Functionalized Carbon Nanomaterials for Theranostic Applications 9780128243664

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FUNCTIONALIZED CARBON NANOMATERIALS FOR THERANOSTIC APPLICATIONS

FUNCTIONALIZED CARBON NANOMATERIALS FOR THERANOSTIC APPLICATIONS Edited by

SHADPOUR MALLAKPOUR Professor, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran

CHAUDHERY MUSTANSAR HUSSAIN Adjunct Professor, Academic Advisor and Director of Chemistry and EVSc Labs, Department of Chemistry and Environmental Sciences, New Jersey Institute of Technology (NJIT), Newark, NJ, USA

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2023 Elsevier Ltd. 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. ISBN: 978-0-12-824366-4 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

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Contents Section A. Functionalized carbon nanomaterials for therapeutic applications Chapter 1. Functionalized graphene nanomaterials: Next-generation nanomedicine Chapter 2. Functionalized carbon nanomaterials: Fabrication, properties and potential applications Chapter 3. Application of functionalized carbon nanomaterials in therapeutic formulations

Section B. Fundamentals and functionalization of CNTs and other carbon nanomaterials Chapter 4. Fundamentals and functionalization of CNTs and other carbon nanomaterials Chapter 5. Carbon nanomaterials: Fundamentals, functionalization, and applications Chapter 6. Carbon nanotubes and other carbon nanomaterials: Prospects for functionalization Chapter 7. Carbon nanotubes and their biomedical applications Chapter 8. Molecular interaction modeling of carbon nanotubes and fullerene toward prioritized targets of SARS-CoV-2 by computer-aided screening and docking studies Chapter 9. Functionalization of carbon nanotubes: Fundamentals, strategies, and tuning of properties

Section C. Functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy Chapter 10. The advances in functionalized carbon nanomaterials for drug delivery

Chapter 11. Functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy Chapter 12. Carbon-based nanomaterials: Potential therapeutic applications Chapter 13. Carbon nanomaterial-based nanocrystals for dental applications Chapter 14. Application of carbon and metal-based nanomaterials in modern health care systems Chapter 15. Modified carbon nanomaterials for diagnosis, drug delivery and stem cell therapy

Section D. Functionalized carbon nanomaterials for biomedical imaging for diagnostics Chapter 16. Functionalized carbon nanomaterials for biomedical imaging Chapter 17. Current advancement and development of functionalized carbon nanomaterials for biomedical therapy

Section E. Functionalized carbon nanomaterials for bio-barcodes for clinical tests Chapter 18. Functionalization of carbon nanotubes: A multifaceted and upcoming diagnostic tool in the clinical domain

Section F. Functionalized carbon nanomaterials for point-of-care applications Chapter 19. Innovative progress in functionalized carbon nanomaterials, their hybrids, and nanocomposites: Fabrication, antibacterial, biomedical, bioactivity, and biosensor applications

Section G. Regulatory and toxicological perspectives of carbon nanomaterials Chapter 20. Regulatory and toxicological perspectives of carbon nanomaterials Chapter 21. Perspectives for the toxicological and biodegradation field of carbonaceous nanomaterials and their hybrids

Section H. Functionalized carbon nanomaterials (FCNMs)—A green and sustainable vision Chapter 22. Functionalized carbon nanomaterials (FCNMs): Green and sustainable vision Index

Contributors

S.M. Ahmed Petrochemical Department, Egyptian Petroleum Research Institute, Cairo, Egypt Elham Azadi Organic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran Ishita Bansal Department of Chemistry, Amity Institute of Applied Sciences, Amity University, Noida, Uttar Pradesh, India Vajiheh Behranvand Organic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran Parameswaran Binod Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Trivandrum, Kerala, India Priya Chauhan School of Studies in Environmental Chemistry, Jiwaji University, Gwalior, India Shashi Chawla Department of Chemistry, Amity Institute of Applied Sciences, Amity University, Noida, Uttar Pradesh, India Sahin Demirci Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey Anchita Diwan Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Baskaran Ganesh Kumar Department of Chemistry, P.S.R. Arts and College (Affiliated to Madurai Kamaraj University, Madurai); Department of Science and Humanities, P.S.R. Engineering College (Affiliated to Anna University, Chennai), Sivakasi, Tamil Nadu, India S. Gorkem Gizer Department of Chemical & Biomedical Engineering, and Materials Science and Engineering Program, University of South Florida, Tampa, FL, United States Dharshini Gopal Grenoble Institut Neurosciences, Univ. Grenoble Alpes, Inserm U1216, Grenoble, France

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Kartika Goyal Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Shikha Gulati Department of Biological Science; Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Chaudhery Mustansar Hussain Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ, United States Ravi-Kumar Kadeppagari Centre for Incubation, Innovation, Research and Consultancy (CIIRC), Department of Food Technology, Jyothy Institute of Technology, Bengaluru, India Suresh Kumar Kailasa Department of Chemistry, S. V. National Institute of Technology, Surat, Gujarat, India Ruckmani Kandasamy Department of Pharmaceutical Technology, Centre for Excellence in Nanobio Translational Research (CENTRE), University College of Engineering, Anna University, Tiruchirappalli, Tamil Nadu, India Nikita Kaushal MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Ambala, India Venkateshwaran Krishnaswami Department of Pharmaceutical Technology, Centre for Excellence in Nanobio Translational Research (CENTRE), University College of Engineering, Anna University, Tiruchirappalli, Tamil Nadu, India Manish Kumar MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Ambala, India Sanjay Kumar Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Beena Kumari Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, Haryana, India Sweta Kumari Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Saliha B. Kurt Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey M.S. Latha Department of Chemistry, Sree Narayana College, Chathannur, Kollam, Kerala, India Aravind Madhavan Rajiv Gandhi Center for Biotechnology, Jagathy, Thiruvananthapuram, Kerala, India

Contributors

Shadpour Mallakpour Organic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran N.A. Mansour Petrochemical Department, Egyptian Petroleum Research Institute, Cairo, Egypt Vijayalakshmi Maruthamuthu Department of Pharmaceutical Technology, Centre for Excellence in Nanobio Translational Research (CENTRE), University College of Engineering, Anna University, Tiruchirappalli, Tamil Nadu, India Vaibhavkumar N. Mehta ASPEE SHAKILAM Biotechnology Institute, Navsari Agricultural University, Surat, Gujarat, India Govindappa Melappa Department of Studies of Botany, Davenegere University, Davanagere, Karnataka, India Shashi Kiran Misra School of Pharmaceutical Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur, Uttar Pradesh, India Shibsankar Mondal Department of Chemical Engineering, University of Calcutta, Kolkata, India Ayush Mongia Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Kulkarni Akshay Narayanrao Centre for Incubation, Innovation, Research and Consultancy (CIIRC), Department of Food Technology, Jyothy Institute of Technology, Bengaluru, India Annu Pandey Department of Chemistry, Chandigarh University, Mohali, Punjab, India Ashok Pandey Centre for Innovation and Translational Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India Kamla Pathak Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India Swastik Paul Department of Chemical Engineering, University of Calcutta, Kolkata, India Eapen Philip Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara, Kerala, India Osman Polat Department of Chemical & Biomedical Engineering, and Materials Science and Engineering Program, University of South Florida, Tampa, FL, United States

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Vimalkumar S. Prajapati ASPEE SHAKILAM Biotechnology Institute, Navsari Agricultural University, Surat, Gujarat, India K.S. Prakash Department of Chemistry, Bharathidasan Government College for Women (Autonomous) (Affiliated to Pondicherry University, Pondicherry), Muthