 2005; Jamieson et al., 2007; Samia, Dayal, & Burda, 2006; Sassolas, Blum, & Leca-Bouvier, 2012).



2  Nanoparticles in Nanosensors and Their Broad Applications

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2.1  Metal-Based Nanoparticles and Their Broad Applications NPs based on metal oxides have a broad range of biomedical applications and they find use in sensors, catalysis, environmental remediation, and energy technology (Fernández-García & Rodriguez, 2011; Osgood, Devaguptapu, Xu, Cho, & Wu, 2016; Polshettiwar, Baruwati, & Varma, 2009). Such NPs have been given considerable attention due to their high chemical activity as well as specificity for reactions and product formation. They behave as unique versatile materials that are intensely affected by the choice of synthesis method, which controls their size and morphology. These are important parameters for tuning the catalytic activity and surface area enhancement. In the past few years, metal oxides have been employed as highly selective catalysts for organic substrates used for industrial applications (Akbari et al., 2018). Hence, optimization of the catalyst is an important step toward increasing its selectivity for reactants and product formation, while adopting green synthetic chemistry for a sustainable future is a topic of increasing interest amongst researchers (Anastas & Eghbali, 2010; Anastas & Kirchhoff, 2002; Anastas, Kirchhoff, & Williamson, 2001). Moreover, noble metals, such as Pt, PtRu, PtSn, Pd, Au, Ru, and Ag, can be used with carbon-based nanomaterials to prepare nanohybrids for applications in heterogeneous catalysis, fuel cells, and chemo/biosensors (Wu, Kuang, Zhang, & Chen, 2011) (Fig. 1).

FIG. 1  Brief summary of the preparation and application of noble metal NP/CNT nanohybrids. Reprinted with permission from the publisher (Wu, B., Kuang, Y., Zhang, X., & Chen, J. (2011). Noble metal nanoparticles/carbon nanotubes nanohybrids: Synthesis and applications. Nano Today, 6(1), 75–90).

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1.  Introduction to Nanosensors

Similarly, MoOx possesses a unique structure, which has attracted a lot of attraction in the field of sensors (Liang et al., 2005; Malikov & Mikhailov, 1997; Prasad et al., 2003). However, much less is reported regarding its catalytic activity (Katrib, Mey, & Maire, 2001; Song et al., 2002). Hence, MoOx doped with Fe for oxidation of Olefin has been reported using a hydrothermal method of synthesis (Bento, Sanches, Medina, Nunes, & Vaz, 2015; Bento, Sanches, Vaz, & Nunes, 2016). Moreover, MoO3 doped with magnetic Fe2O3 with a core shell architecture and coated with glucose to prevent aggregation of Fe2O3 NPs has been reported to demonstrate outstanding catalytic performance and selectivity for epoxide product formation (Zhang, Hu, Zhong, Yan, & Chen, 2014). Similarly, heterogeneous catalyst WOx NPs dispersed on supports, such as mesoporous silica: SBA-15, MCM-48, and MCF, having a high surface area, leads to enhanced catalytic performance (Gao et al., 2008; Herrera et al., 2006; Koo, Kim, & Chang, 2005). Tungsten doped with different metals, W-X/SnO2 where X are different metals with a strong dependence on the additive X, have been reported to act as useful catalysts (Keigo et al., 2011). Similarly, NPs of iron oxide have been widely used, owing to their low toxicity, good dispensability, and easy separation due to their magnetic properties and for which recovery of the catalyst is feasible. Iron oxide NPs are mostly capped by silica-based agents to prevent their aggregation. Free Fe2O3 is very rarely reported for its application as a catalyst, however, bulk Fe2O3 and nano Fe2O3 with different sizes of NPs have been reported (Feng et al., 2007). Diverse morphologies, such as nanofibers and nanotubes of TiO2, have been used as catalyst promoters for Fe2O3 NPs for catalytic activity (Nafria et al., 2013). Cobalt oxide finds wide applications in sensing, electrochemical investigations, and catalysis (Cantalini, Post, Buso, Guglielmi, & Martucci, 2005; Poizot, Laruelle, Grugeon, Dupont, & Tarascon, 2000; Solsona et al., 2008). The size and morphology of catalysts play important roles in deciding the catalytic activity and selectivity. Different CuO NPs are prepared by the hydrothermal method. Similarly, CuO is one of the most important transition metal oxides (Soleimani & Taheri, 2017). Different morphologies have been prepared by different synthesis methods (Cao et al., 2003; Liu & Zeng, 2004; Ng & Fan, 2007; Xiao, Fu, Zhu, Li, & Yang, 2007; Xu, Chen, Jiao, & Xue, 2007; Yu, Yu, Liu, & Mann, 2007; Zhang, Liu, Peng, Wang, & Li, 2006; Zhou, Kamiya, Minamikawa, & Shimizu, 2007). Aggregation and stability, which can limit the catalytic activity as oxidants, are some issues that need proper handling on unsupported CuO NPs. However, supported CuO NPs on Ag nanowires and SiO2 have been investigated (Scotti, Ravasio, Zaccheria, Psaro, & Evangelisti, 2013; Ye et al., 2012). The low catalytic activity of CuO on SiO2 can be overcome by a novel method of using alkali metals, such as Cs and K+, as promoters (He, Zhai, Zhang, Deng, & Wang, 2013). A novel bimetallic oxide system has been introduced, CuO-NiO/SBA-15, as an excellent catalyst by using the postgrafted ultrasonic method (Tang et al., 2016). Hybrid CuO NPs were investigated using core shell nano-architecture with magnetic Fe2O3 NPs as the core and mesoporous silica as the protective shell (Zhang et al., 2014). In one particular study, cerium oxide NPs were employed as environmentally friendly oxidizing catalysts (Deori, Gupta, Saha, Awasthi, & Deka, 2013). Cerium oxide nanoparticles (nanoceria) are also used as an electrode material in gas sensors, as oxide ion conductors in solid oxide fuel cells (SOFCs), and in biomedical applications (Culcasi et al., 2012; Dahle & Arai, 2015; Deori et al., 2013; Pulido-Reyes et al., 2015; Trovarelli, 1996; Wang & Lin, 2004). However, in order to make them soluble and biocompatible, CeO2 NPs are coated with a polymer, such as dextran, for antioxidant activity (Perez, Asati, Nath, & Kaittanis, 2008). Although nanoceria are being used for different applications, their toxicity



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has been a concern for the environment and for humans. They may cause in vitro or in vivo oxidative cell damage leading to cell death. Nanoceria have been synthesized in a number of ways, however, more emphasis is laid on their synthesis by green methods, such as by using Gloriosa superba L. leaf extract, Curvularia lunata culture filtrate, Aloe vera, and Acalypha indica plant leaf extract, as capping agents and, finally, using Hibiscus sabdariffa as a chelating agent (Arumugam et al., 2015; Kannan & Sundrarajan, 2014; Munusamy, Bhakyaraj, Vijayalakshmi, Stephen, & Narayanan, 2014; Priya, Kanneganti, Kumar, Rao, & Bykkam, 2014; Thovhogi, Diallo, Gurib-Fakim, & Maaza, 2015). These nanoceria acting as antioxidant NPs are found to have a profound effect on ROS when nanoceria were coated with Levan as a reductant and stabilizing agent (Kim & Chung, 2016). It was also found that nanoceria protected the neurons and cells from free radical damage depending on size of NPs. These nanoceria behave as ROS scavengers and can be used an alternative therapy to cancer and Alzheimer disease (Rajeshkumar & Naik, 2017). 2.1.1  Metal-Based NPs as Gas Sensors Gas sensors sense changes in the electrical, optical, and junction properties of inorganic materials when they interact with gas molecules. Among the different types of gas sensors, sensors based on semiconductor metal oxides exhibit outstanding features with regards to sensitivity, response time, maintenance, portability, and cost (Dey, 2018). However, nanostructured materials offer a wide range of size-related effects due to large surface-to-volume ratios, displaying characteristic advantages for gas sensing with enhanced surface active sites. A gas sensor should be selective toward a gas in a gas mixture to be an efficient sensor. Likewise, the sensor response and recovery time, as well as being resistant to drift in the sensor response, are important parameters for gas sensors, as are the cost and fabrication (Mehta, Singh, & Khanuja, 2011). A number of synthesis methods are used, such as the sol-gel method, solid state reactions, the wet chemical route, spin coating, and laser ablation. Different size ranges for SnO2 for sensing different gas molecules, such as NH3, H2CO, CH4, and ethanol, have been investigated by controlling the size with annealing, temperature, additives, doping, and capping agents, among others, which suggests that sensitivity increases with decreasing particle size, as can also be seen for indium oxide, which is able to sense oxidizing and reducing gases (Cavicchi, Walton, Aquino-Class, Allen, & Panchapakesan, 2001; Dolbec & El Khakani, 2007; Gagaoudakis et al., 2001; Huang, Manolidis, Jun, & Hone, 2005; Huang, Matsunaga, Shimanoe, Yamazoe, & Kunitake, 2005; Safonova, Bezverkhy, Fabrichnyi, Rumyantseva, & Gaskov, 2002; Shukla, Seal, Ludwig, & Parish, 2004; Singh, Mehta, Joshi, Kruis, & Shivaprasad, 2007; Tan, Ho, Wong, Kawi, & Wee, 2008). Different nanosized semiconductor oxides, such as TiO2, WO3, ZnO, V2O5, Fe2O3, CdO, CuO, Ga2O3, and CdSnO3, are employed to detect different gases, such as H2, CH3OH, LPG, H2S, and CO, with a range of different sizes that directly affect the sensitivity of the sensor (Benkstein & Semancik, 2006; Dario, Michael, Carlo, Paul, & Alessandro, 2008; Li et al., 2009; Liu et al., 2004; Rout, Govindaraj, & Rao, 2006; Waghulade, Patil, & Pasricha, 2007; Wang et al., 2008). The sensitivity, response time, and selectivity of gas sensors can be improved by metal additives, such as Pt or Pd, either by doping the material or using it as a support. These metal additives can substitute the host particles or become dispersed in the interstitial spaces (Mardare & Hones, 1999). This affects the electrical and optical properties of metal oxide NPs (Madhusudhana Reddy

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& Chandorkar, 1999). The metal can agglomerate at the surface of the semiconductor layer as nano- or micrometal aggregates (Ivanovskaya, Bogdanov, Faglia, & Sberveglieri, 2000). The gas sensing ability of semiconductor oxide nanoparticles assisted by metal additives emphasizes the configuration of metal-metal oxide NPs, depending on the type of metal additives a well as where the metal is incorporated in the metal oxide NP (Yamazoe, 1991). A number of research studies have been carried out to pinpoint the importance of metal additives. One example is SeO2 added to In2O3 and formed by the thermal evaporation method to produce a mixed film of SnO2 (Manno, Micocci, Serra, Di Giulio, & Tepore, 2000). In2O3 and WO3 was formed by the laser ablation method and mixed with Pt by the impregnation method to support a doped thin film (Starke & Coles, 2002), while In2O3 with Fe2O3 formed by the sol-gel and coprecursor method, respectively, formed a layer-by-layer surface (Ivanovskaya, Kotsikau, Faglia, & Nelli, 2003) to form an efficient gas sensor that does not depend on either of the morphologies. Increasing the Debye length for NPs, such as SnO2, brings about an improvement in the sensitivity of the sensor; for example, doping SnO2 with trivalent or pentavalent ions affects the Debye length by increasing or decreasing it accordingly (Xu, Tamaki, Miura, & Yamazoe, 1991). In gas sensors, the solid state surface interacts with the gas molecules either through physisorption or chemisorption; the former induces no charge transfer, while the latter process does. It has been demonstrated that at any semiconductor surface, the presence of adsorbed oxygen in the form of O− or O2− is found during chemisorption depending on energy considerations (Kohl, 1989; Liu, Huang, & Meng, 2007). The adsorbed species extracts an electron from the donor level of the NPs and creates an electron deficient or positive charge space near the surface. For a reducing gas Rg, the concentration of the adsorbed O2 species will decrease and an electron will be given back to the conduction band with a decrease in resistance for n-type semiconductors, while the reverse is true for oxidizing gases. P-type semiconductors interacting with Rg will decrease the adsorbed oxygen and produce holes, and thus decrease the conductivity due to the concentration of holes (Patrick, 2017). Either the rate of chemical reaction affecting the electronic states or the electronic activation is responsible for the activation mechanism of metal additives (Pt or Ag on Pd) for semiconductor oxide nanoparticles (Yamazoe, Sakai, & Shimanoe, 2003). Energy band gaps of n-type In2O3 and p-type Ag2O have been studied to elucidate the electronic transitions within the electronic activation method. The higher work function of Ag2O (~5.3 eV) compared with In2O3 (~5.0 eV) results in the formation of a depletion layer at the interface of In2O3 (Jia et al., 2003; Tjeng et al., 1990; Tyagi, 1984). When a reducing gas, such as ethanol, is introduced, it reduces Ag2O to Ag, forming an In2O3-Ag interface, increasing the surface area at the same time and forming an accumulation layer due to the Fermi level being higher for Ag than In2O3, which increases the response of the gas sensor (Balasubramanian & Subrahmanyam, 1991). The response of In2O3 alone depends on the depletion layer formed due to the release of an electron to the adsorbed O2 species and the subsequent removal of O2 by ethanol, whereas at high temperatures the rate of reaction between the oxygen and ethanol increases. The drift problem can be reduced by using metal oxide nanowires in resistive sensors, improving the sensitivity by decorating with PdNPs. 2.1.2  Metal-Based NPs as OLEDs The early 1990s saw a rapid advancement in organic light emitting diodes (OLEDs); however, their lifetime was limited by humidity, oxygen-prone organic materials, and a fast



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­ egradation under conditions of high operating currents (Jain, Willander, & Kumar, 2007). By d introducing inorganic NPs that combined large surface area with light emitting inorganic semiconducting NPs, it was possible to overcome the limitations set by organic materials (Colvin, Schlamp, & Alivisatos, 1994; Murray, Norris, & Bawendi, 1993). It used glass coated with a transparent conducting oxide (TCO) as an electrode and substrate. The second cathode electrode must have a low work function. ITO, its alternative FTO, and Al- or Ga-doped ZnOx, have been researched as electrodes of choice (Bach et al., 1998; Minami, 2008; Raniero et al., 2006). The OLED-NP consists of a sandwiched active NP layer between the two e­ lectrodes; hence, holes from TCO and electrons from the other electrode recombine to emit light. Such a principle of work has been determined by employing quantum dots prepared by a s­ olution-based process with precise control over size, doping, and composites. Attaching different ligands to the particle results in passivation, stabilization, and dispersion in different solvents. Hence, for LED-NP fabrication, QDs remain the first choice. Optimizing the band gap using Cd-free QDs is an area of much research and many promising results have been obtained (Alivisatos, 1996; Tan et al., 2007). The luminescence efficiency of QDs can be improved by modifying the surface with capping agents with the adsorption/emission wavelength shifted toward the blue. The blending of QDs with a hole and an electron conducting polymer sandwiched between the two electrodes demonstrated itself as an efficient LED (Colvin et al., 1994). This method was further modified by using hole-conducting and electron-conducting semiconductors and conducting polymers as host matrices (Dabbousi, Bawendi, Onitsuka, & Rubner, 1995; Li, Rizzo, Cingolani, & Gigli, 2006; Mattoussi et al., 1999). In order to obtain NPs of suitable size and properties, the surface of the QDs is chemically engineered to allow the NPs to be stable in physiological conditions. The surface of the QDs is also important to render the NPs biocompatible. QD-iron oxide has been used to detect and separate tumor cells. 2.1.3  Magnetic Metal-Based NPs Magnetic NPs, if they are to be used in vivo for the purpose of delivering drugs and for real time monitoring, should be biocompatible to physiological pH, should have a surface chemistry to conjugate functional ligands to perform different functions, and should be nontoxic with the end product rapidly discharged from the body (Arruebo, Fernández-Pacheco, Ibarra, & Santamaría, 2007; Berry, 2005; Frullano & Meade, 2007; Riehemann et  al., 2009). These NPs are directed by magnetic fields and can be used in combined therapy, for example, hyperthermia and cancer therapy (Ciofani, Riggio, Raffa, Menciassi, & Cuschieri, 2009). More specifically, iron oxide in the form of magnetite Fe3O4, g-Fe2O3, and MFe2O4, in which M can be Co, Zn, Ni, and iron-based alloys prepared by the coprecipitation method in an aqueous solution of salt in a basic medium, are important NPs for medical applications and therapeutics. Superparamagnetic iron oxide SPIONs have gained acceptance as contrast agents for magnetic resonance imaging (MRI) (Altavilla, 2011). 2.1.4  Metal-Based NPs as Sunscreens The use of nano-sized ZnO and TiO2 NPs in cosmetics and sunscreens due to their uniform coverage has been indispensable in our lives. However, the health implications due penetration by topical use owing to the very small size of the NPs, has been completely ignored. When TiO2 absorbs light, the electron in the valence band can be promoted to the conduction band because of the small energy band gap as compared with the energy absorbed.

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This results in the migration of the electron to the surface of the particle, forming superoxide and hydroxyl radicals with O2 that damage DNA. This may be avoided by chemically attaching an anionic polymer to the surface of TiO2 (William & Raifailovich, 2011). 2.1.5  Metal-Based NPs in Virology and Bacteriology In virology, metal NPs and their oxides (Au, Ag, ZnO, SPIONs, TiO2) have been used for combating HIV, hepatitis, and herpes simplex virus infection (Yadavalli & Shukla, 2017). Therapeutics for HIV, for example, have been closely followed by SPIONs and other metal NPs as drug delivery devices that use TAT protein for targeting receptor cells to block glycoprotein for the virus and prevent infection proliferation (Dodd et al., 2001; Lewin et al., 2000; Rao, Reddy, Horning, & Labhasetwar, 2008; Tkachenko et al., 2004). Similarly, a novel treatment to treat HIV can be accomplished through the use of SPIONs as MRI contrast agents loaded with antiretroviral drugs and guided to the specific location by a magnetic field (Gorantla et al., 2006). The treatment of cells infected with HIV using SPIONs, along with magnetic field heating to >45°C, has been reported (Williams et al., 2013). An antiretroviral drug encapsulated into a SPION nano-carrier with a bilayer coating and guided by a magnetic field was investigated by Jayant et al. to treat neuroAIDs (Jayant et al., 2015). SPIONs can also deliver drugs across the blood-brain barrier (Fiandra et al., 2015). In order to protect the magnetic core from leaching, oxidation and reactions with acids or bases and functionalization with different stabilizers, such as disodium tartrate or polymers, is crucial. Because of their biocompatible nature and unique surface chemistry, SiO2 NPs have been used to detect hepatitis virus. They have also been used as fluorescent dyes functionalized with lanthanide chelates, such as Eu or Tb, to develop highly sensitive and time responsive immune-linked fluorescent assays (Xia, Xu, Zhao, & Li, 2009; Xu & Li, 2007; Yang, Zhang, Qu, Yang, & Xu, 2004). These NPs were tagged with antibodies to detect antigen hepatitis virus and showed more sensitivity than gold-standard AuNPs. Magnetic silica NPs have been used to detect hepatitis B virus and have been employed to kill hepatitis C virus by labeling with DNAzymes (Bae, Tan, & Hong, 2012). TiO2 has been used to inhibit avian influenza virus (H9N2) with a high inhibitory activity when the NPs are activated by UV light (Jiang, Cui, Yang, Cai, & Wu, 2009). Cu2+/TiO2 NPs, however, exhibit higher antiviral activity as compared with their counterpart (Haixin et al., 2010). Additionally, when TiO2 was tagged with DNA to target viral DNA (H3N2), it successfully inhibited the reproduction of the virus (Levina et al., 2014). Similar studies have shown the same with viruses H1N1 and H5N1 (Levina et al., 2015). NPs based on calcium compounds induce inactivation of the influenza virus (Knuschke et al., 2013; Thammakarn et al., 2014; Zhou, Moguche, Chiu, Murali-Krishna, & Baneyx, 2014). ZnO NPs with a tetrapod structure have been engaged to counteract HSV virus at different levels of treating and blocking by electrostatically attaching negatively charged NPs, thus acting simultaneously as virus trappers and blockers for viral activity (Antoine et al., 2012; Mishra et al., 2011; Yadavalli & Shukla, 2017). NPs have wide applications for biomedical technology. NPs such as ZnO, CuO, TiO2, and Fe2O3 (Ismail, Sulaiman, Abdulrahman, & Marzoog, 2015; Jesline, John, Narayanan, Vani, & Murugan, 2015; Ren et al., 2009) have been widely used for their bactericidal and bacteriostatic properties due to the unique large surface-to-volume ratio. This allows a large number of ligands in the form of receptors, such as proteins and phospholipids, to bind to the surface of the pathogenic microbes by contributing to a cascade of events, including the disruption



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of the membrane or protein denaturation, induction of oxidative stress by ROS affecting the DNA, or by blocking the source of food (Cowan, 1999). The green synthesis of NPs by using plants, for example, renders them nontoxic, which is an important implication for in  vivo targeted dosage administration through NPs as a drug delivery device, as well as being environmentally friendly and cheaper (Happy, Soumya, Venkat Kumar, & Rajeshkumar, 2018). Plants, fungi, and algae host a number of phytochemicals that act as both reductants and stabilizers against targeted multidrug-resistant bacterial genes that cause fatal bacterial infections and diseases (Agarwal, Venkat Kumar, & Rajeshkumar, 2017). These NPs are coated with important therapeutic biomolecules, such as amides, aldehydes, polysaccharides, organic acids, and quinone, that allow conjugation between the green NPs and the membrane of the bacteria (Yadav, Kumar, Budhwar, Yadav, & Yadav, 2016). NPs synthesized by greener methods demonstrate better antibacterial activity than those synthesized by physical or chemical methods (Shet, Ghose, Patil, Hombalimath, & College, 2015). ZnO has gained popularity due to its unique features, including being biocompatible with faster electron transfer rates and its activity against a broad spectrum of gram positive and gram negative bacteria having a peptidoglycan layer; nevertheless, (Huang, Wu, & Aronstam, 2010) functionalization of ZnO with maltodextrin increases the internalization of NPs into the bacteria by many fold. 2.1.6  Metal-Based NPs as Supercapacitors The liquid-liquid extraction method was used to codisperse MnO2 NPs formed by reduction in n-butanol and MWCNT in the water/butanol phase by using Lauryl gallate (LG) as a dispersant (Wallar, Zhang, Shi, & Zhitomirsky, 2016). The LG works on the same principal as gallic acid and catecholates incorporating a larger group galloyl and a longer hydrophobic end that helps in steric dispersion. MnO2-MWCNT electrode material was used as a positive electrode for fabrication of asymmetric supercapacitors with carbon-carbon black as the negative electrode. In order to avoid agglomeration of NPs from solution due to the formation of oxo-bridges and hydroxides, it is imperative to mix the NPs with other materials, such as MWCNT, that also improve its conductivity. Hence, in the study, MnO2 NPs were codispersed with MWCNT by extracting it in n-butanol in the presence of LG as a dispersant. The LG interacts through its OH groups to MnO2, while the R group in LG, which comprises the hydrophobic part, is involved with the sidewalls of CNT, and codispersion is possible. The active mass for the electrode is impregnated on Ni-foam as a current collector and results in excellent supercapacitor performance of 8.0 F cm−2 at a scan rate of 2 mV s−1 with a high loading of active mass (Wallar et al., 2016). More information about metal-based nanoparticles in Pharmaceutical Analysis can be obtained in Chapter 5, “Chemical Nanosensors in Pharmaceutical Analysis” and Chapter 6, “Noble Metal Nanoparticles in Electrochemical Analysis of Drugs.”

2.2  Carbon-Based Nanomaterials Because of their versatile properties, such as extraordinary surface-to-volume ratio, electrical conductivity, biocompatibility, mechanical strength, and chemical stability, carbonbased materials, such as multiwalled carbon nanotubes, single-walled carbon nanotubes, ­single-walled carbon nanohorns, fullerenes, graphene, and chemically modified graphene (Erol et al., 2017; Kim, Jang, & Cha, 2017; Teradal & Jelinek, 2017; Zhang & Lieber, 2016), have

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FIG. 2  Carbon nanomaterials, such as the fullerene C60, CNT, graphene, and nanodiamond, for advanced technological applications (Zhai, Srikanth, Kong, & Zhou, 2017).

been extensively used for sensing applications in environmental, biomedical, and energy applications for their enhanced sensitivity and low limit of detection (LOD) (Jariwala, Sangwan, Lauhon, Marks, & Hersam, 2013; Marmisollé & Azzaroni, 2016). The functionalization of carbon based nanomaterials for enhancement of their features is very appealing. Hence, impurities, surface functional groups, and active sites at the surface or edge plane are responsible for boosting the sensing and electrocatalytic activity of such materials (Fig. 2). 2.2.1  Carbon-Based Nanomaterials as Gas Sensors Field effect transistors (FETs) based on CNT quantum wires have been synthesized by the CVD method. They behave as semiconductors in which doped molecules cause an appreciable change in the electrical properties of the CNTs near the surface. These CNTs have been used to sense gases (Tans et al., 1997; Tans, Verschueren, & Dekker, 1998). Hence, an oxidizing gas (NO2) or a reducing gas (NH3) can either decrease or increase the conduction of SWCNTs in FETs (Kong et  al., 2000). The presence of oxygen modifies the electrical conductivity of CNTs (Collins, Bradley, Ishigami, & Zettl, 2000), while the conductivity of SWNTs may change from p-type to n-type in the presence of minute quantities of H2O in an ambient atmosphere (Fujiwara et  al., 2001; Zahab, Spina, Poncharal, & Marlière, 2000). These important greenhouse gases have been studied, lending importance to environmental considerations. The modification of the CNT sidewalls can totally change the behavior of the conductivity to an insulating one; hence, a noncovalent modification to keep the electronic structure of the CNTs intact is preferred (Fujiwara et al., 2001), for example, coating the SWCNTs with Pd to sense hydrogen, thus making the interaction highly specific for the target molecule, which pristine SWCNT could not detect directly (Kong, Chapline, & Dai, 2001). Furthermore, SWCNTs with PEI (polyethylenimine) can change the SWCNT-FET from a p-type to an n-type upon functionalization to detect oxygen (Shim, Javey, Shi Kam, & Dai, 2001).



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Other sensing techniques employing different principles than a FET with CNTs have also been used. Examples of sensors that have been employed to detect different gases include using a thermoelectric chemical response to sense changes in thermoelectric power (Adu, Sumanasekera, Pradhan, Romero, & Eklund, 2001; Sumanasekera et al., 2002), using a change in dielectric constant (Chopra, McGuire, Gothard, Rao, & Pham, 2003), and using a change in resonance frequency by developing sensors based on surface acoustic waves (Penza, Antolini, & Antisari, 2004). SWCNTs have also been used as mechanical sensors based on the shift of strain from the matrix to the D-Raman band of SWCNTs to measure the stress field of a polymer matrix embedded as a glass fiber (Zhao, Frogley Mark, & Wagner, 2003). Different researchers have used enzymes, such as glucose oxidase or horseradish peroxidase, immobilized on SWCNTs to enhance the catalytic signals to sense analytes (Azamian, Davis, Coleman, Bagshaw, & Green, 2002; Sotiropoulou, Gavalas, Vamvakaki, & Chaniotakis, 2003; Zhao et al., 2003). Most of the sensing devices that are based on nanowires other than CNTs, such as SnO2, Mo, Pd, and In2O3 nanowires, work on the principle of a FET that measures changes in the conductance over the gate and bias potential to detect gases (Li et al., 2003; Walter et al., 2002; Walter, Ng, Zach, Penner, & Favier, 2002; Wang, Jiang, & Xia, 2003). 2.2.2  Carbon-Based Nanomaterials as Electrochemical Sensors and in Fluorescence Quenching Functionalized CNTs can be tuned for the delivery of therapeutic agents, such as proteins, peptides, and drugs, and are best suited for pharmaceutical and medical applications (Maduraiveeran, Sasidharan, & Ganesan, 2018). For example, Nb-coated CNTs have been found to electrochemically sense dopamine. CNT-Nb sensors showed higher sensitivity than ones based on pristine CNTs. The ascorbic acid in a rat brain has been measured by using aligned CNT fiber (CNF) as a simple high-performance biosensor (Yang et al., 2016). Graphene consists of a hexagonal geometry with a 2D carbon network, which displays excellent sensitivity and selectivity, durability, a potential window of wide range, good mechanical strength, and outstanding electronic properties (Yu, Zhang, Zhang, & Su, 2017). Many biomedical applications of graphene and its different forms (GO, rGO, GNR), as well as novel graphene-like materials, have been explored (Wang et al., 2017; Zhang & Chen, 2017; Zhu, Du, & Lin, 2017). For example, rGO has been used to detect acetaminophen in body fluids and pharmaceutical formulations. The defects due to O2 vacancies create superb properties, leading to a rapid response with high sensitivity (Adhikari, Govindhan, & Chen, 2015). Graphene, along with metal NPs, such as AuNP/rGO, have been employed to form a nanocomposite for NADH sensing, displaying the excellent electrocatalytic activity of NADH at pH 7 (Govindhan, Amiri, & Chen, 2015). 3D porous graphene is used as a support for immobilizing enzymes to sense various biomolecules functionalized with different metal NPs, such as Fe3O4, Co3O4, and NiO, to explore peroxidase activity (Maduraiveeran et al., 2018; Wang, Zhang, Huang, Zhang, & Dong, 2017). Electrochemical sensors are compact simple sensing devices and depend on the redox potential for detection. Thus, selectivity toward HMs can be accomplished on bare electrodes; however, the sensitivity is improved by using different recognition layers, especially an electrode modified with NPs. Several techniques have been used, such as voltammetry, amperometry, and potentiometry, among which anodic stripping voltammetry (ASV) has a high rate of success for HM detection (Gao, Wei, Yang, Yin, & Wang, 2005; Tarley, Santos, Baêta,

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Pereira, & Kubota, 2009; Wang, Lu, Hocevar, Farias, & Ogorevc, 2000). An electrode modified with NPs can overcome the required large overpotential, a high stripping potential required for analytes, and the interference of other metals and supporting electrolyte ions. Due to high surface area and a faster electron transfer rate, low S/N ratio studies on NP-modified electrodes have sped up (Aragay & Merkoçi, 2012; de la Escosura-Muñiz, Ambrosi, & Merkoçi, 2008). Electrodes modified with NPs, such as graphene, CNTs, and CNFs, have been extensively explored for sensing HMs (Chen et al., 2012; Wanekaya, 2011). CNT-modified electrodes have been constructed to detect Cd2+ and Pb2+ in HCl solution by SWASV, as CNTs are an excellent sorbent of metal ions (Bui, Li, Han, Pham, & Seong, 2012; Musameh, Hickey, & Kyratzis, 2011). The functionalization of hydrophobic CNTs with functional groups to make them hydrophilic changes their affinity to HMs. GCEs modified with CNT/thiacalixarene to detect trace levels of Pb2+ ions have been studied (Wang, Wang, Shi, Peng, & Ding, 2012). Thiacalixarene made it possible to selectively detect Pb2+ ions while the CNTs improved the electron transfer kinetics. Similarly, cysteine-modified CNTs on GCE were studied to detect Pb2+ and Cu2+ ions (Morton, Havens, Mugweru, & Wanekaya Adam, 2009). 2.2.3  Carbon Nanomaterials as High-Performance Energy Storage Devices The use of nonrenewable and unsustainable fossil fuel has caused a global concern that demands replacing it with renewable and clean energy sources, which include lithium ion batteries (LIBs), supercapacitors (SCs), and hydrogen storage. Furthermore, toxic gas emission, GHG, metal ions and other organic species from industry and the agriculture sector have caused severe environmental pollution that has led to ecological unbalance (Holdren, 2007; Winter & Brodd, 2004). With the advancement of technology, and in order to respond to the ever increasing challenge of replacing traditional energy storage and conversion devices, supercapacitors have emerged as promising high-performance energy sources owing to their high energy and power density. Because a surface phenomenon is employed in SCs, carbon electrodes with large surface areas have been used. Limited capacitance because of low accessibility of the electrolyte due to pore size, together with the poor conductivity of activated carbon, translates to limited energy density and power density for capacitors (Frackowiak & Béguin, 2001). Hence, the search for new materials in the domain of nanomaterials has been hotly pursued. Thus, CNTs and graphene have been extensively investigated as active electrodes for SCs due to high SA, mesoporosity and electrolyte accessibility, and good conductivity (Dai, Chang Dong, Baek, & Lu, 2012; Geim & Novoselov, 2007; Zhang, Zhou, & Zhao, 2010). Because of the rich chemistry of CNTs and graphene, numerous strategies could be adopted to functionalize the structures to develop high-performance SCs. Supercapacitors with a high specific capacitance of 180 F g−1 have been developed by using random SWNTs in KOH electrolyte with energy and power density of 10 W h kg−1 and 20 kW kg−1 (An et al., 2001), while entangled MWCNTs in H2SO4 have resulted in a specific capacitance of 102 F g−1 with very small energy and power densities of 1 W h kg−1 and >8 kW kg−1 (Niu, Sichel, Hoch, Moy, & Tennent, 1997), which resulted from a significant decrease in SA. Vertically aligned CNTs (VACNTs) with well-defined tube spacing have demonstrated superior performance compared with randomly entangled MWCNTs for charging/discharging processes (Futaba et al., 2006). Furthermore, to access the inner cavities of VACNTs, plasma etching can be used to



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open the end tips at the top of the VACNTs for access to electrolyte that would otherwise be inaccessible (Lu, Qu, Henry, & Dai, 2009). These VACNTs have improved energy density and power density of 148 W h kg−1 and 315 kW kg−1, respectively (Chen et al., 2010; Dai et al., 2003; Qu & Dai, 2007). High specific capacitances of 365 and 440 F g−1 in H2SO4 and ionic liquid have been demonstrated by VACNTs prepared by CVD (Chen et al., 2004; Zhang, Cao, Yang, & Gu, 2008). Further improvements can be accomplished by functionalizing VACNTs with conductive polymer or metal oxide nanoparticle, such as MnO2, TiO2, or RuO2, which introduce pseudocapacitance to store charge (Hou, Cheng, Hobson, & Liu, 2010; Hu et al., 2012; Huang, Lou, & Chen, 2012; Kim, Tadai, & Mitani, 2005; Wang, Wen, & Li, 2006). The high contact resistance between the CNT active electrode and the current collector, the inefficiency of electrolyte interaction, and the difficulty of scaling up VACNT production for commercialization, has resulted in lower performance than expected (Van Noorden, 2011). However, GO formed from exfoliation of graphite powder by solution oxidation and edge functionalized graphene (EFG) prepared using a ball mill have allowed for mass production of graphene for commercial use of SCs (Jeon et al., 2012, 2013; Park & Ruoff, 2009). Due to poor conductivity, GO is not used directly; however, some investigations have been carried out (Xu et  al., 2011; Zabihinpour & Ghenaatian, 2013). However, pseudocapacitive rGO, due to its improved electrical conductivity, has been widely used (Lin et al., 2011). The residual oxygenated groups on rGO are responsible for exhibiting both EDLCs and pseudocapacitance in rGO soluble in water. The pH has been shown to affect the supercapacitance performance (Bai, Rakhi, Chen, & Alshareef, 2013). N-doped rGO has also been shown to enhance the electrical properties of SCs as doping has a direct effect on capacitance (Gopalakrishnan, Moses, Govindaraj, & Rao, 2013; Yang et al., 2014). Nonstacked GO was prepared by functionalization with melamine resin monomers to inhibit water bonding through H bonds in order to avoid restacking of GO, leading to exceptional supercapacitor properties (Lee et al., 2013). Similarly, for rGO, hexane was used to prepare unstacked rGO for improved SC performance (Yoon et al., 2013). Mg(OH)2 incorporation into the space between the nanosheets results in pseudocapacitive behavior by retaining the functional group containing O2 and preventing restacking of GO during the heating stage (Yan et al., 2014). However, coupling GO with rGO has been a successful strategy to enhance the supercapacitance, that is, MWCNT@GO nanoribbons in which CNTs are used in between the layers of GO sheet to prevent restacking of GO, while rGO in place of GO produces a porous wrinkled structure with high SA to produce efficient pseudocapacitance (Cao et al., 2013; Lin et al., 2013). Chemically, rGO has displayed a high specific capacitance of 276 F g−1 with energy and power density of 1.36 mW h cm−3 and 20 W cm−3, many times higher than its activated carbon counterpart (El-Kady, Strong, Dubin, & Kaner, 2012). Thus, the modification of the pillared 3D structure of VACNT/graphene in NaOH results in a specific capacitance of 1065 F g−1 with an excellent rate capacity and a remarkable retention of charge. Here, VACNT not only acts as a mechanical support for graphene but as an effective conduit for electron transport (Du et al., 2011). To construct highly stretchable SCs with high efficiency to be used as a portable and wearable electronic, SWCNT thin films are coated on elastomeric polydimethylsiloxane (PDMS) (Li, Gu, & Wei, 2012) that has been prestrained, followed by relaxation to generate buckled CN. Macrofilms of fiber-shaped SC based on CNT/PANI have been fabricated as lightweight, flexible, and wearable devices on clothes, bags, and other items (Bae et al., 2011; Cai et  al., 2013). Despite the benefits of using the fascinating properties of GO, ­multilayer

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formation, restacking of the layers, and structural defects hinder practical applications (Novoselov et al., 2012). However, rGO is also not without imperfections related to residual defects and holes. Fortunately, the physical and chemical properties of GO can be tailored by functionalization with oxygenated groups that allow expansion of the chemical diversity of GO and hence show great potential in applications in energy storage and the environment (Gómez-Navarro et al., 2010; Loh, Bao, Eda, & Chhowalla, 2010). GO has been used in lithium ion batteries (LIBs) as an anode to increase the intercalation/ deintercalation of Li ions composited with graphite for enhanced electrical conductivity (Zhang et al., 2013). However, rGO with enhanced conductivity and a range of porosity can replace commercial graphite as an anode, improving the performance of electrochemical reactions in LIBs (Guo et al., 2013; Kuo, Liu, Kuo, Wu, & Wu, 2013). It is known that a Si-based anode exhibits higher specific capacity of ~4200 mA h g−1 compared with carbon; however, with a low cycling capacity due to pulverization limiting its life cycle (Chan et al., 2010; Kasavajjula, Wang, & Appleby, 2007). This is overcome by using a composite of Si with GO/rGO as the anode (Chang et al., 2013; Ren et al., 2014). A GO/rGO hybrid composite has also been used as a cathode material with enhanced performance instead of using polymer or Li-transition metal oxide TMO cathodes (Ha, Jeong, & Lee, 2013; Wang et al., 2013). GO has shown lithiation/delithiation due to OH− rich epoxides on the GO surface, while more effort to improve rGO/TMO as a hybrid cathode is underway due to the better storage of Li ions (Chen et al., 2014; Pham-Cong et al., 2014). However, these efforts to improve the anode/cathode by using graphene are still inadequate due to limited theoretical capacity, while there is an increasing demand for portable electronic devices. At the same time, Li-S batteries, as compared with TMO or phosphate-based cathodes in LIBs, suffer several problems (Bruce, Freunberger, Hardwick, & Tarascon, 2011). However, using GO/rGO can lead to an improvement in operational issues by introducing structural defects in the basal planes and edge planes with oxygenated functional groups acting as active sites for anchoring purposes, which reduces the dissolution of polysulfides during cycling into the electrolyte as well as leading to the self-assembly of a 2D sheet that improves the Li-S electrochemical performance (Bruce et al., 2011; Ji et al., 2011; Lightcap & Kamat, 2013; Xiao et  al., 2013; Zhang et  al., 2012). GO/S composites modified with PEG or amylopectin have been shown to display improved cyclability (Wang et al., 2011; Weidong Zhou et al., 2013). Using S/RGO as a cathode can show better performance due to enhanced electron conductivity (Han et al., 2014; Wang, Wang, & Chen, 2013). GO nanosheets comprising a few layers in the presence of water have been used for the efficient adsorption of CO2 and validated by simulation results (Kim et al., 2014). Water helps in intercalating CO2 into the GO structure, while CO2 and O2 functionalities due to repulsive interactions result in its migration (Yumura & Yamasaki, 2014). The addition of GO into the hybrid system enhances the BET SA, increasing the CO2 storage capacity (Alhwaige, Agag, Ishida, & Qutubuddin, 2013). GO/rGO composite has been very successfully employed to remove harmful gases emitted into the air, including ammonia, by charge transference between NH3 and GO on neighboring carbons close to oxygen functional groups, such as acetone, H2S, and NOx (Mattson et al., 2013; Tang & Cao, 2012). Moreover, GO modified with a MOF metal organic framework in the presence of Zn, which acts to provide active sites, is employed for H2S gas capture (Huang, Liu, & Kang, 2012). The adsorption capacity of GO due to functional groups for Cu2+ is very low compared with other ions, such as Cd2+, Co2+, Au3+, Pd2+, and Pt4+, as they impart structural stability to



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3  Molecularly Imprinted Polymer-Based Nanosensors

GO (Liu et al., 2013; Yang et al., 2010; Zhao, Li, Ren, Chen, & Wang, 2011). However, compositing pyridine with rGO exhibits high adsorption capacity for metals, introducing synergism due to the conducting polymer and with GO facilitating the removal of heavy metal ions (Dinda, Gupta, & Saha, 2013). More information about carbon-based nanoparticles in pharmaceutical analysis can be found in Chapter 5, “Chemical Nanosensors in Pharmaceutical Analysis.”

3  MOLECULARLY IMPRINTED POLYMER-BASED NANOSENSORS Molecularly Imprinted Polymers (MIPs), known as plastic antibodies, are prepared by a template driven process. Thus, cross linking template and functional monomers by noncovalent binding leads to the generation of active sites for the sensitive and selective molecular recognition of target molecules present within the synthetic polymer matrix (Alexander et al., 2006). Hence, MIPs have been employed as sensors and in diagnostics and are a promising material for chemical sensor design due to an economical and straightforward method of preparation, high SA, ruggedness, stability, and reusability for nanomedicine and environmental applications (Ansari & Karimi, 2017a). The MIPs retain “molecular memory” by imprinting binding sites complementary to the target molecules, tuning the shape and chemical properties of the rigid polymer (Ding & Heiden, 2013; Sellergren, 2000). MIPs are prepared with crosslinked organic polymers acting as a template for imprinting recognition sites into the polymer matrix with an excess amount of pyrogenic solvent and an initiator for the process of polymerization (Alexander et al., 2006). Fig. 3 shows a simple process for MIP synthesis. MIP NPs are a robust alternative to antibodies/enzymes as their bioanalogues (Ansari & Karimi, 2017a). Despite the successful application of MIP NPs to sensors (Basozabal, Guerreiro, GomezCaballero, Aranzazu Goicolea, & Barrio, 2014; Chianella et al., 2013), these NPs have not been

+

b a

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M

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Disrupt polymer-template interactions Remove template

+

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FIG. 3  Schematic representation of the synthesis and molecular imprinting process. Reprinted with permission from the publisher (Ansari, S., & Karimi, M. (2017a). Novel developments and trends of analytical methods for drug analysis in biological and environmental samples by molecularly imprinted polymers. Trends in Analytical Chemistry, 89, 146–162).

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engaged or have been engaged very rarely for in vivo cell diagnostics or therapy. MIP NPs “etched” against the peptide melittin, found in bee venom, were injected into the bloodstream of mice along with the melittin and were successful in removing the peptide along with its toxicological effects, resulting in in vivo selective recognition of target molecules (Hoshino et al., 2010). Rigid polymer NPs are targeted to specific cells and tissues by imprinting recognizable elements for binding to endogenous ligands by a lock-and-key mechanism, and transported actively to the site for drug delivery, unlike biodegradable polymer. However, complete biodegradation of such MIPs has still not been reported. The enzymatic degradation of functionalized NPs built for recognition of a target is avoided by imprinting sites for the recognition and binding of target molecules in the MIPs, imparting the desired functionality, which enhances the efficacy of the approach for specific tissue- and cell-targeted drug delivery (Vaughan, Zhang, & Byrne, 2009; Zhang et al., 2015). However, drug delivery applications for MIPs are still in their infancy (Zaidi, 2016). Gagliardi et al. have reported a full biodegradable novel NP by imprinting biotin and biotin conjugated to Bovine serum albumin (BSAb) that mediates endocytosis in the body to a cross-linked acryloyl-terminated PLGA (poly(lactide-co-glycolide))-based degradable MIPNP (Gagliardi, Bertero, & Bifone, 2017). The rigidity was ensured through three sites/cross linkers of MIPNP while biodegradability was conferred through the ester linkages in the PLGA in the structure. MIPNPs as completely biodegradable NPs, displayed good recognition and binding properties with biotin and BSAb as a synthetic drug carrier. The possibility of using molecular imprinting technology for practical applications as a biomimetic material was reported by Mosbach, Sellegren and coworkers in 1985–2000 (Fischer, Mueller, Ekberg, & Mosbach, 1991; Sellergren, Lepistoe, & Mosbach, 1988). MIPs were widely studied from 1990 for techniques based on bioanalytical extractions. The recognition abilities of MIPs can be used for selective extraction of the molecules targeted. Hence, the recognition site imprinted in the polymer matrix depends on the template molecule with regard to its shape, size, and functional groups. Very complex and highly selective matrices have been developed based on different approaches for using MIPs as SPE (solid phase extraction) sorbents, as sensors, conjugated with carbon, and as a magnetic separation for biological and environmental samples. Fig. 4 shows the milestones in molecular imprinting technology (Ansari & Karimi, 2017a). SPE is the best method to extract organic molecules and metal ions in environmental samples; however, the analyte retention depends on nonspecific interactions with the sorbents, such as C18 Silica and activated carbon, causing a selectivity issue and hence results in coextraction of matrix interference along with the target molecules (Ebrahimzadeh, Dehghani, Asgharinezhad, Shekari, & Molaei, 2013). Hence, an MIP based sorbent to enhance the robust analysis of the target molecules is required with enhanced sensitivity and selectivity. However, the separation of polymer particles from the bulk sample due to the size after retention and elution of the analyte has been a limitation (Martín-Esteban, 2013). Magnetic NPs (MNPs) can overcome separation of NPs in sample solutions quickly by application of a magnetic field (Lu, Salabas, & Schüth, 2007). Since MIPs based on MNPs were introduced, the MMIP and SPE processes have seen a manifold enhancement in technique compared with using a conventional SPE sorbent.



3  Molecularly Imprinted Polymer-Based Nanosensors

17

FIG. 4  Milestones in molecular imprinting technology and application of MIPs in bioanalytical extraction techniques. Reprinted with permission from the publisher (Ansari, S., & Karimi, M. (2017a). Novel developments and trends of analytical methods for drug analysis in biological and environmental samples by molecularly imprinted polymers. Trends in Analytical Chemistry, 89, 146–162).

3.1  MIP-Functionalized SPE Highly selective and novel MIPs, which minimize the time needed for analysis, have been used for determining cephalosporin CF antibiotic in milk samples, as well as the screening of cefquinome, cefthiofur, cephalexin, cefazolin, cephalonium, and cephapirin in different samples by MISPE (Baeza et al., 2016). An MIP as an SPE sorbent coupled with HPLC was used to detect ketoprofen, a nonsteroidal antiinflammatory drug (NSAID), in wastewater samples as a fast and selective method of detection (Zunngu, Madikizela, Chimuka, & Mdluli, 2017)

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and also tetracycline TC drugs in animal-derived food (Feng, Wang, Yang, Liu, & Wang, 2016). Novel MOF (HKUST-1)-based MIPs were designed for extraction and preconcentration studies of nicotinamide by ultrasonication-assisted SPE coupled with UV-Vis spectroscopy (Asfaram, Ghaedi, & Dashtian, 2017). A multidrug template MIP as an SPE sorbent for determining naproxen, ibuprofen, and diclofenac from water bodies has been reported (Madikizela & Chimuka, 2016). However, the SPE sorbents largely being used for pharmaceuticals and environmental samples suffer from poor recovery, unspecific binding, and low binding capacity. Hence, a new polymer-based SPE SMIP for selective detection of acetyl salicylic acid as a persistent environmental contaminant excreted by humans is required, increasing the robustness and reusability of the sorbent (Meischl et al., 2016). In recent years, solid phase microextraction SPME has been a favored green analytical method for extraction of trace levels of organic compounds interfaced together with HPLC, GC, and others (Fu et al., 2014; Mehdinia & Aziz-Zanjani, 2013; Spietelun, Pilarczyk, Kloskowski, & Namieśnik, 2010). The fiber coating of SPME is a very important aspect of the extraction capability. However, as with SPE, poor selectivity is a real drawback for its realization as a viable and robust technique (Djozan, Farajzadeh, Sorouraddin, & Baheri, 2011). Nanostructured MIPs functionalized with SPME fiber have been employed as sorbents because of the unique physical and chemical features, thermal stability, and large SA. It has been reported by (Ansari & Karimi, 2017b; Li et al., 2013) that MIPs with surface imprinting technology (SIT) have resulted in improved selectivity, as well as allowing for regeneration of the sorbent, for drug analysis preparation. To increase the mechanical strength of the fiber and its stability, different combinations of SPME with MIP have been sought (MIP in-tube SPME, sol-gel MIP-SPME) in different temperature and microextraction solvents. Thus, a novel MIP coated with a fiber on stainless steel wire with ciprofloxacin as the template was prepared to determine fluoroquinones (FQs) from biological and pharmaceutical samples that require very small quantities of volume (Mirzajani & Kardani, 2016). This method furnishes a cheap alternative and at the same time equips the fiber with high mechanical strength, stability, and reproducibility with highly satisfactory recovery of FQs in the sample and low LOD, with methanol/acetic acid solvent showing the highest efficiency to desorb FQs from extracted analytes. The MISPME was coupled with HPLC to increase the sensitivity for detection of FQs, which enabled trace level detection of UTI-related antibiotics, such as ofloxacin, ciprofloxacin, levofloxacin, and norflorxacin. An electrochemically synthesized MIP printed with a nano-copolymer coating the stainless steel for indomethacin detection in biological samples by using electrochemically wire modulated in-tube SPME in tandem with HPLC/UV was reported to improve extraction efficiency, sensitivity, and selectivity (Asiabi, Yamini, Seidi, & Ghahramanifard, 2016). An MIP coated with a stable monolithic flexible fiber for SPME was developed to determine anticancer biomarkers, such as nonderivatized sarcosine to be used with GC analysis. This fiber was selective, cheap, physically and chemically stable, porous, and homogeneous for efficient extraction of the biomarker in urine samples (HashemiMoghaddam & Hagigatgoo, 2015). An MIP based on polysiloxane nanofiber coated onto stainless steel wire as an SPME sorbent was imprinted for simazine detection coupled with MS/GC detection (Saraji & Mehrafza, 2016). Also, triazine compound could be detected by the novel sorbent, which showed a high efficiency for extraction. MIPs synthesized by precipitation polymerization with a venlafaxine (VEN)-based ­template, which interacts with a functional monomer, such as methacrylic acid (MAA),



3  Molecularly Imprinted Polymer-Based Nanosensors

19

to form a complex by H-bonding, has been developed to maximize the imprinting effect (Miranda, Domingues, & Queiroz, 2016). The MIPSPE method coupled with UHPLC-MS/ MS (ultrahigh-performance liquid chromatography tandem mass spectrometry) was highly selective for VEN in plasma samples of patients being treated with VEN. Trace level detection of VEN, N-desmethylvenlafaxine (NDV), and O-desmethylvenlafaxine (ODV) was possible due to binding capacity for the specific sites in human plasma samples. The sol-gel technique is a powerful sorbent, however, not selective enough. Therefore, when MIP is coupled with the sol-gel method, it produces promising results for biological samples. El-Beqqali et al. have developed a novel selective, rapid, chemically stable MIP-sol-gel tablet for SPE. Methadone-d is a synthetic opioid and an analgesic and is used as the template for MIP in the determination in plasma samples of opiate addicts. Monitoring it is important for the adjustment of daily dosage (El-Beqqali & Abdel-Rehim, 2016). MIPNP was reported by Arabi et  al., for detection of celecoxib (CEL) in human plasma samples by ultrasonic-assisted SPE in tandem with HPLC/UV (Arabi, Ghaedi, Ostovan, Tashkhourian, & Asadallahzadeh, 2016). MIPNPs with MAA as a monomer and CEL as the template exhibited excellent adsorption capacity with a reasonable linear range. The elution of MIPNPs was carried out with different organic solvents/eluents with different volumes, with the highest desorption ability demonstrated with MeOH/deionized water. This simple method had a very low LOD and a very high selectivity with easy removal of the template and low consumption of toxic solvents. A stoichiometric MIP sorbent was synthesized by dos Santos et al. using a noncovalent approach involving 2,6-bis(acrylamido)pyridine as the functional monomer to imprint tegafur anticancer pro drug as the template cross linked with ethyleneglycol dimethacrylate EGDMA monomer (Mattos dos Santos, Hall, & Manesiotis, 2016). An MIP on GCE was used as an electrochemical sensing platform for the detection of metronidazole (MNZ) via the MIP/catalysis method and the MIP/gate effect method, with both methods displaying precision and accurate detection of MNZ (Liu et  al., 2016). However, the MIP/gate effect was able to detect different substances irrespective of the electroactivity, which is an important feature for real samples. Similarly, an electrochemical sensor based on a gold electrode modified with tulathromycin (TLTMC) imprinted with the polymer p-­aminothiophenol and AuNPs electropolymerized on the surface in the presence of tetrabutylammonium perchlorate (TBAP) resulted in a molecularly imprinted sensor (MIS) after removal of the TLTMC template (Sun et al., 2015). To replace the expensive and bulky technology of HPLC and ion mobility spectrometry, a lab-on-chip was fabricated using a novel plastic microfluidic MIP biochip for the selective, rapid detection in plasma samples of Propofol, used an intravenous anesthesia, (Hong et al., 2016). An MIP nanogel sensor with florescent quenching for sensitive and selective detection of the anticancer drug sunitinib, based on coumarin and amino acid in human plasma for point of care (PoC) applications, was studied (Pellizzoni et al., 2016) (Fig. 5).

3.2  MIPs Functionalized as Magnetic MIPs A magnetic-based hybrid MIP can be removed easily by a magnet after absorbing the t­argeted compound and hence the SPE method using an MIP is simpler compared with an MIP using a cartridge and displays promising features for future applications. A magnetic MIP (MMIP)-based novel hybrid core-shell magnetic separation was reported for biotin and

20

1.  Introduction to Nanosensors 400

0 µM

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FIG. 5  (A) Emission spectrum of MIP 1.5 (60 μg mL−1) alone and upon addition of increasing concentrations of

sunitinib. (B) Stern-Volmer plots of the emissions of MIP 1.5, NIP 0.5, and 7-hydroxycoumarin upon addition of increasing concentrations of sunitinib. (CI) picture of a 60 μg mL−1 solution of MIP 1.5 upon excitation with a 365 nm UV lamp. (CII) picture of the same solution after the addition of 50 μM sunitinib; (D) Picture of a spot of 25 μg MIP 1.5 on filter paper before and after the addition of 300 ng of sunitinib. Reprinted with permission from the publisher (Pellizzoni, E., Tommasini, M., Marangon, E., Rizzolio, F., Saito, G., Benedetti, F., …, Berti, F. (2016). Fluorescent molecularly imprinted nanogels for the detection of anticancer drugs in human plasma. Biosensors and Bioelectronics, 86, 913–919).

biotinylated DNA as a robust and cheap method with high immobilization and binding capacity as a cheaper alternative than streptavidin MPs. The readout may be based on fluorescence, enzyme labeled, or an optical readout (Ben Aissa, Herrera-Chacon, Pupin, Sotomayor, & Pividori, 2017). An MMIP for detecting cocaine using Fe3O4 stabilized by PEG as a ­magnetic component mixed with EGDMA as the functional monomer along with cross linker to form a core shell particle by alpha sonication was investigated in a urine sample by the SPE method (Sánchez-González, Jesús Tabernero, María Bermejo, & Bermejo-Barrera, & Moreda-Piñeiro, 2016). This novel material could be used to detect COC, benzoylecgonine (BZE), cocaethylene (CE), and ecgonine (EG) methyl esters in MISPE for drug addicts. The magnetic particle can be easily separated with the help of a magnet, making batch analysis possible during the loading and eluting stages. In another experiment, highly selective magnetite NPs functionalized with an MIP as a magnetic sorbent were used as a batch SPE technique for COC monitoring and extraction in small volumes of sample (Sánchez-González et al., 2016). Roxithromycin was detected by using highly selective and magnetically responsive MMIPs, with H2O chosen as the extraction solvent after optimizing conditions (Ding et al., 2016). The analyte was analyzed after elution for MMIP by the HPLC or LC-MS/MS technique. Several conditions, such as pH, volume of eluent, desorption time, time of loading, extraction temperature and composition, were investigated. Finally, a facile and novel method to prepare magnetic field modulated self-assembled electromagnetic MIPs (EMMIPs) has been demonstrated, which have the additional benefits of being conductive and demonstrating electrochemical ­performance



3  Molecularly Imprinted Polymer-Based Nanosensors

21

along with magnetic properties using Fe3O4@rGO/PANI/NPs (Zhu et al., 2016). The biomimetic EMMIP modification of a magnetic glassy carbon electrode as a recognizing membrane using highly ordered self-assembly under the induction of a magnetic field was investigated for efficient, sensitive, and selective detection of insulin in biological samples with the possibility of real-time clinical diagnosis. This method offered convenient membrane fabrication and easy removal by peeling it off using an external magnet. In another method to prepare nano-MIPs, Fe3O4 NPs were synthesized as magnetic cores with SiO2 shells to form Fe3O4@ SiO2. The Fe3O4@SiO2 was grafted with a CC group to interact with a functional monomer, such as methyl acrylic acid (MAA), and a cross linker, such as EGDMA, and with tizanidine as the template for tizanidine detection in a blood plasma sample. It showed excellent binding capacity with no significant decline in the signal (Sheykhaghaei, Sadr, & Khanahmadzadeh, 2016). The determination and extraction of diclofenac (DFC) in biological and water samples by MMIPs allowed selective, sensitive, fast, and simple analysis with excellent regeneration capabilities by using Fe3O4-NPs coated with SiO2 as the magnetic component and 4-vinyl pyridine (4-VP) as the functional monomer, together with EGDMA as the cross linker (Pebdani, Shabani, & Dadfarnia, 2016). In another investigation, atrazine herbicide was analyzed in tap water by a florescence sensing strategy using 5-(4,6-dichlorotriazinyl) aminofluorescein (5DTAF) with an Fe3O4 chitosan NP-based MMIP with enhanced binding capacity for atrazine (Liu et al., 2016). Fe3O4 NPs with an MIP core shell structure with EDGMA as the functional monomer to extract a selective target in real samples, as well as an MIP modified with chitosan wrapped around Fe3O4 NPs to selectively detect/extract sulfonamides from water samples, has been reported (Ma & Shi, 2015; Madrakian, Fazl, Ahmadi, & Afkhami, 2016; Qin, Su, Wang, & Gao, 2015). The coupling of Fe3O4@MIP based on an EDMA functional monomer with CNT as the SPE sorbent for levofloxacin in serum has been reported (Xiao et al., 2015). An MIP modified with silica NPs for doxorubicin has been investigated using direct spectroscopic techniques (Ahmadi, Madrakian, & Afkhami, 2015). Also, florescent sensors based on an MMIP comprising CdTe QDS and ferroferric oxide NPs have been introduced for the selective detection of ciprofloxacin or norfloxacin in urine (Gao et al., 2014). The efficient determination of mefenamic acid (MFA) has also been reported for MIPNPs as resonance light scattering nanosensors (Ahmadi, Madrakian, & Afkhami, 2014).

3.3  MIPs Modified With Carbon Nanomaterials The combined advantage of an MIP with CNT and graphite has been explored for adsorption and chemical sensing. The pores of hollow fibers of polypropylene comprised of MIPMWCNTs for electrochemical extraction, coupled with HPLC-UV to determine naproxen in a single-step extraction from environmental and biological samples, showed successful diffusion from the sample solution to the lumen of the hollow fiber via MIP-MWCNTs sites (Tahmasebi, Davarani, & Asgharinezhad, 2016). In another method, MMWNTs were prepared by a low-cost, facile, novel process using dopamine as the functional monomer and human serum albumin as the template and Fe3O4 as the magnetic component to form MMWNTs@ Fe3O4@MIPs for SPE coupled with HPLC to detect HSA in urine samples. This demonstrated high selectivity and adsorption capacity for HSA (Yin, Yan, Zhang, & Wang, 2015). The configuration of an MIP with CNT and graphene displays promising results due to the combined

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advantages. The rate of adsorption and desorption is enhanced due to the large SA offered for SPE, as documented for an MIP conjugated with CNT for selective determination of emodin from Kiwi root. Polyaniline-modified MWNT modified with MIPs for high adsorption capacity as an SPE column was used for the detection of a targeted compound in real samples (Yang et  al., 2014). For detection of trimethoprim (TMP), an electrochemical sensor based on GCE fabricated by polymerizing PPY and MIP in aqueous media by the CV method has been developed (da Silva, Pacheco, McS Magalhães, Viswanathan, & Delerue-Matos, 2014). Similarly, 1,4 dihydroxyanthraquinone has been electrochemically detected by MWCNTs functionalized with PPY-modified MIPs using the conducting CV method (Nezhadali, Senobari, & Mojarrab, 2016). An MIP adduct has been formed by sol-gel-based graphite/ MWCNT/AuNPs/Si-C abraded composite paper with a coating of cross-linker and initiator brought in contact with a cover glass, with template l-Cys and functional monomer, by microcontact imprinting technology for the detection of diseases with acute l-cysteine depletion. It offers real sample measurements, such as those employing blood and pharmaceutical samples, with satisfactory LOD (Prasad & Singh, 2015). An MWCNT modified with MIPs to detect diazepam in tablets has also been reported (Hosseini & Motaharian, 2015), as well as for the detection of metronidazole (MNZ), without any need for a separation technique (Yuan et al., 2015). An MWCNT/MIP/CPE for the detection of MFA through differential pulse voltammetry was used to obtain a linear range for MFA concentration (Madrakian, Haghshenas, Ahmadi, & Afkhami, 2015). In the same way, dopamine was determined using a fluorescence method with polyindol/graphene QDs conjugated to an MIP, promoting noncovalent interaction for superior selectivity and linear range detection (Zhou, Wang, Yu, Wu, & Shen, 2015).

3.4  MIPs as Sensors Electrochemical sensors have been widely used as powerful tools for detecting different chemical compounds and biological molecules. Using this surface technique for the analysis of analytes, electrochemical sensors modified by MIPs have been employed for their superior molecular recognition capability. Theophylline is an inexpensive drug, which, if used at a high dosage, is toxic. For determining theophylline on GCE, an MIP-based electrochemical sensor was developed using 4-amino-5-hydroxy-2,7-napthalenedisulfonic acid as the functional monomer. The modification of a GCE improves the detection limit and electron transfer rate compared with a bare electrode (Aswini, Mohan, & Biju, 2016). Quercetin (QC) and rutin have been electrochemically determined by AuNP-modified p-aminothiophenol functionalized MWCNT sheet, which displays superior results compared with bare GCE (Yola & Atar, 2014). An optical sensor based on SPR, employing diclofenac as the template by light-induced polymerization, immobilizes the as-prepared MIP onto the Au sensor chip as the substrate by covalent interactions (Altintas, Guerreiro, Piletsky, & Tothill, 2015). An MIP-decorated nanoporous Au leaf NPGL, Au/IL/ porous Pt/carboxyl graphene, an MIP functionalized with Pd NPs, and AuNPs modified with p-aminothiophenol have been used to detect targeted compounds in real samples by an electrochemical method (Chen, Huang, Zeng, Tang, & Li, 2015; Li et al., 2015; Sun et al., 2015; Yang, Zhao, & Zeng, 2014). Nanoporous Ni has been used as an interesting candidate with an MIP for a novel electrochemical sensor for detecting MNZ with remarkably low LOD (Li et al., 2015). Nanocarriers based on poly(MAA-co-TRIM) [TRIM: trimethylolpropane trimethacrylate] carrying an erythromycin ERY template show sustained release of ERY (Kempe, Parareda



4 Dendrimers

23

Pujolràs, & Kempe, 2015). Fe3O4/SiO2 NPs with Tragacanth Gum as cross linker, N-vinyl imidazole IV as functional monomer, and quercetin QC as the template, have been prepared as core shell magnetic NPs synthesized by the sol-gel method and display excellent recognition ability for QC as well as being an effective in vitro drug delivery application in PBS (Kempe et al., 2015). Silica NP-based MIPs have been employed for the selective binding of human serum albumin (HSA) and GOx by interacting with amino acid–constituting side chains on the SiNPs by SPR analysis (Bhakta, Seraji, Suib, & Rusling, 2015). The modification of an SPR gold chip surface with allyl mercaptane for the attachment of MIP nanofilm poly(2-hydroxyethylmethacrylatemethacryloylamidoglutamic acid) [p(HEMAGA)] imprinted with amoxicillin (AMOX) was developed as an SPR sensor. The surface was characterized by FTIR, ellipsometry, and contact angle measurements. It displayed a LOD of 0.022 ng mL for chick egg and human plasma samples (Yola, Eren, & Atar, 2014). A resonance light scattering (RLS) virus-affinity sensor was developed employing a thermoresistive MIP with poly(N-isopropylacrylamide) (pNIPAAm) as the shell coating for SiO2 NPs as support to provide biocompatibility and inertness to the matrix. The pNIPAAm displayed changes in the expansion and shrinkage of the polymer with temperature, which not only recognized but released the template of the virus hepatitis A HAV within half an hour. It demonstrated high adsorption capacity and selectivity toward HAV compared with a nonMIPs-imprinted counterpart (Liu et al., 2017). More information about MP-based nanosensors in pharmaceutical analysis can be found in Chapter 8, “Molecularly imprinted polymer-based nanosensors for pharmaceutical analysis” by Sevinc Kurbanoglu Aysu Yarman, Frieder W. Scheller, and Sibel A. Ozkan.

4 DENDRIMERS Dendrimers are an important and unique class of polymers, defined as synthetic, hyperbranched, monodispersed, spherically shaped, 3D molecules with monomers originating from the core and sequentially extending to the periphery by repetitive reaction steps forming branchings, which endow them with a distinctive architecture with a typical size in the range 2–10 nm and a highly controlled structure. These dendrimers act as an emerging nanometric scaffold, which adds to their tendency to act as nanocarriers due to the availability of surface functional groups and a hydrophobic environment within the core that allows encapsulation of poorly water soluble guest molecules (Abbasi et al., 2014). Dendrimers functionalized with different ligands have been investigated extensively for biomedical applications to deliver bioactive molecules as therapeutics to the targeted sites, thus reducing access to nonspecific sites. The most popular and least toxic of the dendrimers is polyamidoamine (PAMAM) dendrimer with unmatched molecular features (Mankbadi, Barakat, Ramadan, Woodcock, & Kuhn, 2011). However, the existence of localized cationic charge at the surface of the dendrimers due to amino groups limits their caliber for nanomedicine applications (Roberts, Bhalgat, & Zera, 1996), such as affecting surface cell membrane stability, hemolytic toxicity and cytotoxicity, and drug outflow, which can be attenuated by modifying the surface with PEGylation (Bhadra, Bhadra, Jain, & Jain, 2003), surface engineering (Kesharwani, Gajbhiye, Tekade, & Jain, 2011), or conjugation with other nanocarriers to form nanohybrids

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with ­liposome, CNTs, and NPs (Khopade, Caruso, Tripathi, Nagaich, & Jain, 2002; Li, Li, Zhao, Duan, & Hou, 2010; Qin et al., 2011). This could be accomplished by enveloping the dendrimers due to their smaller size, or the QDs in the core, or conjugation by chemical means with CNTs; even biodegradable dendrimers (Agrawal, Gupta, & Jain, 2007) and polypeptide dendrimers (Jain, Gupta, & Jain, 2014) have been reported.

4.1  Dendrimer-Nanostructured Hybrid System Because of their unique properties, dendrimers, such as PEG-modified PAMAM, can be used as templates for the synthesis of stable polydispersed NPs, improving solubility in organic solvents, such as for the synthesis of Au and CdS NPs (Crooks, Zhao, Sun, Chechik, & Yeung, 2001). Similarly, the immobilization of protein albumin BSA was more efficient compared with using modified NPs when PAMAM G5 dendrimers grafted onto aminosilanemodified magnetite NPs were used (Pan, Gao, & Gu, 2005). Furthermore, AgNPs synthesized by comediation using PAMAM G1.5 grafted with polyvinyl-pyrrolidone (PVP) can affect the size, shape, and stability of the NPs, which were found to be stable for around 2 months at room temperature without aggregating (Li, Luo, & Tan, 2005). The mole ratio of PAMAM and PVP had an important role to play regarding the morphology and size distribution of the as-prepared AgNPs. A rigid shell of Maltose-decorated poly (propylene imine) PPI glycodendrimers with G2-5 have been synthesized to stabilize AuNPs for drug delivery applications and to combat the toxicity issues of the putative dendrimers in use. The higher generation of oligosaccharide-modified PPI dendrimers G4-5 were found to exhibit auto-­ reduction while acting as stabilizing agents. Dendrimers G4-5 resulted in the formation of small AuNPs that were stabilized by entrapment within the dendritic scaffold (DENP), while dendrimer-stabilized NPs (DSNP) at the interface were formed with G2-3 glycodendrimers (Pietsch, Appelhans, Gindy, Voit, & Fahmi, 2009). Pt NPs were stabilized by using carbosilane dendrimer through a hydrosilylation reaction in which an excess of hydrosilane resulted in capping the NPs through Pt-Si bonds, later capped by dendrimers, while an excess of olefin resulted in a Pt-C bond by a direct capping and stabilization by the dendrimer (Li et  al., 2010). Moreover, it has been shown that dendrimer-based magnetoplexes have improved transfection efficiency for therapeutic gene delivery applications to the targeted cells and can overcome the barriers afforded by viral and nonviral vectors. Thus, PAMAM G6 dendrimer functionalized with SPIONs was evaluated as a magnetofection vector by introducing PEI/ DNA via electrostatic interactions, which, when guided in the presence of a magnetic field, led to accumulation of magnetoplexes on various targeted cell lines and their subsequent uptake with high transfection efficiency (Liu et al., 2011). A nano-electrocatalytic membrane for catalyzing the H2O2 reaction by employing a dendrimer-NP system was devised for sensing glucose amperometrically at 0.0V versus SCE, which successfully avoids the interference of ascorbic and uric acid during electrooxidation on a modified ITO electrode surface. This is accomplished by a layer-by-layer (LBL) electrodeposition of PAMAM G4 dendrimer with a redox mediator, Co hexacyanoferrate-modified AuNPs on ITO in the presence of poly(vinylsulfonic acid) PVS. This membrane acts as the substrate for immobilizing GOx in the presence of cross linkers, such as BSA and glutaraldehyde (Crespilho et al., 2006). Dendrimer-NP nanocomposites have also been employed for catalysis. A Pd-nanoparticle core shell dendrimer (NCD) assembly with Frechet dendrons linked to Pd by Pd-C bonds are more efficient in



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4 Dendrimers

R¢= phenyl R = NO2 CHO CN COOH I, Br, CI COOCH3 OCH3 H H

Pd H2 R

R¢1

R

R¢1

FIG. 6  Palladium nanoparticle-cored Fréchet type G1-dendrimer (Pd-G1) stabilized by Pd-carbon bonds. Reprinted with permission from the publisher (Kumar, V. K. R., & Gopidas, K. R. (2011). Palladium nanoparticle-cored G1-dendrimer stabilized by carbon–Pd bonds: Synthesis, characterization and use as chemoselective, room temperature hydrogenation catalyst. Tetrahedron Letters, 52(24), 3102–3105).

catalyzing hydrogenation of CC bonds in organic molecules with high stability, selectivity, and reusability, while reducible functional groups and halogens remain unaffected (Kumar & Gopidas, 2011) (Fig. 6). G1-G5 PPI dendrimer functionalized with AuNPs by LBL has been reported as a chemiresistor vapor sensor by harnessing sensitive materials with complex circuitry for a straightforward study of the chemical selectivity and electrical resistivity of vapors of toluene, 1-propanol, and H2O as a function of the size of the PPI dendrimer. It was observed that the film resistivity increased by dosing it with the respective vapors, increasing with increased dendrimer generation, while with water vapor it remained unaffected (Krasteva, Guse, Besnard, Yasuda, & Vossmeyer, 2003). Similarly, Au-PAMAM G3 and Au-PPI G4 dendrimers were used to build up a nanocomposite chemiresistive film sensor to register changes in conduction by sorption of toluene, methanol, and water vapor by the neutron reflectometry technique. This technique enables the resolution of the fine details regarding structural changes of the film after sorption of vapors, along with their distribution. The presence of a large number of amide and amine groups in the aliphatic segments of the dendrimer resulted in the formation of H-bonds with water. Hence, water is more strongly adsorbed by the hydrophilic PAMAM, while polar methanol has a strong affinity to hydrophobic PPI. At the same time, nonpolar toluene was sensed as a thin film, suggesting weak interactions with the dendrimerNP hybrid assembly (Krasteva, Möhwald, & Krastev, 2009). The overexpression of the neuronal protein Synuclein (α-SYN) is linked to neurodegenerative diseases and hence the sensitive and selective detection of it is very important for clinical diagnostics. An electrochemical immunosensor for α-SYN was developed by immobilizing PAMAM G4 dendrimer with terminal amino groups composited with AuNPs onto an electrode modified with poly-o-aminobenzoic acid rife with COO groups to form covalent bonds. This nanohybrid composite not only provides a platform to detect the protein with high sensitivity, but is also responsible for boosting the electron transfer process. The horseradish peroxidase-secondary antibody (HRP-Ab2), linked to Au nanoparticles, was introduced onto the modified electrode and hence a dual signal amplification resulted, leading to catalysis of H2O2 in the presence of thionine with high sensitivity and stability to detect α-SYN (An et al., 2012). An electroactive nano-membrane designed by alternating bilayers of PAMAM G4 and PVS on AuNPs by the LBL method for oxygen reduction on an ITO electrode

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1.  Introduction to Nanosensors

was investigated and it showed an increase in reduction current for O2 studied through CV and EIS up to three bilayers only (Crespilho, Nart, Oliveira, & Brett, 2007). In order to improve the delivery of cancer therapeutics at the targeted site of a tumor and to reduce overall side effects, a dendrimer-based drug delivery system is seen as a promising platform. Hence, PAMAM G4 dendrimer modified with Herceptin-conjugated diglycolamic acid was synthesized as a drug cisplatin carrier and demonstrated improved in vitro and in vivo anticancer activity against human ovarian cancer cell lines (Kesavan et al., 2015). Similarly, a small 5 nm PAMAM dendrimer coated with larger 200 nm gelatin NPs as a shielding layer was engaged for deep penetration of the loaded drug methotrexate into the cancer cells by endocytosis and hence improved its anticancer efficacy and penetration ability. This nanocarrier later releases PAMAM by degradation of gelatin in response to a biomarker of the cancer matrix metalloproteinase-2 in the acidic tumor environment, which is transported to the cancer cells (Fan et al., 2017). A photoluminescent hybrid comprising quantum dot-sized G2 and G3 PPI dendrimer coating Ni-Fe nanoalloy has shown promise for clinical diagnostics, drug delivery applications, and imaging techniques (Malinga, Arotiba, Krause, Mapolie, & Mamba, 2012).

4.2  Dendrimers Conjugated to Carbon-Based Nanomaterials Although very promising candidates for biomedical applications, such as biosensing and biocatalysis, the noncompatibility and nondispersibility, especially in water, of CNTs limits their medicinal applications (Joshi, Merchant, Wang, & Schmidtke, 2005). Several groups have dabbled in improving the dispersibility of CNTs in water by modification of the surface and partial oxidation (Bottini et al., 2005), but did not attain viable hydrophilicity. However, conjugation of CNTs with dendrimers to harness the aqueous solubility and active functional groups on the dendrimer to enhance its hydrophilicity has been a worthwhile strategy. To develop monodispersed metal NPs to catalyze the synthesis of CNTs with controlled tube size, new strategies evolved, including dendrimer-based Cobalt nanoclusters, which distinguishes them from Co NPs, with precise control of the cluster size and surface functionalization and these are thus employed as catalytic particles for the synthesis of SWCNTs (Geng, Li, Zhou, Huck, & Johnson, 2006). Dendrimers, due to their unique structural features, have been extensively explored as electrochemical sensors to detect various bioanalytes and, hence, efforts have been directed to synthesize such electrochemical sensing platforms, especially based on enzymes and hemeproteins. These active molecules can easily be immobilized onto the dendrimers to produce effective conducting interfaces applicable to many fields. The amine groups at the surface of the dendrimers are able to efficiently and conveniently bind bioreceptors that enhance the sensitivity and selectivity of the dendrimers for sensing bioanalytes. An electrochemical sensor for the detection of DNA was developed by employing a nanocomposite comprised of PPY-coated MWCNT, which was further conjugated to PAMAM G4 by the electrochemical method. The nanohybrid was further modified with ferrocenyl Fc groups as a redox marker for DNA. The MWCNT/PPY/PAMAM/Fc demonstrated a detection limit of 0.3 fM for DNA hybridization by varying the response signal of Fc. This nanocomposite was applied to real DNA samples from Mycobacterium tuberculosis and, hence, was further applied for diagnostics for pathogens (Miodek, Mejri, Gomgnimbou, Sola, & Korri-Youssoufi, 2015).



4 Dendrimers

27

Similarly, MWCNT/PAMAM G4 on GCE was developed to electrochemically detect paracetamol in commercial tablets and real serum samples. This sensing platform exhibited excellent sensing performance in the presence of interferents and, hence, could be applied to practical analysis (Zhang et al., 2016). Dendrimer-CNT nanocomposites have been successfully prepared by using abundant amino group-terminated PAMAM G4 with CNTs, circumventing the aqueous dispersibility problem of CNTS for the sensitive detection of glucose. This was used to develop a bienzymatic HRP and GOx mediator free biosensor, which displayed a fast response and a low LOD (Zeng et al., 2007). Similarly, the dispersibility of CNTs was enhanced by developing an amperometric biosensor for glucose, which was fabricated by immobilizing MWCNTs with the mediator ferrocenecarboxaldehyde on the electrode to improve electrical communication together with chitosan to graft GOx by the CV method. This nanocomposite greatly enhanced the enzyme oxidation of glucose (Qiu, Zhou, Guo, Wang, & Liang, 2009). An electrochemical biosensor for the detection of fructose in beverages and food was reported, which worked by immobilizing fructose dehydrogenase and cysteamine functionalized PAMAM with G2-4 on a Au electrode; it had a linear range of 0.25–5.0 mM (Damar & Odaci Demirkol, 2011). Fluorinated dendrimer block copolymer was synthesized with a good yield and led to high dispersibility of SWNTs, fullerenes, and MNPs acting as guest molecules (Yoshioka, Suzuki, Mugisawa, Naitoh, & Sawada, 2007). A simple amperometric biosensor for the detection of glutamate based on self-assembled glutamate dehydrogenase (GLDH) and PAMAM dendrimer functionalized with Pt to improve the surface area for electron transfer was reported with a sensitivity of 433 μA μM−1 cm−2 (Tang, Zhu, Xu, Yang, & Li, 2007). However, another unique and sensitive amperometric biosensor-based PPY film doped bionanocomposite was investigated. GLDH and Pt modified PAMAM were self-assembled by LBL onto MWCNTs to form a bionanohybrid biosensor trapped in electropolymerized film of PPY on a GCE. This nanohybrid film exhibited a high catalytic ability toward glutamate with, however, a lower sensitivity than reported by (Tang, Zhu, Xu, et  al., 2007), that is, 51.48 μA μM−1 cm−2, a low LOD, low interference, and excellent stability. However, the stability of the nanofilm depends on the number of polymerization cycles (Tang, Zhu, Yang, & Li, 2007). Yet another improved glutamate biosensor in serum was constructed through immobilization of glutamate oxidase via covalent bonding onto carboxylated MWCNTs, chitosan, and AuNP for improved electron transfer kinetics and conductivity between the electrode and the modified interface and it displayed a high sensitivity of 155 nA μM−1 cm−2 and a reasonably low LOD with a very fast response (Batra & Pundir, 2013). A biocompatible nanohybrid formed from the conjugation of PAMAM with MWCNTs through covalent linkage for gene delivery applications was explored for its improved ability to immobilize green fluorescent protein pEGFP- N1 with high transfection efficiency into HeLa cell lines and for its reduced cytotoxicity compared with pristine CNTs and dendrimers (Qin et al., 2011). MWCNTs modified with PPI and MWCNTs functionalized with PPI conjugated to AgNPs have been explored for their antimicrobial properties against gram positive and gram negative bacteria and for their aqueous dispersibility (Murugan & Vimala, 2011). As can be noticed, most of the literature related to dendrimer-CNT nanohybrids is concerned with the CNT dispersibility in the aqueous phase. Dendrimers conjugated to CNTs or graphene are known to increase the electrochemical signal sensitivity and support a low LOD (Siriviriyanun & Imae, 2013; Vusa, Manju, Berchmans, & Arumugam, 2016). Imatinib is a specific anticancer drug that requires an e­ ffective ­monitoring

28

1.  Introduction to Nanosensors

FIG. 7  Preparation of HF-PGE. The polypropylene hollow fiber wall-pencil graphite lead electrode. Reprinted with permission from the publisher (Hatamluyi, B., & Es’haghi, Z. (2017). A layer-by-layer sensing architecture based on dendrimer and ionic liquid supported reduced graphene oxide for simultaneous hollow-fiber solid phase microextraction and electrochemical determination of anti-cancer drug imatinib in biological samples. Journal of Electroanalytical Chemistry, 801, 439–449).

of the drug for optimal efficacy. Dendrimer/GO behaves as a good sorbent material to preconcentrate the drug and, hence, can be used to detect it in real samples. Hence, a nanocomposite of PAMAM with rGO was deposited onto a pencil graphite lead electrode (PGE), which was then carefully placed into a polypropylene hollow fiber (HF) wall (HF/PGE), in which the Imatinib, in the presence of carrier IL-1-butyl-2,3-dimethylimidazolium hexafluorophosphate, preconcentrates in the pores and is detected by the electrochemical method with reasonable selectivity and sensitivity, thus showing the nanocomposite assembly to be a better sensing platform than PGE modified with nanocomposite (Fig. 7) (Hatamluyi & Es’haghi, 2017).

5 CONCLUSIONS The advent of nanotechnology has opened new prospects for the electrochemical sensing of a variety of redox active analytes. In recent years, there has been an explosion of research directed toward developing sensitive electrochemical sensors based on nanomaterials, which find many applications in the pharmaceutical industry. Nanoparticles based on metal oxides have demonstrated, due to their unique physicochemical properties, applications in the biomedical field, sensors, catalysis, environmental remediation, and energy technology. However, carbon-based electrochemical sensors have garnered much attention over the past few years owing to their unique structural characteristics, which confer electrical conductivity and stability to the modified electrode for the analysis of real samples. Metal NPs composited with the nanosensing features of GR have been investigated for the electrochemical detection of various bio- and organic analytes to enhance the sensitivity and selectivity of the

REFERENCES 29

e­ lectrodes. Similarly, dendrimers functionalized with different ligands have been investigated extensively for biomedical applications to deliver bioactive molecules as therapeutics to the targeted sites, thus reducing access to nonspecific sites and, hence, improving the sensitivity and selectivity of the sensor. Thus, MIPs have been employed as sensors in diagnostics and are promising materials for chemical sensor design due to an economical and straightforward method of preparation, high SA, ruggedness, stability, and reusability for nanomedicine and environmental applications. Despite the successful sensor applications of MIPs, these NPs have not been engaged or have been engaged very rarely for in vivo cell diagnostics or therapy and this needs further exploration. However, when employed as sensors with metal NPs added to MMIP or carbon-based nanomaterials, they allow enrichment of the properties of the nanocomposites in terms of stability and sensitivity. Moreover, they are considered most appropriate for applications in the biomedical field.

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FURTHER READING

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Zhang, A., & Lieber, C. M. (2016). Nano-Bioelectronics. Chemical Reviews, 116(1), 215–257. Zhang, Y., Liu, X., Li, L., Guo, Z., Xue, Z., & Lu, X. (2016). An electrochemical paracetamol sensor based on layer-bylayer covalent attachment of MWCNTs and a G4.0 PAMAM modified GCE. Analytical Methods, 8(10), 2218–2225. Zhang, J., Liu, J., Peng, Q., Wang, X., & Li, Y. (2006). Nearly monodisperse Cu2O and CuO nanospheres: Preparation and applications for sensitive gas sensors. Chemistry of Materials, 18(4), 867–871. Zhang, X., Wang, G., Yang, M., Luan, Y., Dong, W., Dang, R., … Yu, J. (2014). Synthesis of a Fe3O4–CuO@ meso-SiO2 nanostructure as a magnetically recyclable and efficient catalyst for styrene epoxidation. Catalysis Science & Technology, 4(9), 3082–3089. Zhang, L. L., Zhou, R., & Zhao, X. S. (2010). Graphene-based materials as supercapacitor electrodes. Journal of Materials Chemistry, 20(29), 5983–5992. Zhao, Q., Frogley Mark, D., & Wagner, H. D. (2003). Direction-sensitive stress measurements with carbon nanotube sensors. Polymers for Advanced Technologies, 13(10-12), 759–764. Zhao, G., Li, J., Ren, X., Chen, C., & Wang, X. (2011). Few-layered graphene oxide nanosheets As superior sorbents for heavy metal ion pollution management. Environmental Science & Technology, 45(24), 10454–10462. Zhou, W., Chen, H., Yu, Y., Wang, D., Cui, Z., DiSalvo, F. J., & Abruña, H. D. (2013). Amylopectin wrapped graphene oxide/sulfur for improved cyclability of lithium–sulfur battery. ACS Nano, 7(10), 8801–8808. Zhou, Y., Kamiya, S., Minamikawa, H., & Shimizu, T. (2007). Aligned nanocables: Controlled sheathing of CuO nanowires by a self-assembled tubular glycolipid. Advanced Materials, 19(23), 4194–4197. Zhou, W., Moguche, A. O., Chiu, D., Murali-Krishna, K., & Baneyx, F. (2014). Just-in-time vaccines: Biomineralized calcium phosphate core-immunogen shell nanoparticles induce long-lasting CD8(+) T cell responses in mice. Nanomedicine, 10(3), 571–578. Zhou, X., Wang, A., Yu, C., Wu, S., & Shen, J. (2015). Facile synthesis of molecularly imprinted graphene quantum dots for the determination of dopamine with affinity-adjustable. ACS Applied Materials & Interfaces, 7(22), 11741–11747. Zhu, C., Du, D., & Lin, Y. (2017). Graphene-like 2D nanomaterial-based biointerfaces for biosensing applications. Biosensors and Bioelectronics, 89, 43–55. Zhu, W., Xu, L., Zhu, C., Li, B., Xiao, H., Jiang, H., & Zhou, X. (2016). Magnetically controlled electrochemical sensing membrane based on multifunctional molecularly imprinted polymers for detection of insulin. Electrochimica Acta, 218, 91–100. Zhu, C., Yang, G., Li, H., Du, D., & Lin, Y. (2014). Electrochemical sensors and biosensors based on nanomaterials and nanostructures. Analytical Chemistry, 87(1), 230–249. Zumwalde, R., & Hodson, L. (2009). Approaches to safe nanotechnology: Managing the health and safety concerns associated with engineered nanomaterials (p, 125). National Institute for Occupational Safety and Health. NIOSH (DHHS) Publication.. Zunngu, S. S., Madikizela, L. M., Chimuka, L., & Mdluli, P. S. (2017). Synthesis and application of a molecularly imprinted polymer in the solid-phase extraction of ketoprofen from wastewater. Comptes Rendus Chimie, 20(5), 585–591.

Further Reading Ambrosini, S., Beyazit, S., Haupt, K., & Tse Sum Bui, B. (2013). Solid-phase synthesis of molecularly imprinted nanoparticles for protein recognition. Chemical Communications, 49(60), 6746–6748. Canfarotta, F., Waters, A., Sadler, R., McGill, P., Guerreiro, A., Papkovsky, D., … Piletsky, S. (2016). Biocompatibility and internalization of molecularly imprinted nanoparticles. Nano Research, 9(11), 3463–3477. Hashemi-Moghaddam, H., Kazemi-Bagsangani, S., Jamili, M., & Zavareh, S. (2016). Evaluation of magnetic nanoparticles coated by 5-fluorouracil imprinted polymer for controlled drug delivery in mouse breast cancer model. International Journal of Pharmaceutics, 497(1), 228–238. Jain, S. C., Willander, M., & Kumar, V. (2011). Conducting Organic Materials and Devices. Vol. 81. Elsevier Science. Liu, X., Ren, J., Su, L., Gao, X., Tang, Y., Ma, T., … Li, J. (2017). Novel hybrid probe based on double recognition of ­aptamer-molecularly imprinted polymer grafted on upconversion nanoparticles for enrofloxacin sensing. Biosensors and Bioelectronics, 87, 203–208. Moczko, E., Poma, A., Guerreiro, A., Perez de Vargas Sansalvador, I., Caygill, S., Canfarotta, F., … Piletsky, S. (2013). Surface-modified multifunctional MIP nanoparticles. Nanoscale, 5(9), 3733–3741.

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Niu, H., Yang, Y., & Zhang, H. (2015). Efficient one-pot synthesis of hydrophilic and fluorescent molecularly imprinted polymer nanoparticles for direct drug quantification in real biological samples. Biosensors and Bioelectronics, 74, 440–446. Poma, A., Guerreiro, A., Whitcombe Michael, J., Piletska Elena, V., Turner Anthony, P. F., & Piletsky Sergey, A. (2013). Solid-phase synthesis of molecularly imprinted polymer nanoparticles with a reusable template–“Plastic Antibodies”. Advanced Functional Materials, 23(22), 2821–2827. Shen, X., Svensson Bonde, J., Kamra, T., Bülow, L., Leo Jack, C., Linke, D., & Ye, L. (2014). Bacterial Imprinting at Pickering Emulsion Interfaces. Angewandte Chemie International Edition, 53(40), 10687–10690.

C H A P T E R

2 Immobilization Techniques of Nanomaterials Elif Burcu Aydin⁎, Muhammet Aydin⁎, Mustafa Kemal Sezginturk† ⁎

Tekirdag Namık Kemal University, Scientific and Technological Research Center, Tekirdag˘ , Turkey †Bioengineering Department, Çanakkale Onsekiz Mart University, Faculty of Engineering, Çanakkale, Turkey

1 INTRODUCTION Pharmaceuticals are large molecules composed of organic compounds that are utilized at low concentration in the diagnosis, treatment, and prevention of diseases and abnormal conditions. The uncontrolled use of pharmaceuticals affects the health of humans and other creatures and, therefore, the sensitive detection of these pharmaceuticals is important. For example, the overdose use of antibiotics will cause microbial resistance. Because of this microbial resistance, common infections have become difficult to treat and an increase in the cost of treatment has been observed. Furthermore, the domestic use of pharmaceuticals leads to pharmaceuticals entering the environment through excretion. This excretion causes contamination in environmental matrices, such as drinking water, and adversely affects human and animal health. For example, they affect the hormone concentration in the body and disrupt the endocrine system. Apart from pharmaceutical use in humans, veterinary drugs affect the food products that are derived from these animals (Sanvicens, Mannelli, Salvador, Valera, & Marco, 2011). Generally, analytical techniques for the detection of pharmaceuticals are based on liquid and gas chromatography/mass spectrometry. Apart from these techniques, LC with UV detection and capillary electrophoresis are used. Because pharmaceuticals have to be derivatized owing to the low volatility before GC analysis, LC-MS analysis is preferable (Sanvicens et al., 2011). However, these techniques require a lot of time, several pieces of laboratory equipment, specialized personnel, and complex sample preparation steps. Furthermore, they are very expensive. Compared with these chromatographic techniques, biosensors are simple and low cost (Cháfer-Pericás, Maquieira, & Puchades, 2010; Sanvicens et al., 2011).

New Developments in Nanosensors for Pharmaceutical Analysis https://doi.org/10.1016/B978-0-12-816144-9.00002-X

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Copyright © 2019 Sibel A. Ozkan and Afzal Shah. Published by Elsevier Inc. All rights reserved.

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2.  Immobilization Techniques of Nanomaterials

Biosensors are analytical devices that provide rapid, quantitative, and sensitive analysis, without the requirement of specialized personnel (Gil & Melo, 2010; Saha, 2012). They are the most preferred screening method due to simple procedures for use and automatic design (Cháfer-Pericás et al., 2010). They contain an immobilized biological material (enzyme, antibody, nucleic acid, aptamer, cell), which interacts specially with the transducer. These signals can be electrical, thermal, and optical (Chen et al., 2017; Gil & Melo, 2010; Saha, 2012). Apart from these advantages, they have some limitations. One example is the instability of biological material, which can lose its activity in a short time due to the nature of the molecule and the environmental conditions. Biological material is immobilized on the solid electrode by adsorption, covalent bonding, cross-linking, entrapment, and encapsulation (Cháfer-Pericás et al., 2010). Electrochemical sensors and biosensors are usually utilized for the detection of a wide range of analytes. In electrochemical biosensors, the main transducer (electrode) is usually made of noble metals (e.g., Pt and Au), carbon derivatives (glassy carbon, carbon paste) and semiconductive materials (indium tin oxide, fluorine-doped tin oxide). These materials are used as electrodes because of wide potential windows, low background current, chemical inertness, and low cost. These electrodes can be modified to improve the performance of the biosensor by using nanomaterials for pharmaceutical and biomedical analysis (Gil & Melo, 2010). Electrochemical biosensors are preferable to other types of biosensors due to low detection limits and wide detection ranges. Moreover, the selectivity of electrochemical biosensors in complex samples is excellent. They require very small sample volumes and they are useful for analyzing low concentrations of drug products and metabolites (Gupta, Dubey, & Malik, 2013). In sum, the determination of pharmaceuticals and residues in biological, environmental, and food matrices is quite important. However, the current analytical methods mentioned above are able to detect pharmaceuticals at very low concentrations, but they require a lot of time for sample preparation, concentration, and/or extraction before the analysis when using these devices. Biosensors offer a lot of advantages over existing techniques, such as less analysis time and real-time analysis. Incorporating nanomaterials into biosensor design can improve the performance of the system (Cristea & Ciui, 2015). A schematic representation of a biosensor is shown in Fig. 1. The present chapter provides a comprehensive overview of the applications of biosensors using nanomaterials for pharmaceutical analysis. It covers the basics of different immobilization strategies of nanomaterials in pharmaceutical analysis. The nanomaterial immobilization procedures are summarized by using tables and are explained using developed biosensors. The linear ranges and detection limits of these biosensors are compared and discussed.

2  NANOMATERIALS USED IN BIOSENSORS FOR PHARMACEUTICAL DETECTION The trend of using nanomaterials in biosensing systems has led to improvements in the sensitivity and selectivity of the biosensor and has increased the success of biosensors (Cristea & Ciui, 2015). Nanomaterials are usually utilized for the fabrication of biosensors due to their good electrical, optical, mechanical, and thermal features. They are known, a­ ttractive



2  Nanomaterials Used in Biosensors for Pharmaceutical Detection

49

FIG. 1  A schematic representation of a modified biosensor.

materials for developing new methods in the development of biosensors. They have excellent features, such as high surface area, good electrical conductivity, unique thermal and mechanical properties, and high stability (Cristea & Ciui, 2015; Lan, Yao, Ping, & Ying, 2017; Sanvicens et al., 2011). Different kinds of nanomaterials, such as carbon nanomaterials, metal nanoparticles, magnetic nanoparticles, and quantum dots, have been used to construct many biosensors for pharmaceutical detection. Combining these unique features of nanomaterials with the biorecognition elements of biosensors has been reported to improve the analytical performance of biosensors, such as improved stability and selectivity (Cristea & Ciui, 2015; Lan et al., 2017). Over the past 20 years, interest has increased in the modification of electrodes because the modification procedures improve the performance of the biosensor. A wide range of electrode modifiers, such as graphene, CNTs, quantum dots, and metal NPs, have been used in the chemical modification of electrodes (Gholivand & Mohammadi-Behzad, 2015). Also, the modification of working electrodes with nanomaterials is important to achieve a fast electron transfer between the electrode and the analyte, a low detection limit, a wide linear detection range, high stability, good reproducibility, and excellent sensitivity and selectivity (Wong, Scontri, Materon, Lanza, & Sotomayor, 2015). The preparation and application of nanomaterials are significant in material and chemical technology. Nanoparticles with different compositions, sizes, and shapes have been used in different analyses. The use of unmodified electrodes suffers from several disadvantages, such as low reproducibility, electrode fouling, slow electron transfer, high overpotential, and low selectivity and sensitivity. Because

50

2.  Immobilization Techniques of Nanomaterials

of this, the modification of electrodes with convenient compounds is of utmost importance. Therefore, various compounds and techniques are used for the modification of electrodes (Ensafi, Allafchian, & Rezaei, 2013).

2.1  Carbon Nanomaterials Carbon nanomaterials, including carbon nanotubes, carbon nanofibers, fullerenes, and graphene, have gained attention because of their extraordinary features. Among these, CNT and graphene are the mostly utilized carbon nanomaterials in biosensors for pharmaceuticals detection (Lan et al., 2017). Recently, chemically modified electrodes have gained interest owing to their success in different applications. Carbon-based nanomaterials, such as carbon nanofibers, carbon nanotubes (CNTs), and mesoporous carbons, have been utilized for the modification of electrodes in different applications due to their low cost and convenient electrocatalytic activity for a variety of redox reactions, a broad potential window, and relatively inert electrochemistry (Ensafi & Allafchian, 2013). 2.1.1  Carbon Nanotubes Carbon nanotubes (CNTs) are one-dimensional (1D) carbon nanomaterials that are formed by rolling a single layer of graphite or graphene sheets. CNTs were discovered by Ijima in 1991 and he reported that the diameter and length of CNTs are in the range of the nanometer and micrometer scales (Kurbanoglu, Ozkan, & Merkoçi, 2017). CNTs include two classes. One class consists of single-walled CNTs, defined by the number of rolled sheets. Both ­single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs) are excellent modifiers to construct biosensors owing to their good mechanical, electrical, and chemical features. They are able to modify with carboxyl or amino groups or to integrate with other materials, such as polymers, ionic liquids, or metal nanoparticles (Zeng, Zhu, Du, & Lin, 2016). By using these functional groups, CNTs can connect to biomolecules. They facilitate the electron transfer between the electrolyte solution and the electrode, and furthermore a lot of metal nanoparticles can be combined onto CNTs to form many electroactive sites and to increase the sensitivity and detection limits of the electrodes (Lan et al., 2017). Furthermore, CNTs are a new type of inorganic material with a nanostructure that is a promising modification material for different types of biomolecules (Karimi-Maleh, Moazampour, Ahmar, Beitollahi, & Ensafi, 2014). CNTs gained attention owing to their excellent structure and extraordinary features. They have unique features, such as large surface area and effective catalytic activity, that promote charge transfer reactions when they are utilized as an electrode immobilization substance (Fernandes et al., 2015). They are used in different applications due to their role in improving the performance of biosensors and sensors. They have unique features, such as unique electronic and mechanical properties, high surface area, high sorption capacity, and good chemical stability. MWCNTs have higher electron transfer rates and higher sorption capacity than SWCNTs. Because of this, MWCNTs are preferable (Chen, Ma, & Su, 2010). In the study of Ensafi et al. (2013), they used MWCNTs with MgCr2O4 nanoparticles as the decorator material of a working electrode. In this study, MgCr2O4 nanoparticles were utilized as a mediator in the voltammetric detection of azithromycin. Differential pulse voltammetry



2  Nanomaterials Used in Biosensors for Pharmaceutical Detection

51

was the quantification method and two linear ranges (0.25–4 and 4–10 μM) with a detection limit of 0.07 μM was obtained (Ensafi & Allafchian, 2013). For diclofenac detection, different MWCNT-based biosensors have been developed. Afkhami, Bahiraei, and Madrakian (2016) used a GCE electrode modified with AuNPs/MWCNTs, finding a linear range and detection limit of 0.03–200 and 0.02 μM, respectively. Arvand, Gholizadeh, and Zanjanchi (2012) used a GCE electrode modified with hydrophobic ionic liquid MWCNTs and found a wide linear range (0.18–119 μM) and a low detection limit (0.04 μM). A carbon paste electrode (CPE) modified with MWCNTs and ionic liquid composite material was used for diclofenac detection and this biosensor had a linear range of 0.3–750 μM and a detection limit of 0.09 μM (Goodarzian et  al., 2014). Paimard, Gholivand, and Shamsipur (2016) used MWCNTs and Fe3O4 as mediators due to their excellent structure, high chemical stability, physical features, high surface area, good conductivity, and biocompatibility. The integration of MWCNTs and Fe3O4 was a successful procedure to improve sensor performance (Paimard et al., 2016). The following were used for paracetamol detection: a GCE modified with MWCNT functionalized cobalt nanoparticles (Kutluay & Aslanoglu, 2014), a carbon paste electrode modified with MWCNT functionalized fullerene and Cu nanoparticles (Mao, Li, Jin, Yu, & Hu, 2015), a GCE modified with Pd/graphene oxide (GO) (Li, Liu, et al., 2014), a CPE modified with Pt functionalized MWCNTs (D’Souza et al., 2015), a GCE modified with poly(4-vinyl)pyridine functionalized MWCNTs (Ghadimi, Tehrani, Ali, Mohamed, & Ab Ghani, 2013), and a GCE modified with graphene nanosheet functionalized MWCNTs (Arvand & Gholizadeh, 2013). 2.1.2 Graphene Graphene is a two-dimensional (2D) carbon nanomaterial and is formed from a sheet of sp2 bonded carbon atoms that are arranged into a rigid honeycomb lattice (Bahadır & Sezgintürk, 2016; Lan et al., 2017). Recently, graphene has gained attention owing to its large surface area, high thermal and electrical conductivity, good mechanical strength, and low cost (Rahi, Karimian, & Heli, 2016; Zhang & Wei, 2016). It can be synthesized by different techniques, such as mechanical exfoliation, chemical vapor deposition, and the chemical and electrochemical Hummers method (Kurbanoglu & Ozkan, 2017). The most used graphene derivative is graphene oxide (GO). GO is a remarkable nanomaterial due to its extraordinary electrical, physical, and chemical features. GO and its nanocomposites provide high surface area, high specific capacitance, and good electrical activity (Wong et al., 2015). These properties make graphene a suitable matrix material for several applications, such as electrochemical biosensing and energy storage (Zhang, Zhang, & Zhang, 2016). GO can be synthesized by exfoliation of graphite oxide in water using sonication. GO increases the hydrophilicity of graphene sheets due to oxygen-containing functional groups on its surface that facilitate the binding of biomolecules and provide a large surface area for biomolecule immobilization (Kurbanoglu & Ozkan, 2017; Tran, Son, & Min, 2016). 2.1.3 Fullerene Fullerene contains 12 pentagons and varying numbers of hexagons. It is composed of 60 closely packed carbon atoms. Using fullerene in the construction of biosensors improves the stability and potential window (Kurbanoglu et al., 2017). Fullerene has gained interest due to its remarkable electrochemical features and electrocatalysis. Using this material for modification provides an increase in the peak currents in electro analysis due to the chemical

52

2.  Immobilization Techniques of Nanomaterials

stability of fullerene. A composite of fullerene with other nanomaterials, such as CNTs, has a significant role in the dispersion and catalytic activity of the fullerene (Rahimi-Nasrabadi, Khoshroo, & Mazloum-Ardakani, 2017). 2.1.4  Quantum Dots Quantum dots are semiconductor nanocrystals, such as CdS, ZnS, and CdTe, that have excellent optical and electronic features, such as high luminescence, long-term photo stability, broad absorption bands, and size-tunable, narrow, symmetric emission (Lan et al., 2017). Aptamers and antibodies can make a conjugate with QDs without affecting their emission properties. During this conjugation, they do not affect the specificity of aptamers and antibodies. The surface modification of QDs improves their optical, chemical, electrochemical, and photocatalytic features. Because of this, a new electrode with different chemistry was formed by QDs modified with different functional groups. This new surface is important in several electroanalytical applications (Gholivand & Mohammadi-Behzad, 2015).

2.2  Metal Nanoparticles Metal nanoparticles are the most popular materials due to their unique biocompatibility and catalysis features. They have large surface area, good electron transfer kinetics, and excellent absorption sites to antibodies, enzymes, and antigens. Metal nanomaterials have attracted interest for the construction of biosensors for pharmaceutical determinations (Lan et  al., 2017; Zeng et al., 2016). The most used metal nanoparticles are AuNPs. The use of metal nanoparticles for modifying electrodes enhances the electroanalysis efficiency and electron transfer process in thermodynamic and kinetic reactions. In thermodynamic reactions, these nanostructures can oxidize or reduce pharmaceuticals at suitable potentials (at lower potentials for electrooxidation and at less negative potentials for electroreduction) due to the nanosize effect. In kinetic reactions, nanostructures accelerate electron transfer owing to the large surface area and nanosize effect. Metal and metal oxide nanomaterials catalyze the oxidation and reduction reactions of pharmaceuticals through the direction of a mediated electron transfer mechanism (Zeng et al., 2016). Noble metals, such as Au, Ag, Pt, and Pd, have been used for the electrode modification owing to their inertness against oxidation reactions and excellent biocompatible features. They have attracted interest due to high catalytic activities in chemical reactions. These nanoparticles have been used for the construction of biosensor and sensor platforms. Pd nanoparticles are usually utilized because of their high abundance and low cost (Li, Liu, et al., 2014). Many noble nanoparticles are anchored to graphene materials using different strategies to form composites. The aim of forming composites is to make robust platforms for biosensing applications (Zeng et al., 2016). In addition, metal oxide nanoparticles (ZnO, CuO, NiO, TiO2) have similar advantages and they have low cost and a simple fabrication process. Therefore, they have been utilized for the enhancement of electron transfer kinetics in biosensors (Tran et al., 2016). Gold nanoparticles (AuNPs) have some advantages, such as large surface area, high electron transfer capacity, high stability, good biocompatibility, and high conductivity and, therefore, they have been utilized to improve the sensitivity and the detection limit of the sensor. They are also convenient for surface immobilization procedures and can act as successful conduction centers and facilitate the electron transfer. Furthermore, they can conjugate to thiol-modified oligonucleotides (Taghdisi, Danesh, Ramezani, & Abnous, 2016).



2  Nanomaterials Used in Biosensors for Pharmaceutical Detection

53

2.3  Magnetic Nanoparticles Magnetic nanoparticles have attracted interest owing to their large surface area and good biocompatibility and, therefore, they are utilized in the biosensor construction process. They have supermagnetic features below 500 nm in size. Furthermore, they can be integrated with transducer materials and provide analyte detection by attraction under a magnetic field. The use of MNPs in biosensor construction increases the sensitivity and decreases the LOD and provides a quick analysis (Lan et al., 2017; Zeng et al., 2016).

2.4  Modification Strategies for Nanomaterial-Based Biosensors In recent years, nanomaterial-based biosensors have had an important place in pharmaceutical analysis. Therefore, different strategies for electrode modification have been developed. The strategies have a significant role because the success of the electrode modification method affects the biosensor performance in such areas as the detection limit, the linear range, and the stability. Various techniques have been used for the modification of biosensors using nanomaterials, such as chemical adsorption, self-assembly, electrochemical deposition, drop casting, electropolymerization, and molecular imprinting. The most used method is drop casting. The nanomaterial-based biosensors are summarized in Table 1. This table also summarizes the modification methods and strategies of electrodes. Several of these biosensors are explained in the subsections of this chapter. 2.4.1  Drop Casting Drop casting is a simple, useful, and low-cost method to produce layers of molecules and small-area films. A specific amount of dissolving substance in a volatile solvent is dropped on the surface and the solvent is allowed to evaporate. The solvent selection is based on the hydrophobic nature of the surface and the complete wetting of the surface is provided. Using very dilute solutions provides a homogenous deposition (Mannini, 2009). The drop casting method is an uncontrollable method but it has a limitation in small-area film and coating formation (Eslamian & Soltani-Kordshuli, 2017). Various analytes have been detected using different electrodes based on the drop casting method. Platinum nanoparticles (PtNPs) have high electrocatalytic activity to the reduction of H2O2. Bo et  al. (2013) used PtNPs as an electrode modifier material and constructed a biosensor via the drop casting method for clenbuterol detection. PtNPs were formed on the electrode surface after reduction of chloroplatinic acid into atomic platinum. The detection limit of clenbuterol was 43.96 nM. Another clenbuterol biosensor was fabricated by Zhai et al. (2015). They used sulfonated graphene sheets and carboxylated MWCNTs. Graphene-based materials have also been used as catalysts in biosensors. Graphene-based nanocomposites were successfully designed due to the π-π interaction between graphene sheets. This nanocomposite was dropped on the electrode surface and dried. The detection limit of this biosensor was 4.6 nM. This low detection limit originated from the excellent properties of GO. Furthermore, the modified electrode had a large active surface area for the catalysis of clenbuterol and accelerated the electron transfer between the electrode and electrolyte (Zhai et al., 2015). An electrochemical sensor was constructed by Sgobbi et al. (2016) for the simultaneous determination of sulfamethoxazole and trimethoprim. The working electrode was SPE ­modified

TABLE 1  Nanomaterial modification methods and strategies Detection principle

Principle

Biomolecule

Immobilization technique

Oxytetracycline Tetracycline Doxycycline

Colorimetric biosensor

Peroxidase like activity of Fe3O4 MNPs

Chemical

Anticancer drug ctDNA

Fluorescence switch sensor

Chloramphenicol

Analyte

Linear Range

Detection limit Ref.

Mixing

50–1000 nM 100–1000 nM 50–1000 nM

26 nM 45 nM 48 nM

Wang et al. (2016)

Glutathione stabilized gold Chemical nanocluster

Mixing

0.1–6 μM 0.5–8 μg/mL

20 nM 0.1 μg/mL

Jiang, Feng, Liu, Fan, and Wang (2016)

Electrochemical

Three-dimensional reduced Chemical graphene oxide modified GCE

Drop casting

1–113 μmol/L

0.15 μmol/L

Zhang et al. (2016)

Streptomycin

Optic

Exonuclease III, SYBR gold and aptamer complimentary strand

Chemical

Mixing

–

54.5 nM

Taghdisi, Danesh, Nameghi, Ramezani, and Abnous (2016)

Pyrazinamide

Electrochemical

Aqueous nanodiamond dispersion on GCE

Chemical

Drop casting

7.9 × 10−7– 4.9 × 10−5 mol/L

2.2 × 10−7 mol/L Simioni, Silva, Oliveira, and Fatibello-Filho (2017)

Amoxicillin

Electrochemical

DMBQ/ZnO/CNTs nanocomposite modified CPE

Chemical

Addition in CPE

1.0–950 μM

0.5 μM

Karimi-Maleh, Tahernejad-Javazmi, Gupta, Ahmar, and Asadi (2014)

Tetracycline

Colorimetric assay

Triple-helix molecular switch gold NPs

Chemical

Mixing

0.3–10 nM

266 pM

Ramezani, Danesh, Lavaee, Abnous, and Taghdisi (2015)

Morphine

Electrochemical

Mercaptobenzaldehyde and ds-DNA modified Au electrode

Aptamer

Self-assembly

0.05–500 μmol/L

0.01 μmol/L

Talemi and Mashhadizadeh (2015)

Tetracycline

Electrochemical

Aptamer complexexonuclease I modified Au electrode

Aptamer

Self-assembly

–

450 nM

Taghdisi, Danesh, Ramezani, and Abnous (2016)

Oxytetracycline

Electrochemical

Graphene oxide-AuNPs nanocomposite

Aptamer

Drop casting

–

–

Liu et al. (2017)

Ampicillin

Electrochemical

AuNPs-methylene blue modified Au electrode

Aptamer

Self-assembly

5–12,500 μM

1 μM

Yu and Lai (2018)

Dopamine

Electrochemical

Au@carbon dots-chitosan modified GCE

Chemical

Drop-cast

0.01–100 pM

0.001 pM

Huang et al. (2014)

Chloramphenicol Oxytetracycline

Electrochemical

AuNPs modified GCE

Aptamer

Electrochemical deposition of AuNPs

0.0005–50 ng/mL

0.15 ng/mL 0.10 ng/mL

Yan, Gan, Li, Cao, and Chen (2016)

Penicillin

Electrochemical

Coimmobilization of MWCNTs-hematein-βlactamase on GCE

Enzyme

Adsorption

–

50 nM

Chen et al. (2010)

Clenbuterol

Electrochemical

1,4-Benzendithiol PtNB modified Au electrode

Chemical

Adsorption

0.1–0.8 μM

43.96 nM

Bo et al. (2013)

Chloramphenicol

Electrochemical

Aptamer conjugated magnetic nanoparticles modified bioassay

Antibody

Adsorption

0.01–1 ng/mL

0.01 ng/mL

Wu et al. (2015)

Epinephrine

Electrochemical

MWCNT-chitosan Chemical biopolymer nanocomposite modified GCE

Adsorption

0.05–10 μM

0.03 μM

Reddy, Satyanarayana, Goud, Gobi, and Kim (2017)

Streptomycin

Colorimetric Fluorescence

AuNPs modified aptasensor

Aptamer

Adsorption

– –

73.1 nM 47.6 nM

Emrani et al. (2016)

Atorvastatin

Electrochemical

Nano-silica and zinc oxide NPs modified GCE

Chemical

Adsorption

–

0.7 nM (DPV) 0.12 nM (SWV)

Bukkitgar, Shetti, and Kulkarni (2018)

Tetracycline

Electrochemical

MWCNT-GO modified CPE

Chemical

Adsorption

2 × 10−5– 3.1 × 10−4 mol/L

3.6 × 10−7 mol/L Wong et al. (2015)

Paracetamol

Electrochemical

MWCNT and polyaniline modified Au electrode

Microbial

Electrodeposition

5–630 μM

2.9 μM

Bayram and Akyilmaz (2016)

Sulfaquinoxaline

Electrochemical

Graphite modified GCE

Chemical

Addition in CPE

5 × 10−6–10−3 M

3 × 10−6 M

Soleymanpour and Rezvani (2016)

Phenazopyridine

Electrochemical

Chitosan-MWCNTs modified pencil graphite electrode

dSDNA

Adsorption

0.01–50 μg/mL

0.003 μg/mL

Ensafi, Lesani, Amini, and Rezaei (2015)

Sulfonamide

Electrochemical

Magnetic beads modified graphite epoxy composite electrode

Antibody

Mixing

4.22–175.53 nM

1.44 nM

Zacco et al. (2007)

Continued

TABLE 1  Nanomaterial modification methods and strategies—cont’d Analyte

Detection principle

Principle

Biomolecule

Immobilization technique

Linear Range

Detection limit Ref.

Isoxsuprine hydrochloride

Electrochemical

Chitosan-ZnO/polypyrrole Chemical modified GCE

Adsorption

–

–

Hassanein, Salahuddin, Matsuda, Kawamura, and Elfiky (2017)

Oxytetracycline

Electrochemical

MWCNTs + HRP modified CPE

Enzyme

Addition in CPE

15 μM–1.5 mM

35 nM

Ghodsi, Rafati, and Shoja (2016)

Ampicillin

Fluorescence

AuNPs modified magnetic beads modified assay

Aptamer

Mixing

0.1–100 ng/mL

0.07 ng/mL

Luo et al. (2017)

Amoxicillin allergy Electrochemical

Dendrimer modified arrays Chemical of gold nanodisk

Adsorption

0.025–2 μg/mL

0.6 ng/mL

Soler et al. (2015)

Penicillin G

Electrochemical

Bilayer lipid membrane modified AuNPs immobilized GCE

Antibody

Electrodeposition

3.34 × 10−3–103 M

2.7 × 10−4 M

Li et al. (2015)

Dopamine

Electrochemical

PEGylated arginine functionalized magnetic NPs modified GCE

Microbial

Adsorption

1–9 mM

7.25 μM

Chandra, Arora, and Bahadur (2012)

Chloramphenicol

Electrochemical

3D CNT/CuNPs modified GCE

Chemical

Drop casting

–

10 μM

Munawar et al. (2018)

Streptomycin Tetracycline Penicillin G

Colorimetric

QD modified fluorescence immunoassay

Chemical

Commercial kit

0.01–25 ng/mL 0.01–25 ng/mL 0.01–10 ng/mL

5 pg/mL 5 pg/mL 5 pg/mL

Song et al. (2015)

Kanamycin

Colorimetric

AuNPs modified colorimetric assay

Chemical

Chemical modification

3.35–53.75 nM

3.35 nM

Ha, Jung, Kim, Kim, and Yoon (2017)

Neomycin

Electrochemical

SWCNTs modified paper supported sensor strips

Chemical

Dip-dry coating method

0.2–125 ng/mL

0.04 ng/mL

Wu et al. (2012)

Tetracycline Cefixime

Electrochemical

AuNPs modified SPGE

Chemical

Adsorption

10−5–10−3 mol/L

0.54 μM 1.27 μM

Asadollahi-Baboli and Mani-Varnosfaderani (2014)

Cephalosporins Sulfonamides Tetracyclines

Electrochemical

Magnetic beads modified antibodies

Antibody

Adsorption

–

–

Conzuelo et al. (2014)

Sulfamethoxazole

Electrochemical

AuNPs modified SPCE

Enzyme

Electrodeposition

20 μM–0.2 mM

22.6 μM

Torno-de Román, Alonso-Lomillo, Domínguez-Renedo, and Arcos-Martínez (2016)

Sulfamethoxazole Trimethoprim

Electrochemical

MWCNTs/PB nanocubes modified SPE

Chemical

Drop casting

1–10 μM 0.1–10 μM

38 nM 60 nM

Sgobbi, Razzino, and Machado (2016)

Paracetamol

Electrochemical

Carboxylated MWCNTs modified GCE

Chemical

Covalent binding

1–230 μM

0.092 μM

Li, Feng, Li, Zhang, and Zhong (2014)

Glutathione Piroxicam

Electrochemical

FePt/CNTs modified CPE

Chemical

Adsorption

0.004–340 μM 0.5–550 μM

1 nM 0.1 nM

Karimi-Maleh et al. (2014)

Nilutamide

Electrochemical

Functionalized MWCNTs modified GCE

Chemical

Drop casting

0.02–21 μM 28–535 μM

0.22 μM

Karthik et al. (2017)

Ofloxacin

Electrochemical

Drop casting of MWCNTspolylysine coated GCE

Enzyme

Drop casting

0.26–25.6 ng/mL

0.15 ng/mL

He, Zang, Liu, He, & Lei (2015)

Methamphetamine cocaine

Colorimetric

Nonaggregated Au@Ag

DNA

Micro cuvette

0.5–200 nM

0.1 nM

Mao et al. (2015)

Azithromycin

Electrochemical

MWCNTs decorated with MgCr2O4 modified GCE

Chemical

Drop casting

0.25–4 μM 4–10 μM

0.07 μM

Ensafi et al. (2013)

Terbutaline

Electrochemical

MWCNTs and zirconium oxide modified GCE

Chemical

Drop casting

10–160 nM

2.25 nM

Baytak, Teker, Duzmen, and Aslanoglu (2016)

Clenbuterol

Electrochemical

Sulfonated sheets and MWCNTs modified GCE

Chemical

Drop casing

0.01–5 μM

4.6 nM

Zhai et al. (2015)

Diclofenac

Electrochemical

NiO/CNTs carbon paste electrode

Chemical

Mix

0.05–520 μM

0.01 μM

Sanati, Karimi-Maleh, Badiei, Biparva, and Ensafi (2014)

Daunorubicin

Electrochemical

Ag-4-ATP-MWCNT modified CPE

DNA

Mix

10−9–10−5 M 3 × 10−10–10−9 M

3 × 10−10 M

Saljooqi, Shamspur, and Mostafavi (2017)

Isoproterenol Acetaminophen Tryptophan

Electrochemical

MWCNTs paste electrode

Chemical

Mix

0.04–400 μM 5–500 μM 10–800 μM

0.009 μM 1 μM 4 μM

Karimi-Maleh, Moazampour, Ahmar, et al. (2014)

Eserine Neostigmine

Electrochemical

Tetrathiafulvalenetetracyanoquinodimethane ionic liquid CPE

Chemical

Sol gel method

0.1–1000 nM 1–500 nM

2.6 × 10−2 nM 0.3 nM

Zamfir, Rotariu, and Bala (2013)

Mebendazole

Electrochemical

Graphene nanosheets and carbon nanospheres/ Chitosan based nanocomposite film modified elect.

Chemical

Drop casting

0.02–1 μM

10.5 nM

Ghalkhani and Shahrokhian (2013)

Continued

TABLE 1  Nanomaterial modification methods and strategies—cont’d Analyte

Detection principle

Principle

Biomolecule

Immobilization technique

Linear Range

Detection limit Ref.

Zidovudine

Electrochemical

Ag nanofilm and MWCNT modified GCE

Chemical

Electrodeposition

0.37–1.5 mM

0.15 μM

Rafati and Afraz (2014)

Warfarin

Electrochemical

CdS-quantum dotscarboxylated MWCNTs/ chitosan composite film modified GCE

Chemical

Drop casting

0.05–80 μM

8.5 nM

Gholivand and Mohammadi-Behzad (2015)

Paracetamol Dopamine

Electrochemical

Co NPs functionalized MWCNTs modified GCE

Chemical

Chemical deposition

5.2 × 10−9– 4.5 × 10−7 M 5 × 10−8–3 × 10−6 M

10−9 M 1.5 × 10−8 M

Kutluay and Aslanoglu (2014)

Amlodipine Enalapril

Electrochemical

MWCNTs modified CPE

Chemical

Mix

0.58–5.9 μM 2–57 μM

0.049 μM 0.81 μM

Valezi et al. (2014)

Irinotecan

Electrochemical

Poly(methylene blue)MWCNTs modified GCE

Chemical

Drop casting

8 × 10−6–8 × 10−5 M

2.14 × 10−7 M

Karadas et al. (2013)

Atorvastatin

Electrochemical

Cetyltrimethylammonium bromide ion-pair, MWCNTs ionic liquid modified graphite paste electrode

Chemical

Mix

10−9–10−3 M

10−9 M

Jalali and Ardeshiri (2017)

Sulfasalazine

Electrochemical

BiNPs-MWCNTs modified GCE

Chemical

Drop casting

5 × 10−8–10−5 M

1.3 × 10−8 M

Nigović, Jurić, and Mitrović (2017)

Sulfacetamide

Electrochemical

SWCNT-poly Chemical 1,5-diaminonapthalene modified graphite electrode

Electrochemical polymerization

0.005–1.5 mM

0.11 μM

Yadav, Choubey, Agrawal, and Goyal (2014)

Mefenamic acid

Electrochemical

MWCNTs modified CPE

Chemical

Mix

2–1000 nM

1.2 nM

Madrakian, Haghshenas, Ahmadi, and Afkhami (2015)

Metaproterenol

Electrochemical

ITO NPs and MWCNTs modified GCE

Chemical

Drop casting

3 × 10−8–2.2 × 10−5 M 1.2 × 10−8 M

Baytak and Aslanoglu (2015)

Folic acid

Photo­ electrochemical

Interwoven titanate nanotubes and carbon nanohorns modified GCE

Chemical

Drop casting

10−10–10−5 M

Dai et al. (2016)

2.5 × 10−11

Tamoxifen

Electrochemical

Polyaniline modified Pt electrode/HRP

Norfloxacin

Electrochemical

Amiloride

Enzyme

Drop casting

1–11 ng/mL

0.07 ng/mL

Radhapyari, Kotoky, Das, and Khan (2013)

MWCNTs modified Chemical pyrolytic graphite electrode

Drop casting

1.2–1000 μM

40.6 nM

Agrawal et al. (2013)

Electrochemical

Nafion-CNT-nano composite modified GCE

Chemical

Drop casting

0.8–570 μM

0.47 μM

Desai and Srivastava (2012)

Ganciclovir

Electrochemical

Fe3O4/carboxylated MWCNTs modified GCE

Chemical

Drop casting

80–53,000 nM

20 nM

Paimard et al. (2016)

Isoproterenol

Electrochemical

Pyrogallol red modified MWCNTs paste electrode

Chemical

Mix

0.8–570 μM

0.47 μM

Keyvanfard and Alizad (2016)

Olanzapine

Electrochemical

Amine functionalized TiO2/MWCNTs modified GCE

Chemical

Drop casting

012–33 μM

0.09 μM

Arvand and Palizkar (2013)

Tramadol

Electrochemical

Polypyrrole MWCNTs modified GCE

Chemical

Molecular imprinting

0.2–2 nM 2–20 nM

0.03 nM

Deiminiat, Rounaghi, and Arbab-Zavar (2017)

Verapamil

Electrochemical

MWCNTs modified GCE

Chemical

Drop casting

2.5–70 μM

2 μM

Chamjangali, Goudarzi, Bagherian, and Reskety (2015)

Promethazine

Electrochemical

MWCNTs/SiO2/Al2O3/ Nb2O5 modified GCE

DNA

Drop casting

20–100 μM

5.9 μM

Marco, Borges, Tarley, Ribeiro, and Pereira (2013)

Antidementia drug Electrochemical

Conducting polymer Enzyme modified graphite electrode

Electro­ polymerization

0.01–12 mM

0.014 mM

Turan et al. (2014)

Imipramine

Electrochemical

Gold paste electrode

DNA

Mix

10–50 μM 2–30 μM 0.005–0.05 μM

0.0005 μM

Jankowska-Śliwińska, Dawgul, and Pijanowska (2017)

Captopril

Electrochemical

CNT modified CPE

Chemical

Mix

10−7–3.5 × 10−4 M

3 × 10−8 M

Beitollahi, Taher, Ahmadipour, and Hosseinzadeh (2014)

Sulfamethoxazole

Electrochemical

CNT modified CPE

Chemical

Mix

0.35–30 μg/mL

0.1 μg/mL

Arvand, Ansari, and Heydari (2011)

Continued

TABLE 1  Nanomaterial modification methods and strategies—cont’d Detection principle

Principle

Biomolecule

Immobilization technique

Methadone Acetaminophen

Electrochemical

MWCNTs modified GCE

Chemical

Mebendazole

Electrochemical

CNT modified GCE

Clozapine

Electrochemical

Diazepam

Analyte

Linear Range

Detection limit Ref.

Drop casting

5–100 μM 0.45–90 μM

0.28 μM 0.35 μM

Amiri-Aref, Raoof, and Ojani (2013)

Chemical

Drop casting

0.06–3 μM

19 nM

Ghalkhani, Beheshtian, and Salehi (2016)

MWCNTs/new coccine doped polypyrrole modified GCE

Chemical

Drop casting

0.01–5 μM

3 nM

Shahrokhian, Kamalzadeh, and Hamzehloei (2013)

Electrochemical

Fullerene functionalized CNTs/ionic liquid modified GCE

Chemical

Drop casting

0.3–700 μM

87 nM

Rahimi-Nasrabadi et al. (2017)

Fluvoxamine

Electrochemical

HgNPs-MWCNTs modified GCE

Chemical

Drop casting

0.01–0.33 μM

0.003 μM

Madrakian, Soleimani, and Afkhami (2015)

Rosuvastatin calcium

Electrochemical

CNT-GO modified GCE

Chemical

Drop casting

0.48–46.72 μM

0.06 μM

Silva, Zanin, Vicentini, Corat, and Fatibello-Filho (2015)

Pemetrexed

Electrochemical

Over-oxidized polypyrrole- Chemical MWCNTs modified GCE

Drop casting

8 × 10−7–10−4 M

2.04 × 10−7 M

Karadas and Ozkan (2014)

Mesalazine N-Acetylated metabolite

Electrochemical

CNT-nafion modified GCE

Chemical

Drop casting

5.8 × 10−8– 2.5 × 10−6 M 10−7–5 × 10−6 M

1.2 × 10−8 M 2.6 × 10−8 M

Nigović, Sadiković, and Jurić (2016)

Sertraline

Electrochemical

Ni-levodopa film electropolymerized GCE

Chemical

Electro­ polymerization

0.05–5.5 μM

95 nM

Shoja, Rafati, and Ghodsi (2016a)

Acetaminophen

Electrochemical

Imidazole derivative MWCNT modified GCE

Chemical

Drop casting

136.4–500 μM

–

Nasirizadeh et al. (2013)

Norfloxacin

Electrochemical

CuO-MWCNTs modified GCE

Chemical

Drop casting

1–47.7 μM

0.321 μM

Devaraj, Deivasigamani, and Jeyadevan (2013)

Captopril

Electrochemical

1,4-Phenylene-N-Nbis(O,O-diphenyl phoramidate- CdS quantum dots-MWCNTs modified GCE

Chemical

Drop casting

0.05–90 μM

15 nM

Paimard et al. (2016)

Tramadol

Electrochemical

SiO2@Fe3O4 NPs modified CPE

Chemical

MIP

0.01–20 μM

0.004 μM

Afkhami, Ghaedi, Madrakian, Ahmadi, and Mahmood-Kashani (2013)

Paracetamol

Electrochemical

MWCNTs-chitosan-copper complex modified GCE

Chemical

Drop casting

0.1–200 μM

0.024 μM

Mao et al. (2015)

Metronidazole

Electrochemical

MIP-MWCNTs modified GCE

Chemical

Drop casting

1.71 × 10−4– 2.05 × 10−1 mg/L

492 × 10−5 mg/L Yuan et al. (2015)

Paracetamol

Electrochemical

CuNPs-fullerene/ MWCNTs modified GCE

Chemical

Mix

4 × 10−9–4 × 10−7 M

7.3 × 10−11 M

Brahman, Suresh, Lokesh, and Nizamuddin (2016)

Dexamethasone

Electrochemical

Fullerene-C60-modified Chemical pyrolytic graphite electrode

Drop casting

0.05–100 μM

55 nM

Goyal, Gupta, and Chatterjee (2009)

Zolmitriptan

Electrochemical

AgNPs-MWCNTs modified Chemical GCE

Drop casting

10−8–8 × 10−7 M

1.47 × 10−9 M

Karadas, Bozal-Palabiyik, Uslu, and Ozkan (2013)

Levodopa

Electrochemical

Organic nucleophilic functionalized carbon nanotube modified GCE

Enzyme

Drop casting

0.1–1.9 μM

40 nM

Shoja, Rafati, and Ghodsi (2016b)

Diclofenac sodium

Electrochemical

AgNPs/MWCNTs modified GCE

Chemical

Electrodeposition

0.03–200 μM

0.02 μM

Afkhami et al. (2016)

Artesunate

Electrochemical

GO-PANI modified ITO

Chemical

Electrochemical deposition

0.05–0.40 ng/mL

0.012 ng/mL

Radhapyari et al. (2013)

Paracetamol

Electrochemical

Pd/GO modified GCE

Chemical

Drop casting

0.005–0.5 μM 0.5–80 μM

2.2 nM

Li, Liu, et al. (2014)

Ractopamine

Electrochemical

Mn2(PO4) nanoflowers modified GCE

Antibody

Drop casting

0.01–1000 ng/mL

9.32 pg/mL

Zhang et al. (2015)

Acetaminophen

Electrochemical

N-doped carbon nanotubes-MnFe2O4 NPs modified GCE

Chemical

Drop casting

10−6–10−3 M

0.83 μM

Fernandes et al. (2015)

Paracetamol

Electrochemical

MWCNTs modified GCE

Chemical

Drop casting

2 × 10−10–2.5 × 10−8 M 9 × 10−11 2.5 × 10−8– 1.5 × 10−5 M

Kutluay and Aslanoglu (2013)

Continued

TABLE 1  Nanomaterial modification methods and strategies—cont’d Analyte

Detection principle

Acyclovir

Principle

Biomolecule

Electrochemical

Tiron-doped polypyrrole MWCNTs modified GCE

Chemical

Cefixime

Electrochemical

2-Aminoethanethiol functionalized MWCNTs modified GCE

Norfloxacin

Electrochemical

Cefixime

Immobilization technique

Linear Range

Detection limit Ref.

Electro­ polymerization

0.03–10 μM

10 nM

Shahrokhian, Azimzadeh, and Amini (2015)

Chemical

Drop casting

10−10–10−8 M

2.2 × 10−11 M

Yola, Eren, and Atar (2014)

MWCNTs-MIP modified GCE

Chemical

Electro­ polymerization

10−7–8 × 10−6 M

4.6 × 10−8 M

Silva, Pacheco, Silva, Viswanathan, and Delerue-Matos (2015)

Electrochemical

NiFe2O4 magnetic NPsMWCNTs modified GCE

Chemical

Drop casting

0.1–100 μM 100–600 μM

0.02 μM

Ensafi and Allafchian (2013)

Valganciclovir

Electrochemical

MWCNTs modified GCE

Chemical

Drop casting

7.50 × 10−9–10−6 M

1.52 × 10−9 M

Dogan-Topal, BozalPalabıyık, Uslu, and Ozkan (2013)

Dopamine

Electrochemical

MWCNTs/poly(glycine) modified GCE

Chemical

Electro­ polymerization

5 × 10−7–4 × 10−5 M

1.2 × 10−8 M

Thomas et al. (2013)

Cisplatin

Electrochemical

MWCNTs modified SPCE

Chemical

Drop casting

1.45 × 10−5–10−4 M

4.6 × 10−6 M

Materon, Wong, Klein, Liu, and Sotomayor (2015)

Methimazole

Electrochemical

MWCNTs-rutin modified GCE

Chemical

Drop casting

0.1–26 μM

18 nM

Dorraji and Jalali (2015)

Diclofenac

Electrochemical

MWCNTs/Cu(OH)2 NPs/ Chemical ionic liquid nanocomposite GCE

Drop casting

0.18–119 μM

0.04 μM

Arvand et al. (2012)

Artemisin

Electrochemical

Polymer polyhydroxyalkanoategold nanocomposite ITO electrode

Enzyme

Drop casting

0.01–0.08 μg/mL

0.0035 μg/mL

Phukon, Radhapyari, Konwar, and Khan (2014)

Acetaminophen Pyridoxine

Electrochemical

Functionalized CNTs/ poly(methylene green)/ graphite composite electrode

Chemical

Drop casting

30–200 μM 0.1–0.6 mM

4.3 μM 9.4 μM

Barsan, Toledo, and Brett (2015)

Paracetamol

Electrochemical

Platinum decorated MWCNTs/Triton X-100 CP matrix

Chemical

Drop casting

0.09–10 μM

17.71 nM

D’Souza et al. (2015)

Furosemide

Electrochemical

Carboxyl-MWCNT modified GCE

Chemical

Drop casting

0.03–140 μg/mL

0.007 ng/mL

Heidarimoghadam and Farmany (2016)

Brucine

Electrochemical

SWCNTs-nafion modified GCE

Chemical

Drop casting

1–8000 nM

0.11 nM

Savalia and Chatterjee (2017)

Paracetamol

Electrochemical

Poly(4-vinyl pyridine)/ MWCNTs modified GCE

Chemical

Drop casting

0.02–450 μM

1.69 nM

Ghadimi et al. (2013)

Cardiolipin

Electrochemical

AuNPs modified SPE

Chemical

Polymerization

2–60 pM

1.2 pM

Chandra, Zaidi, Noh, and Shim (2011)

Clonazepam

Electrochemical

AgNPs/MWCNT nanocomposite modified GCE

Chemical

Drop casting

5 × 10−8–2.5 × 10−6 M 6 × 10−9 M

Habibi and Jahanbakhshi (2014)

Morphine Codeine

Electrochemical

MWCNTs modified SnO2Zn2SnO4 nanocomposite paste electrode

Chemical

Mix

0.1–310 μM 0.1–600 μM

0.009 μM 0.009 μM

Taei, Hasanpour, Hajhashemi, Movahedi, and Baghlani (2016)

Codeine Caffeine

Electrochemical

SWCNT modified carbon ceramic electrode

Chemical

Drop casting

0.1–230 μM 0.4–300 μM

0.11 μM 0.25 μM

Habibi, Abazari, and Pournaghi-Azar (2014)

Paracetamol Cetirizine Phenylephrine

Electrochemical

MWCNTs-PtNPs modified CPE

Chemical

Mix

3.51 × 10−7– 5.61 × 10−5 M 1.9 × 10−71.93 × 10−4 M 2.9 × 10−7– 5.69 × 10−5 M

2.79 × 10−8 M 5.86 × 10−8 M 283 × 10−8 M

Kalambate and Srivastava (2016)

Paracetamol

Electrochemical

MWCNTs-graphene nanosheet nanocomposite modified electrode

Chemical

Drop casting

0.8–110 μM

0.1 μM

Arvand and Gholizadeh (2013)

Diclofenac

Electrochemical

MWCNTs-ionic liquid modified CPE

Chemical

Mix

0.3–750 μM

0.09 μM

Goodarzian et al. (2014)

Valganciclovir

Electrochemical

MIP composed of 2,2′-dithiodianiline and AuNPs modified GCE

Chemical

MIP

1–500 nM 500–2000 nM

0.3 nM

Gholivand and Torkashvand (2016)

64

2.  Immobilization Techniques of Nanomaterials

with MWCNTs decorated with Prussian blue nanoparticles. Prussian blue (PB) was utilized as an electron transfer mediator due to its good electrocatalysis feature. However, it has low conductivity and low stability. The use of MWCNTs with high conductivity prevents these drawbacks. During the preparation of the electrode, 5 μL PB/MWCNT nanocomposite was dropped on the electrode and dried at room temperature (Sgobbi et al., 2016). Another sulfamethoxazole biosensor was prepared by mixing MWCNTs in paste electrode constituents (Amiri-Aref et al., 2013). An enantioselective and sensitive amperometric biosensor was fabricated for the detection of chiral antibiotic ofloxacin. The principle of this biosensor was based on a dual amplification strategy using multiwall carbon nanotubes-poly(l-lysine) as a matrix. The MWCNTs were negatively charged by their carboxylic acid groups and the PLL film was positively charged by its amino groups; the MWCNTs/PLL film can be tightly formed on the electrode surface. This matrix was used for the immobilization of the antigen and multienzyme-­antibody functionalized gold nanoflowers as an electrochemical detection label. HRP molecules on gold nanoflowers reduces H2O2 and provided the determination of ofloxacin. This developed biosensor showed a response to S-OFL and R-OFL in the range from 0.26 to 25.6 ng/mL and 0.37 to 12.8 ng/mL. In addition, the detection limits were 0.15 and 0.30 ng/mL, respectively (Fig. 2) (Zhang et al., 2015).

FIG. 2  Schematic representation of OFL immunosensor.



2  Nanomaterials Used in Biosensors for Pharmaceutical Detection

65

The nonsteroidal prostate anticancer drug nilutamide was detected by using a GCE electrode modified with functionalized MWCNTs. The functionalized MWCNTs had excellent electrocatalytic activity to nilutamide. This biosensor had wide detection ranges (0.01–21 and 28–535 μM) and low LOD (0.2 nM). Furthermore, this biosensor was successful in serum and tablet samples (Karthik et al., 2017). ZrO2 had good conductivity and had large surface area when utilized in composites that made it an attractive material in biosensing applications. Baytak et al. (2016) developed a sensor by using a GCE modified with MWCNTs and ZrO2 NPs composite. A linear calibration range (10–160 nM) was found between the current and the terbutaline concentration (Baytak et al., 2016). A GCE modified with graphene nanosheets and carbon nanospheres/chitosan composite was developed for mebendazole detection and the principle of this biosensor was the electrooxidation of mebendazole. The detection limit was 10.5 nM (Ghalkhani & Shahrokhian, 2013). In another study, a CNT-modified GCE was developed by Ghalkhani et al. (2016). The detection principle was the same. The detection limit was 19 nM. The low LOD of the first biosensor originated from the features of graphene (Ghalkhani et al., 2016). An electrochemical warfarin sensor was developed by Gholivand and MohammadiBehzad (2015) with a GCE modified with CdS-quantum dots-MWCNTs/chitosan. As shown in Fig. 3, the electrode preparation of the biosensor was based on the drop casting method. Also, functionalized MWCNTs were cast on the electrode surface. Then, chitosan was electrodeposited on this electrode. The resulting electrode was immersed into a solution containing CdS-QDs in the presence N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS). CdQDs were bound covalently to the carboxylic groups of functionalized MWCNTs. This biosensor had a wide linear range of 0.05–80 μM and a low detection limit of 8.5 nM (Gholivand & Mohammadi-Behzad, 2015).

FIG. 3  Schematic representation of warfarin sensor.

66

2.  Immobilization Techniques of Nanomaterials

Bismuth nanoparticles (BiNPs) are innovative materials and have excellent properties, such as biocompatibility, electrocatalytic activity, good conductivity, and large surface area. Nigović et  al. (2017) used a BiNP-CNT composite for the detection of sulfasalazine. This nanocomposite modified surface showed excellent synergy, remarkable electrochemical properties, and an increased voltammetric response to the drug. For the preparation of the biosensor, BiNP-CNT/GCE composite was dropped on the electrode surface. This biosensor had a wide linear range and low LOD (Nigović et al., 2017) 2.4.2  Electrochemical Deposition Electrochemical deposition is an important technique to modify an electrode surface. The electrochemical deposition of gold nanoparticles is usually utilized as a modification strategy in the literature. The reason for the use of AuNP deposition is the good conductivity and large adsorption capacity of AuNPs (Yan et  al., 2016). Yan et  al. (2016) fabricated an electrochemical aptasensor for chloramphenicol and oxytetracycline detection. In this study, high-capacity, magnetic, hollow, porous nanotracers coupled with exonuclease-assisted target recycling was utilized to improve sensitivity (Fig.  4). Liu et  al. (2017) used GR-3D Au nanocomposite to improve the electron transfer and loading capacity of biomolecules. GR-3D Au nanocomposite was immobilized on the GCE surface by a one-step electrochemical coreduction (Liu et al., 2017).

FIG. 4  Schematic representation of the simultaneous detection of chloramphenicol and oxytetracycline.



2  Nanomaterials Used in Biosensors for Pharmaceutical Detection

67

In the study of Torno-de Roman (2016), an electrochemical deposition of AuNPs was performed on the carbon working electrode. In this study, tyrosinase was used as the biorecognition molecule. Tyrosinase was crosslinked to SPCE and sulfamethoxazole was measured amperometrically (Afkhami et al., 2016). Zidovudine is the first drug approved for the treatment of HIV virus infection. The determination of this drug in serum is important for human health. Rafati and Afraz (2014) developed a silver nanofilm/MWCNT nanocomposite biosensor for zidovudine detection. The use of silver nanostructures provided biocompatibility and improved the chemical, electrical, and electrocatalytic properties. The large surface-to-volume ratio enhanced the signal because many analyte molecules interact with the nanostructures (Rafati & Afraz, 2014). 2.4.3  Electrochemical Polymerization Electropolymerization is an effective and successful strategy to form a polypyrrole (PPy) film using an anodic potential in a solution containing pyrrole and an anionic dopant. The selection of the anionic dopant is important for the preparation of an adherent and conductive film, and influences the deposition yield, morphology, and electrical neutrality of the electropolymerized PPY film (Yola et al., 2014). PPy and CNT composite have a lot of advantages, such as good electrocatalytic activity, good stability, and good reproducibility, strong adherence to the electrode surface, a lot of active sites, high electrical conductivity, nanoporosity, and large surface area. These features provide the unique performance of electrodes modified with PPy/CNT for sensor applications. Moreover, CNTs provide a backbone for a homogenous deposition of PPy. Conducting polymers are important electrode materials due to their charge transfer properties and biocompatibility (Aydın, Aydın, & Sezgintürk, 2017). Bayram and Akyilmaz (2016) deposited carboxylated MWCNTs and aniline on a gold electrode. ZnO nanoparticles have a large surface area, which enhances the interaction between immobilization matrix materials and desired analytes; thus, they provide high sensitivity analysis and their small size provides fast adsorption/desorption kinetics and also rapid response time. Polypyrrole (PPy) is a conductive polymer that has high stability. The combination of ZnO nanoparticles and PPy increases the stability of the sensor. Hassanein et al. (2017) fabricated a sensitive conductive nanocomposite sensor based on chitosan, ZnO nanoparticles, and PPy nanocomposite. The matrix material preparation method was based on the oxidative polymerization of pyrrole (Hassanein et al., 2017). Poly 1,5-diaminonapthalene and CNT were electropolymerized on the graphite electrode. This composite film had an efficient catalytic response to electro-oxidation of sulfacetamide (SFA). The peak current of SFA was linear in the concentration range of 0.005–1.5 mM and this biosensor had low LOD (0.11 μM) (Yadav et al., 2014). In the study of Radhapyari et al. (2013), an electropolymerized GrO-PANI nanocomposite film on an ITO electrode was used as an immobilization matrix. The biorecognition molecule was HRP enzyme and it was immobilized on this electrode by an adsorption technique. Electrochemical impedance spectroscopy was used as a detection method. The biosensor had a linear range between 0.05 and 0.40 ng/mL (Radhapyari et  al., 2013). An interesting study was performed by Shoja et  al. (2016a) for sertraline detection in human serum. For the construction of the biosensor, firstly they modified a GCE with MWCNTs by the drop casting method, then they electrodeposited AuNPs on this modified electrode. After that, Ni(II)-levodopa film was electropolymerized on the GCE. This Ni(II)-LD/AuNPS/MWCNT

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­ anocomposite had high electrocatalytic activity toward sertraline oxidation. Differential n pulse voltammetry was utilized to determine sertraline in the range of 0.05–5.5 μM with a low LOD (95 nM) (Shoja et al., 2016a). 2.4.4  Molecularly Imprinted Polymer Molecularly imprinted polymers are synthetic materials, which recognize the target analyte molecule by generation recognition regions. They mimic biorecognition elements, such as antibodies, hormones, and enzymes. The advantages of this method are easy preparation, low cost, and high chemical and mechanical stability. For the construction of MIP-based biosensors, imprinted polymeric film is electropolymerized on the electrode surface. In this fabrication process, the polymer thickness can easily be controlled by changing the experimental conditions (Shoja et al., 2016a). Molecularly imprinted polymers are utilized as recognition elements, targeting small-sized analytes that are technically difficult to imprint. MIP-based sensors show high specificity and low sensitivity. Munawar et al. (2018) developed 3D composite/MIP structures for chloramphenicol detection. After functionalization of CNTs with amino groups, reaction centers for the deposition of CuNPs were generated. This composite material was employed to design a nanohybrid material with MIP (Shoja et al., 2016a). For molecularly imprinted electrochemical sensor preparation, polypyrrole is widely electropolymerized. PPy is a biocompatible material and feasible for the immobilization of different compounds. Furthermore, PPy-imprinted polymer is stable, robust, and resistant to experimental conditions. PPy has been utilized in the construction of biosensors for pharmaceutical detection. The use of MIP improves the selectivity and sensitivity of the biosensor. However, to improve the performance of the biosensor, different nanomaterials, such as graphene, MWCNTs, and metallic NPs, have been used. Among these nanomaterials, MWCNTs are the most popular material because they facilitate electron transfer reactions owing to their excellent mechanical strength, good electrical conductivity, large surface area, and excellent chemical stability. Silva, Zanin, et al. (2015) developed a MIP-based electrochemical sensor with MWCNTs deposited on the electrode. A molecularly imprinted film was constructed by electropolymerization via cyclic voltammetry of pyrrole in the presence of norfloxacin as a template molecule. This developed biosensor had a linear range between 10−7 M and 8 × 10−6 M, with a low LOD (4.6 × 10−8 M) (Silva, Zanin, et al., 2015). The molecular imprinting technique has been utilized for molecular recognition and this technique creates specific cavities in cross-linked polymeric matrices. Yola et al. (2014) developed a sensitive imprinted electrochemical biosensor based on Fe@AuNPs-2-aminoethanethiol functionalized MWCNTs for cefexime detection (Yola et al., 2014). Norfloxacin is a synthetic fluoroquinolone antibiotic and shows broad spectrum antimicrobial activity to gram-negative and gram-positive bacteria. Agrawal, Chandra, Goyal, and Shim (2013) developed an MWCNT-modified pyrolytic graphite electrode for norfloxacin detection (Agrawal et al., 2013). In the study of Devaraj et al. (2013), CuO nanoleaves and a GCE modified with MWCNTs was used for norfloxacin detection (Devaraj et al., 2013). The detection limits were 40.6 and 0.03 nM, respectively. The low detection limit of this biosensor originated from the conductivity of the CuO nanoleaves. It increased the conductivity and electrochemical properties of the electrode. Tramadol is a synthetic monoamine uptake inhibitor that is utilized for pain treatment. A nano-molecularly imprinted bead polymer was prepared and used for the construction of



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a chemically modified carbon paste electrode. Molecularly imprinted polymer with a molecular recognition cavity was fabricated using SiO2@Fe3O4 as the core and the supporting material. The carbon paste electrode modified by molecularly imprinted polymer and multiwalled carbon nanotubes was constructed by a combination of MIP and MWCNTs in the CPE (Afkhami et al., 2013). Deiminiat et al. (2017) fabricated an electrochemical imprinted sensor for tramadol detection. They used a functionalized MWCNT layer and a thin molecularly imprinted film. This thin film of molecularly imprinted polymer was formed from polypyrrole. The detection limits were 4 and 0.03 nM, respectively. The low detection limit originated from the superior properties of CNTs (Deiminiat et al., 2017). Shahrokhian et al. (2015) developed a voltammetric biosensor based on a MWCNT-coated GCE electrode. For construction of the MIP, tiron-doped polypyrrole was electropolymerized for acyclovir detection. This biosensor was utilized for a highly sensitive detection of acyclovir in pharmaceuticals and plasma. This biosensor had a wide linear range (0.03–10 μM) and a low detection limit (10 nM) (Silva, Zanin, et al., 2015). 2.4.5  Self-Assembly and Adsorption of Nanomaterials SAMs provide a simple and widely utilized method of immobilizing nanomaterials onto electrodes and they allow for the control of the composition and thickness of the transducer surface (Putzbach & Ronkainen, 2013). The self-assembly of cysteine on gold electrodes has been used in many applications. Cysteine is a hydrophobic amino acid that allows it to interact with different chemical molecules. The stable, well-organized, and densely packed SAMs formed by cysteine on the gold electrode. This process provides selective, sensitive, and rapid analysis. Asadollahi-Baboli and Mani-Varnosfaderani (2014) constructed gold NP film on a cysteine-modified gold electrode. An amperometric penicillin sensor was developed by Chen et  al. (2010). They coimmobilized multiwalled carbon nanotubes, hematein, and β-lactamase on a GCE using a layerby-layer assembly method. Penicillinase was used as a biorecognition element. It catalyzed penicillin and caused a decrease in the pH. The pH change was followed amperometrically. Hematein was used as a pH-sensitive redox probe. MWCNTs were utilized for electron transfer enhancement and an effective immobilization material (Chen et al., 2010). Another penicillin biosensor was fabricated by Li et  al. (2015). Anti-Penicillin G antibodies were used as biorecognition elements and immobilized on a bilayer lipid membrane modified with AuNPs. The NPs-modified bilayer lipid membrane improved the mechanical, electrical, and optical features. Furthermore, it was biocompatible and increased the electrochemical signal (Fig. 5) (Li et al., 2015). Furthermore, layer-by-layer (LBL) self-assembly is a promising technique for the fabrication of multifunctional nanocomposite films. The disadvantages of this technique include loose interactions and having poor stability and reproducibility. An MWCNT film layer modified with carboxylic acid was assembled using a layer-by-layer technique on a GCE. Li, Feng, et al. (2014) fabricated this biosensor for paracetamol detection. This modified electrode had a remarkable electrocatalytic activity to paracetamol detection. An acetylcholinesterase biosensor was fabricated to detect carbamate drugs, including serine and neostigmine. The detection principle of the biosensor was based on the electrocatalytic oxidation of tetrathiafulvalene/tetracyanoquinodimethane (TTF/TCNQ)/ionic liquid gel. Very low detection limits of 26 pM eserine and 0.3 nM neostigmine were obtained (Zamfir et al., 2013).

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FIG. 5  Schematic representation of AuNPs-modified bilayer lipid membrane.

The use of CNT/IL-based composite materials in biosensor construction has three advantages: (i) long-term stability due to mechanical, electrical, and thermal features of CNT, (ii) good solvent and conductivity features of ILs, and (iii) convenient interaction between CNTs and ILs (Rahimi-Nasrabadi et al., 2017). Fullerene-modified CNTs/IL nanocomposite was used as an electrode matrix material. This biosensor was used for diazepam detection. Fullerene-functionalized CNTs and ionic liquid has high electrocatalytic activity toward the reduction of diazepam. The electrocatalytic current increased linearly with diazepam concentration in the range of 0.3–700 μM. The detection limit was 87 nM (Madrakian, Soleimani, & Afkhami, 2015). 2.4.6  Addition Nanomaterials in Carbon Paste Electrodes A carbon paste electrode (CPE) is a heterogeneous carbon electrode composed of a mixture that includes carbon powder (graphite and other carbonaceous materials) and a proper waterimmiscible or nonconducting binder. The use of carbon paste as an electrode material was first reported in 1958 by Adams. After many research studies, several modifiers, including enzymes, polymers, and nanomaterials, have been utilized with these versatile electrodes. CPEs are suitable in both electrochemical studies and electroanalysis due to excellent properties, such as very low background current (compared with solid graphite or noble metal electrodes), ease of preparation, low cost, large potential window, simple surface renewal process, and simple miniaturization. Apart from these advantages, different substances during the paste preparation (modified carbon paste electrode) allow the construction of electrodes with the desired composition (Beitollahi et al., 2014). The success of the operation mechanism of a CPE depends on the modifier materials used. These modifier materials affect the selectivity and the sensitivity of the biosensor (Soleymanpour & Rezvani, 2016). An interesting magneto carbon paste electrode (MMW/CPE) was developed by Madrakian, Haghshenas, et al. (2015) for mefenamic acid (MFA) detection. Firstly, magnetic molecularly imprinted polymer NPs were synthesized and then added to the MFA solution. Then, the MMW/CPE was immersed in MFA solution and magnetic molecularly imprinted polymer NPs were captured by this electrode (Fig.  6). For the carbon paste electrode preparation, MWCNTs were added to mineral oil and graphite powder and formed a CPE (Madrakian, Haghshenas, et al., 2015).



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FIG. 6  Schematic representation of biosensor for mefenamic acid detection.

Beitollahi et  al. (2014) developed a benzoyl ferrocene-modified CNT paste electrode for captopril detection. The electrochemical behavior of captopril was examined by cyclic voltammetry. To analyze the effects of benzoyl ferrocene and CNTs, a benzoyl ferrocene-­modified CPE without CNTs, a carbon nanotube paste electrode without benzoyl ferrocene, and an unmodified CPE in the absence of both benzoyl ferrocene and CNTs were constructed. The results obtained showed that the biosensor modified with benzoyl ferrocene and CNTs had improved performance toward captopril oxidation (Arvand et  al., 2011). In another study, Karimi-Maleh, Tahernejad-Javazmi, Ensafi, et al., 2014 developed a piroxicam biosensor that was prepared by mixing graphite powder and FePt/CNTs nanomaterial.

3 CONCLUSION Recent advances in technology provide easy detection of pharmaceuticals in several types of samples. For the detection of pharmaceuticals, usually traditional techniques are used. Because of some disadvantages, such as long analysis time, expensive equipment, and the requirement for specialized personnel, biosensors have been developed to overcome these drawbacks. This chapter summarizes the recent advances in biosensors modified with nanostructured materials for the sensing or biosensing of pharmaceuticals. It also highlights the main role of nanomaterials in the preparation of biosensors. A variety of studies, discussed above, illustrate that nanomaterials improve the performance of biosensors and have positive effects on the sensitivity, reproducibility, selectivity, and stability of biosensors.

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In the next few years, effective technology will provide rapid production of nanomaterialbased biosensors with high-quality specifications at low cost. Furthermore, by using these techniques, the developed biosensors can be commercialized. Future innovative research will focus on developing multifunctional nanomaterials to make biosensors more robust. Such robust biosensors will be more suitable for applications employing real samples.

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An electrochemical sensor prepared by sonochemical one-pot synthesis of multiwalled carbon nanotube-supported cobalt nanoparticles for the simultaneous determination of paracetamol and dopamine. Analytica Chimica Acta, 839, 59–66. Lan, L., Yao, Y., Ping, J., & Ying, Y. (2017). Recent advances in nanomaterial-based biosensors for antibiotics detection. Biosensors and Bioelectronics, 91, 504–514. Li, Y., Feng, S., Li, S., Zhang, Y., & Zhong, Y. (2014). A high effect polymer-free covalent layer by layer self-assemble carboxylated MWCNTs films modified GCE for the detection of paracetamol. Sensors and Actuators B: Chemical, 190, 999–1005. Li, J., Liu, J., Tan, G., Jiang, J., Peng, S., Deng, M., … Liu, Y. (2014). High-sensitivity paracetamol sensor based on Pd/ graphene oxide nanocomposite as an enhanced electrochemical sensing platform. Biosensors and Bioelectronics, 54, 468–475. Li, H., Xu, B., Wang, D., Zhou, Y., Zhang, H., Xia, W., … Li, Y. (2015). 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Luo, Z., Wang, Y., Lu, X., Chen, J., Wei, F., Huang, Z., … Duan, Y. (2017). Fluorescent aptasensor for antibiotic detection using magnetic bead composites coated with gold nanoparticles and a nicking enzyme. Analytica Chimica Acta, 984, 177–184. Madrakian, T., Haghshenas, E., Ahmadi, M., & Afkhami, A. (2015). Construction a magneto carbon paste electrode using synthesized molecularly imprinted magnetic nanospheres for selective and sensitive determination of mefenamic acid in some real samples. Biosensors and Bioelectronics, 68, 712–718. Madrakian, T., Soleimani, M., & Afkhami, A. (2015). Electrochemical determination of fluvoxamine on mercury nanoparticle multi-walled carbon nanotube modified glassy carbon electrode. Sensors and Actuators B: Chemical, 210, 259–266. Mannini, M. (2009). Molecular magnetic materials on solid surfaces. Firenze University Press. Mao, A., Li, H., Jin, D., Yu, L., & Hu, X. (2015). Fabrication of electrochemical sensor for paracetamol based on multiwalled carbon nanotubes and chitosan–copper complex by self-assembly technique. Talanta, 144, 252–257. Marco, J. P., Borges, K. B., Tarley, C. R. T., Ribeiro, E. S., & Pereira, A. C. (2013). Development of a simple, rapid and validated square wave voltametric method for determination of promethazine in raw material and pharmaceutical formulation using DNA modified multiwall carbon nanotube paste electrode. Sensors and Actuators B: Chemical, 177, 251–259. Materon, E. M., Wong, A., Klein, S. I., Liu, J., & Sotomayor, M. D. (2015). Multi-walled carbon nanotubes modified screen-printed electrodes for cisplatin detection. Electrochimica Acta, 158, 271–276. Munawar, A., Tahir, M. A., Shaheen, A., Lieberzeit, P. A., Khan, W. S., & Bajwa, S. Z. (2018). Investigating nanohybrid material based on 3D CNTs@ Cu nanoparticle composite and imprinted polymer for highly selective detection of chloramphenicol. 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Determination of ganciclovir as an antiviral drug and its interaction with DNA at Fe3O4/carboxylated multi-walled carbon nanotubes modified glassy carbon electrode. Measurement, 77, 269–277. Phukon, P., Radhapyari, K., Konwar, B. K., & Khan, R. (2014). Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin. Materials Science and Engineering: C, 37, 314–320. Putzbach, W., & Ronkainen, N. J. (2013). Immobilization techniques in the fabrication of nanomaterial-based electrochemical biosensors: A review. Sensor, 13(4), 4811–4840. Radhapyari, K., Kotoky, P., Das, M. R., & Khan, R. (2013). Graphene–polyaniline nanocomposite based biosensor for detection of antimalarial drug artesunate in pharmaceutical formulation and biological fluids. Talanta, 111, 47–53. Rafati, A. A., & Afraz, A. (2014). Amperometric sensing of anti-HIV drug zidovudine on Ag nanofilm-multiwalled carbon nanotubes modified glassy carbon electrode. Materials Science and Engineering: C, 39, 105–112. Rahi, A., Karimian, K., & Heli, H. (2016). Nanostructured materials in electroanalysis of pharmaceuticals. Analytical Biochemistry, 497, 39–47. Rahimi-Nasrabadi, M., Khoshroo, A., & Mazloum-Ardakani, M. (2017). Electrochemical determination of diazepam in real samples based on fullerene-functionalized carbon nanotubes/ionic liquid nanocomposite. Sensors and Actuators B: Chemical, 240, 125–131. Ramezani, M., Danesh, N. M., Lavaee, P., Abnous, K., & Taghdisi, S. M. (2015). A novel colorimetric triple-helix molecular switch aptasensor for ultrasensitive detection of tetracycline. Biosensors and Bioelectronics, 70, 181–187. Reddy, K. K., Satyanarayana, M., Goud, K. Y., Gobi, K. V., & Kim, H. (2017). Carbon nanotube ensembled hybrid nanocomposite electrode for direct electrochemical detection of epinephrine in pharmaceutical tablets and urine. Materials Science and Engineering: C, 79, 93–99. Saha, M. (2012). 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C H A P T E R

3 The Effect of Nanomaterials on the Drug Analysis Performance of Nanosensors Tayyaba Kokab⁎, Azeema Munir⁎, Afzal Shah⁎,†, Sevinc Kurbanoglu‡, Muhammad Abid Zia§, Sibel A. Ozkan‡ ⁎

Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan †Department of Chemistry, College of Science, University of Bahrain, Sakhir, Bahrain ‡Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey §University of Education Attock Campus, Attock, Pakistan

1 INTRODUCTION Chemical compounds, such as pesticides, drugs, proteins, nucleic acids, metabolites, pollutants, food additives, explosives, and others must be frequently checked by sensors as they may cause a risk to human health, public safety, and the ecosystem (Rodrigues & Mota, 2016). A sensor that is capable of measuring a physical quantity consists of an active detecting material and a signal transducer to produce output signals in the form of electrical, thermal, mechanical, or optical signals, which are then processed and displayed on a digital readable system. The sensitivity, selectivity, resolution power, response time, calibration characteristics, linearity, repeatability, stability, and efficiency of a sensor depend upon the nature of its active sensing material. Stimuli-responsive materials can undergo alteration in one or more of their physicochemical features corresponding to size, structure, solubility, permeability, and electrical, mechanical, or optical properties in response to external stimuli, such as electric field, light, temperature, pH, biological signals, and magnetic fields. Sensors may be either direct or indirect, such as active and passive sensors (Khanna, 2012). However, depending upon their active material sensing abilities, they may be electrical, optical, mechanical, chemical, electrochemical, photo-­electrochemical, bio-catalytic, fluorescent, plasmonic, surface-enhanced Raman (SER), or biosensors. For example, ion-sensitive sensors can detect the activity of ions in a sample solution and transduce it into an electrical signal. Chemical sensors convert bio/chemical data into

New Developments in Nanosensors for Pharmaceutical Analysis https://doi.org/10.1016/B978-0-12-816144-9.00003-1

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Copyright © 2019 Sibel A. Ozkan and Afzal Shah. Published by Elsevier Inc. All rights reserved.

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3.  The Effect of Nanomaterials on the Drug Analysis Performance of Nanosensors

an analytical signal when there are some interactions between chemical or biochemical species with the sensor surface, for example, in a pH sensor. Therefore, electrochemical sensors are the most common analytical approach for biological samples in which an electrode acts as a signal transducer and the response is measured in the form of electrical parameters (I, V, R, Cp) that can be used to detect analytes in any physical state (gas, liquid, solid). Moreover, the selectivity of the sensors toward a specific analyte can be achieved by immobilization of a unique recognizer group, that is, a receptor/ligand/probe on the sensor surface that can detect a single analyte with high affinity and specificity (Khanna, 2012).

1.1  Nanomaterials Used for Sensor Development Microsensors of 1 mm to 100 nm and nanosensors with dimensions under 100 nm, are miniaturized devices developed from the evolution of technology from the macroscale to the nanoscale (Meixner, 2008). The design and development of chemical and electrochemical sensors at the nanoscale is the most typical strategy to improve their sensing features. The increased surface area of the sensor makes it more exposed to analyte species and produces superior capabilities to detect analytes at lower concentrations (Yonzon et al., 2005). Some examples of nanoscale materials are: (1) zero-dimensional (0D) nanostructures, such as nanoporous material, core/shell NPs, and NPs dispersed in materials; (2) one-dimensional (1D) structures, such as graphene sheets, nanolayers, and thin films; (3) two-dimensional (2D) structures, such as carbon or metallic nanotubes and nanowires; and (4) three-dimensional (3D) structures, such as gold or silver NPs, quantum dots, fullerenes, carbon nanodots, dendrimers, nano-diamonds, nanohorns, and nano-onions (Göpel, 1994). The features of nanomaterials that arise at the nanoscale, such as high specific surface area, and the ability to tailor the dimensions and shape, along with the structural, compositional, and multifunctional intrinsic properties, make them suitable candidates for the fabrication, design, and development of ultrasensitive electrochemical, mechanical, plasmonic, photo-biocatalytic, SER, and bio-sensors. Nanomaterials of plasmonic NPs, nanowires (NWs), polymeric NPs, liposomes, dendrimers, metallic NPs, QDs, nanotubes (NTs), magnetic NPs, nanohybrids, nanobimetallic alloys, nanocomposites, and multifunctional nanomaterials either form the active sensing layer of a sensor or they act as an effective support to bind/immobilize enzymes, catalysts, or other electrocatalytic active species to produce simple, detectable, low-cost, and reproducible sensor units (Agrawal & Prajapati, 2012). As the electrode size is decreased to nanoscale, radial (3D) diffusion becomes dominant, leading to faster reactant transport toward the electrode surface, decreased charging current, and fewer deleterious effects of solution resistance. In “Pharmaceutical Nanotechnology,” nanosensors, nanobiosensors, nanoprobes, nanoelectrodes, or nanoelectrochemical sensors are used for analyzing and detecting biomolecules, viruses, bacteria, biomarkers, cancer, or other infectious diseases, as well as drugs and their excipients in biological samples, both qualitatively and quantitatively. They mostly consist of nanostructure-based electrodes used in electrochemical techniques, such as voltammetry, amperometry, electrochemical impedance spectroscopy (EIS), potentiometry, polarography, electrochemiluminescence, and conductometry with a signal-transduction mechanism, or SPR, SER, and SEF plasmonic sensors (Bhatia, 2016). In Table 1, some selected electrochemical nanosensors have been summarized that are based on single NPs up to nanocomposite active materials with structure variations from simple to complex morphologies (Scheme 1).

Nanosensor

Technique

Analyte

Medium

Linear Range

LOD/LOQ

Application

Ref

1.

AgNP/ MWCNT/GCE

CV, DPV

Zolmitriptan

pH 7.0

0.01–0.8 μM

1.47 nM

Tablets/human urine

Karadas, BozalPalabiyik, Uslu, and Ozkan (2013)

2.

ILMWCNTPE

CV, SWV

Methyldopa

pH 7.0

0.4–400 μM

1 μM

Tablets/patient urine

Fouladgar and Karimi-Maleh (2013)

3.

MC1R-Ab/nSiNPs/PPy/ SPE

CV

Melanoma cells

pH 7.4

50–7500 cells/2.5 mL

–

Cancer diagnosis Seenivasan, Maddodi, Setaluri, and Gunasekaran (2015)

4.

PPO/Fe3O4NPZnO/ZnHCF/ PtE

CV, EIS,

Acetaminophen

pH 7.0

0.04–10,000 μM

0.04 μM

Medicine

Seenivasan et al. (2015)

5.

ZnO nanotubes

Potentiometric

Iodide ion

–

1–10,0000 μM

0.5 μM

Pharmaceutical products

Ibupoto, Khun, and Willander (2013)

6.

Cu NWs/CPE

CV, FFT-SWV

Trifluralin

pH 4.0

2 × 10−2–100 nM

8 pM

Urine and plasma

Mirabi-semnakolaii et al. (2011)

7.

Carbon film electrode

CV

Glucose

5–7

0–1.5 mM

60 μM

Human blood serum/saliva

Florescu and A Brett (2005)

8.

Carbon dots (C-dots)/(GCE)

ECL amplification

Glutathione

–

0.1–1.0 μM

54.3 nM

Biological samples

Niu, Zhu, Cosnier, Zhang, and Shan (2015)

9.

ssDNA/MPTS/ AuNPs/SPE

DPV

Salmonella typhi

pH 7.4

1.0 × 10−2–5 nM

50 pM

Human blood serum

Das et al. (2014)

10.

Double shelled Cu/Cu2O nanoclusters/ carbon NS

Amperometry

Glucose

–

10–690 μM 1190–3690 μM

Human blood serum/saliva

Yin, Cui, Wang, and Nie (2016)

11.

Plant root nodule like NiO–MWCNT

Amperometry

Glucose

–

0.001–14 mM

Human blood serum/saliva

Prasad, Gorjizadeh, Rajarao, Sahajwalla, and Bhat (2015)

19 μM

81

Continued

1 Introduction

Sr #



TABLE 1  Some Selected Electrochemical Nanosensors From Single NPs to Nanocomposite Active Materials With Simple to Complex Morphologies

82

Sr #

Nanosensor

Technique

Analyte

Medium

Linear Range

LOD/LOQ

Application

Ref

12.

PA specific peptide/ MWCNT/ PANI/GCE

SWV

Anthrax protective antigen

pH 7.3

–

0.4 pM

Anthrax biomarker detection

Huan, Ganesh, Han, Yoon, and Chung (2011)

13.

MIP-PGE

DPV

Paracetamol

–

1.25–4.5 mM

0.79 μM

Medicine

Özcan and Şahin (2007)

14.

MWNT-COOH/ PPy/GC

CV

DNA

–

0.069–0.86 pM

0.23 mM

Biological samples

Cheng, Zhao, Tu, He, and Fang (2005)

15.

Poly (Nacetylaniline)/ CNT

CV

Hydroquinone

–

1–5000 μM

0.8 μM

Skin of Melasma patients

Kong, Yin, Liu, and Wei (2007)

16.

PPy–CNT/ NaOH

CV

Dopamine

–

0.04–1.4 μM

Up to 1.7 nM

Mammalian sample

Adekunle et al. (2011)

17.

PPy/CdS NPs

CV

ODN

–

3.7–370 nM

∼1 nM

Peptide/protein

Peng et al. (2006)

18.

MWNTs/PANI/ ClOx/GC

CV

Choline

–

1–2000 μM

0.3 μM

Vitamins

Qu, Yang, Jiang, Shen, and Yu (2005)

19.

ZnO Nanorod/ Al Ga N/Ga N

Amperometry

Glucose

7.4

0.5 nM–14.5 μM

0.5 nM

Biological samples

Kang et al. (2007)

20.

PDDA/GOx/ PDDA/CNT/ GC

Amperometry

Glucose

7.4

15 μM–6 mM

7 μM

Biological samples

Liu and Lin (2006)

21.

MWCNT-HF/ QD/PGE

DPV

Arg, Ala, Met and Cys

–

0.287–33,670 μM

0.081 μM

Protein samples

Hooshmand and Es’haghi (2017b)

3.  The Effect of Nanomaterials on the Drug Analysis Performance of Nanosensors

TABLE 1  Some Selected Electrochemical Nanosensors From Single NPs to Nanocomposite Active Materials With Simple to Complex Morphologies—cont’d



1 Introduction

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SCHEME 1  Systematic illustration of pharmaceutical nanotechnology. Reprinted with permission from the publisher (Bhatia, S. (2016). Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications. In Natural polymer drug delivery systems (pp. 33–93). Cham: Springer International Publishing. https://doi. org/10.1007/978-3-319-41,129-3_2).

1.2  Morphological and Structural Characterization Techniques for Nanomaterials Nanospheres (NPs) and nano-ellipse morphologies have the lowest shape anisotropies. Shapes with greater anisotropies include nanowires, nanofibers, nanobelts, thin films, and nanotubes, which are wires, fibers, belts, thin layers, and hollow cylindrical shapes at the nanoscale, respectively. The characterization of nanomaterial sizes, morphologies, structures, porosities, and crystalline phases is mainly carried out by means of scanning probe microscopy (SPM), scanning electron microscopy (SEM), scanning near-field optical microscopy (SNOM), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), neutron diffraction, X-ray scattering, atomic force microscopy (AFM), Raman spectroscopy (RS), UV-Vis spectroscopy, electric force microscopy (EFM), transmission electron microscopy (TEM), photoluminescence spectroscopy, fluorescence spectrometry, magnetic force microscopy, contact angle measurements, X-ray photoelectron spectroscopy (XPS), and acoustic wave techniques. Fig. 1 presents some nanomaterial morphologies characterized by SEM (Guo et al., 2015). An X-ray diffractometer is used to measure the extent of crystallinity and crystal structure in distinctive XRD patterns of nanostructures along with the average crystallite size, which can be calculated by the Debye Scherrer formula, D = Kλ/β cos θ. The shape of the unit cell fixes the Miller indices h, k, and l, which describe the d-spacing of Bragg’s law, 2d sin θ = nλ. The specific surface area measurements by the BET and Langmuir methods are important for studies of the surface reactions of NPs, anion-cation exchange, porosity, surface content, adsorption, and catalysis. The optical properties of nanomaterials can be characterized by

84 nanorods, nano-octahedrons, nanotriangles, nanodisks, core-shell nanorice, concave gold nanocuboids, nanocrescents, and branched crystalline, respectively. Reprinted with permission from the publisher (Guo, L., Jackman, J. A., Yang, H.-H., Chen, P., Cho, N.-J., & Kim, D.-H. (2015). ScienceDirect Strategies for enhancing the sensitivity of plasmonic nanosensors. Nano Today, 10, 213–239. https://doi.10.1016/j.nantod.2015.02.007).

3.  The Effect of Nanomaterials on the Drug Analysis Performance of Nanosensors

FIG.  1  SEM images of various nanostructure morphologies for nanosensors (A, E) Ag nanocubes and nanoshells (B, C, D, F, G, H, I, J) Au



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UV-Vis, electrochemiluminescence, photoluminescence, and fluorescence spectrometry, depending upon the concentrations, shapes, agglomeration states, dimensions, and refractive index. UV-Vis spectroscopy is well known as absorption spectroscopy and is used to study the optical density of nanomaterials based on the Beer-Lambert law, which states that, at constant path length, the absorbance is proportional to the amount of the absorbing species in the sample. Fluorescence and PL spectroscopies are based upon luminescence phenomena in which the photon excites the electron of a sample molecule, which then emits light in the visible region on de-excitation, with the emission intensity being monitored as a function of the emission wavelength (Barhoum & García-betancourt, 2018). Scanning probe microscopy (SPM) facilitates the identification of structural properties, as well as surface modification of a nanomaterial at the atomic scale, which helps in the creation of unusual nanostructures by atomic and molecular manipulation. Imaging techniques, such as SEM coupled with EDX, provide direct surface images, element ratios, and chemical information on a nanomaterial by electron beam interactions with the material and the generation of fast signals with a resolution limit of 1.2 nm. Furthermore, TEM gives qualitative and quantitative chemical information via high-resolution images of a sample at a resolution level of  triangular bipyramids > spheres. Nanorods possess the highest RI sensitivity because they have the highest aspect ratio. However, nanostructures having sharper tips, such as nanobranches or nanostars, can provide higher sensitivity even than nanorods (Liu & Huang, 2013). This is because the corners of triangles, as well as the edges and corners of nanorods and cubes, and the tips of nanostars and nanoprisms, have a higher concentration of EMF in LSPRs that can be tuned to achieve high sensitivity of sensors (Jeong et  al., 2016). Consequently, the morphologydependent LSPR behavior of nanostructures becomes valuable for the simultaneous ­detection

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FIG.  3  TEM images of (A) nanospheres (B) nanostars (C) their UV-vis-NIR spectra in colloidal solution and (D) cast films for SERS and SEF substrates (solid lines), laser lines used for excitation indicated by arrows. Reprinted with permission from the publisher (Rodríguez-Lorenzo, L., Álvarez-Puebla, R. A., de Abajo, F. J. G., & Liz-Marzán, L. M. (2010). Surface enhanced raman scattering using star-shaped gold colloidal nanoparticles. Journal of Physical Chemistry C, 114(16), 7336–7340. https://doi.10.1021/jp909253w).

FIG.  4  Graphical LSPR shift from bare nanotriangles and nano-hemispheres vs multilayer thickness. Reprinted with permission from publisher (Haes, A. J., Zou, S., Schatz, G. C., & Van Duyne, R. P. (2004). A nanoscale optical biosensor: The long range distance dependence of the localized surface plasmon resonance of noble metal nanoparticles. Journal of Physical Chemistry B, 108(1), 109–116. https://doi.10.1021/jp0361327).



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of various biomolecules in one solution via a mixture of nanorods with varied aspect ratio with well-separated SPR peaks (Jain et al., 2008). Furthermore, zinc oxide nanostructures, such as nanorods, nanowires, nanobelts, nanotubes, tetrapods, and nanoflowers, are extensively used as nanosensors. ZnO nanorods, by virtue of their huge surface area, interfacial electron transfers, and their waveguide structures, are used as an enhanced fluorescent (Yin et al., 2015). However, Akhtar et al. reported further enhancement of ZnO fluorescence by a synthesized ZnO nanoflower (NF) shape as the NF form has a larger surface area than a nanorod and thus possesses high sensitivity when used as a ThT fluorescence-based amyloid biosensor. ZnO nanoflowers can take many forms; commonly the petals of nanoflowers are identical to sheets or are needle shaped. The 9.8-fold increase in the intensity of fluorescence compared with the needle shape is due to the waveguiding capability of ZnO NFs as their petals act as reflecting mirrors (Akhtar, Metkar, Girigoswami, & Girigoswami, 2017). Similarly, ZnO tetrapods also have unique physicochemical performance, 3D self-assembly properties, and improved sensing abilities due to their wire-like tips with high potential barriers (Paulowicz et al., 2018). In addition, nanoshells of Gold (Au) with reduced shell thickness and a junction/hybridized nanosensor offer a nearly exponential increase in plasmonic sensitivity and hollow nanoshells, in which the medium RI changes on both surfaces, show a six times improved sensitivity compared with Au nanospheres (Jain et al., 2008). Moreover, gold nanocages, consisting of ultrathin porous walls and hollow interiors, have an optical resonance peak in the near-infrared (650–900 nm) region, which makes them suitable for biomedical sensing because this region is a transparent window for soft tissues and blood. A ligand-modified nanocage sensor applicable for targeting cancer, sentinel lymph node mapping, and photoacoustic tumor imaging was investigated. The LSPR of Au nanocages and nanorods lies at 650 nm, but the absorption cross section of a nanocage is 3.0 × 10−15 m2 and 6.0 × 10−15 m2 for 30 nm and 45 nm size, respectively. This is greater than nanorods (1.9 × 10−15 m2), as well as five times greater than conventional dye molecules, making them well suited for SLN mapping and PA imaging, as represented by Chen et al. (2010). However, Wang et al. stated that nanorice geometry exhibits the greatest sensor sensitivity compared with all other reported morphologies of metal NPs, such as triangular nanoprisms, nanorods, spherical nanoshells, and nanocubes. As nanorice “hybrid NPs” have high architecture variations that are a combination of nanorods (longitudinal and transverse tunable PR) and nanoshells (inner and outer shell surface tunable PR), the LSPR features include an intense local field and highly tunable PR, respectively (Wang, Brandl, Le, Nordlander, & Halas, 2006). Compared with nanorods and nanowires, nanotubes and nanoporous structures possess a highly dispersed structure and high surface area. Consequently, nanosensors of these structures also possess better performance and enhanced sensitivity. Nanowires made of conductive materials can work well in liquid/gas environments, but their nanopore and nanochannel forms require an ionic solution in electrochemical sensing as they become nonconductive in these forms. Nanotubes can change into nanowire and nanopore molecular wiring structures because of their convex and concave heterogeneous configuration and electrostatic screening, which becomes strong on a reduction of size due to the curvature effect (Chen, Tang, Zhan, Sun, & Hou, 2018). Patolsky et al. reported a glucose nanosensor with the alignment of GOx linked to an Au electrode via SWCNTs as electrical nanoconnectors, that is, SWCNTs electrically linked the enzyme active site and the electrode surface for electron transfer over a path

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of >150 nm in which the electron transport rate can be regulated by controlling the length of the SWCNTs (Patolsky, Weizmann, & Willner, 2004). Similarly, Kong et al. reported a sensor using GOx immobilized on ferricyanide-coated SWCNTs, based on the adsorption of glucose on its surface, and this in turn modifies the emission on charge transfer and fluorescence quenching of the PL spectrum. Ferricyanide donates electrons to the nanotubes and quenches their fluorescence when glucose is oxidized by GOx and produces H2O2, which reacts with ferricyanide and donates its electrons. As a result, the IR fluorescence of nanotubes increases depending upon the glucose concentration (Agrawal & Prajapati, 2012). Furthermore, sensors based on a nanofiber morphology respond better than nanofilms, for example, LiCl-doped TiO2 nanofibers exhibited excellent features, such as high sensitivity, faster response and stability, linearity, ultrafast recovery behavior, and better reproducibility, which can be explained by the 1D nanostructure of TiO2 fibers providing a large surface area and a fast rate of mass and charge carrier transfer compared with a 2D nanofilm (Li, Zhang, Zheng, Wang, et  al., 2008). Another example is a modified nanosensor for the analysis of glutathione in human serum samples employing a manganese dioxide (MnO2) nanosheet, a redox active 2D nanomaterial, fabricated on polymer dots (PDs), as shown in Fig. 5. The working mechanism of the nanosensor is based on the green fluorescence of PDs, which is then quenched through the integrated MnO2 nanosheets by an inner filter effect (IFE), that is, the nanosensor is in the off state in the absence of GSH. When GSH is present in the sample, it reduces the MnO2 nanosheets into Mn2+ and, as a result, nanosensor fluorescence recuperates and it turns on as the IFE disappears. Thus, the nanosensor follows a mechanism in which it changes from an off state to an on state to detect GSH with a concentration range of 0.5–200 μM and an LOD of 0.1 μM, with high sensitivity (Han et al., 2018). MnO 2 + 2GSH + 2H + → Mn 2 + + GSSG + 2H 2 O.

FIG. 5  (A) Schematic diagram for the analysis of GSH of IFE-based PDs-MnO2 fabricated nanosensor switch turnoff to turn-on mechanism. (B) The UV-Vis spectra of MnO2 nanosheets (a) in the presence and (b) in the absence of GSH (c) excitation spectrum of the PDs. Reprinted with permission from the publisher (Han, L., Liu, S. G., Zhang, X. F., Tao, B. X., Li, N. B., & Luo, H. Q. (2018). A sensitive polymer dots‑manganese dioxide fluorescent nanosensor for “turn-on” detection of glutathione in human serum. Sensors and Actuators B: Chemical, 258, 25–31. https://doi.10.1016/j.snb.2017.11.056).



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Likewise, electrodes modified with Au NWs with duplex DNA and methylene blue (MB) are used to develop electrochemical aptamer-based nanosensors (E-AB nanosensors) for assay of ATP with excellent sensitivity and selectivity. In the presence of ATP, MB signals reduce due to dissociation from duplex DNA because of strong interactions between the aptamer and the ATP. A CV of the Au NW and nanodisk electrodes (Liu, Li, Zhang, Zhu, & Shi, 2015), shown in Fig. 6, illustrates that no solution-filled cracks occur on the NW surface of the electrode. The active surface area of the NW electrode, calculated by the equation ic = 2ACdlv (ic charge current, Cdl capacitance of electrode, v scan rate), is ~2.2 × 10−8 cm2. However, core/ shell nanostructures on NWs further improve their sensitivity. For example, Lupan et  al. fabricated a highly sensitive nanosensor based on n-type semiconducting SnO2 nanowires: Zn2SnO4 dots on an Au electrode via a FIB/SEM system. A configurational assessment revealed SnO2:Zn2SnO4 core-shell fragments on SnO2 NWs, which induced a high sensitivity and efficiency for the nanosensor at the order of 1.5 time, due to more charge separation than a solo NW with the same dimensions (Lupan et al., 2018). Hollow spheres of NiO and SnO2 are widely used for alcohol sensing because their lattice structure can accommodate dopant for further improvement of the sensing response (Chaniotakis & Buiculescu, 2014). Solid silica nanobeads and “yolk-shell” silica nanobeads usually act as nanocarriers because they do not have any sensing ability, that is, probes or biomarkers are immobilized and encapsulated on them for sensing. Fig. 7 displays a scheme of gold NPs (analyte recognizer) and QDs (signal transducer) used to functionalize the silica nanobead surface for glucose sensing due to oxidation of glucose via gold NPs and the photoluminescence quenching ability of QDs (Ma et al., 2015). However, mesoporous silica materials combine the inherent feature of extraordinarily high surface area to pore volume with changeable pore sizes, depending upon the added enzyme dimensions and mechanical stability. Many enzymes, such as β-hydroxybutyrate dehydrogenase, choline oxidase, laccase, formaldehyde dehydrogenase (FDH), lactate oxidase, and acetylcholinesterase, were encapsulated into mesoporous silica to fabricate high-performance nanobiosensors (Hasanzadeh, Shadjou, Eskandani, & La Guardia, 2012). However, the hollow mesoporous silica structure has further improved upon the performance of the mesoporous

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FIG.  7  General scheme of silica nanobead modification for nanobiosensor applications, including a silica ­ anobead-based matrix, analyte detector (functional groups, ligands, antibodies), and signal transducer (fluorescein n and NPs). Reprinted with permission from the publisher (Ma, Q., Li, Y., & Su, X. (2015). Silica nanobead-based sensors for analytical and bioanalytical applications. TrAC—Trends in Analytical Chemistry, 74, 130–145. https://doi.10.1016/j.trac.2015.06.006).

structure as hollow mesoporous silica has a broad distribution of surface curvatures, such as concave curvatures, that are present within the mesoporous channels and controlled by pore size, while convex curvatures located at the outer surface depend upon the pore sizes and pore distributions. For examples, the encapsulation of pH-sensitive dyes into the surface curvature of board distributed hollow mesoporous silica NPs (HMSNs) (both concave and convex) can extend the pH sensing range five units (3.2–9.0) and increase the pKa values of fabricated pH sensors, due to high dye density within the HMSNs (Tsou, Hung, & Mou, 2014). Furthermore, the sensitivity enhancement depends on the increase of analyte concentration in the proximity of the electrode and that is why mesoporous metal oxides are often integrated at electrode surfaces to improve electrochemical analysis. For example, mesoporous titania film can incorporate dendrimer within its pores for use in sensing phenolic compounds. Because the distance between dendrimers and analytes decreases inside mesopores, which facilitates hydrogen bonding between analytes and dendrimer molecules, the sensitivity and stability of sensor is enhanced. Similarly, mesoporous In2O3 nanorods and α-Fe2O3 mesopore core-shell nanospheres comprising tiny, well-aligned NPs, were revealed to offer an increased number of grain junctions compared with larger-grain NPs or nonporous NPs, and they thus yield superior sensitivity and selectivity for drug analysis (Melde & Johnson, 2010). Moreover, Au nanodendrite, a 3D porous network nanostructure, was synthesized and utilized by Ngoc et  al. for the electrochemical sensing of As3+ in an ultralow concentration range and compared with bare-Au and AuNP integrated electrodes, as described in Fig. 8. Due to the high surface area of the 3D Au nanodendrite porous network, it revealed the highest sensitivity of 0.046 ± 4.2 × 10−5 μAppb−1, as well as the highest reproducibility and peak intensity compared with the other electrodes, which indicates a sensor-to-sensor morphology dependent superiority (Ngoc et al., 2011). Furthermore, nanoporous architectures based on spherical, truncated cubic, and equilateral octahedral forms of single crystal magnetites (Fe3O4) were synthesized by Zhao et al. and are shown in Fig. 9. Subsequently, the samples exhibited ferromagnetism at 2 K and became almost paramagnetic at 300 K, excluding the cubic shape. Thus, they have potential for use as magnetic carriers, sensors, and in imaging because of high magnetization and lower coercive forces. Consequently, magnetic NPs with spherical morphology revealed



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FIG. 8  (A) Voltammograms of three different electrodes at 1 ppm As(III) solution. (B) Voltammograms of Au nanodendrite network electrode at different concentrations of As(III) solution, inset calibration curve of peak height vs concentrations. Reprinted with permission from the publisher (Ngoc, T., Ganesh, T., Soo, K., Kim, S., Han, S., & Chung, H. (2011). A three-dimensional gold nanodendrite network porous structure and its application for an electrochemical sensing. Biosensors and Bioelectronics, 27(1), 183–186. https://doi.10.1016/j.bios.2011.06.011).

a high surface area (318.9 m2 g−1), smooth surface, low size distribution range, and high saturation magnetization (92 emu g−1) to offer the maximum signal and good diffusion in liquid media (Zhao et al., 2008).

5  MORPHOLOGICAL EFFECT OF SPECIFIC NANOMATERIALSBASED SENSORS Nanostructures of various shapes constructed of a single composition, such as carbon, inorganic metal/metal oxides, polymers, transition metal/metal oxides, and others, demonstrate widely different sensing properties based solely upon their morphological architecture.

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FIG. 9  Hysteresis loops of Fe3O4 with distinct shapes investigated at 300 K (black line) and 2 K (red line—grey in print version) confirmed the s­ tructure-dependent magnetic properties of the magnetites. Reprinted with permission from the publisher (Zhao, L., Zhang, H., Xing, Y., Song, S., Yu, S., Shi, W., …, Cao, F. (2008). Morphology-controlled synthesis of magnetites with nanoporous structures and excellent magnetic properties. Chemistry of Materials, 20(1), 198–204. https://doi.10.1021/cm702352y).

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6  TYPES OF NANOSTRUCTURES 6.1  Carbon Nanostructure-Based Sensors The CNMs, particularly CNTs and GOs, owing to various outstanding properties, are extensively used as biosensors for the loading of several drugs. They have the ability to penetrate the cell membrane, as scaffolds for the advancement in tissue engineering, by providing a similar microenvironment as that of the extracellular matrix, and to form composite molecules with DNA or RNA, genes, proteins, and nucleic acid (Punetha et  al., 2017). Carbon nanostructures include QDs, carbon nanotubes (CNTs), nanohorns, graphene sheets, carbon dots, fullerenes, nanodiamonds, nano-onions, and carbon matrices with conductive polymers or silica NP fillers. Clausmeyer et al. developed a pulled pipette black carbon nanoelectrode that contains a nanocavity with electrodeposited PB film in it. The nanocavity increased the film stability by trapping the parts that become dissolved or detached and that were rapidly redeposited on the electrode (Clausmeyer, 2016). A graphene structure with surface defects, such as hinges and clefts, has a high surface area for binding of functional molecules compared with an ultra-uniform structure. Fig. 10 displays a comparative CV of a Cu/Gr-sheetsmodified electrode, a Gr-sheets electrode, and a Cu/GC electrode for glucose sensing. The Cu/Gr-sheets cause a synergistic effect on the electrode with a LOD of 0.5 M, a fast response of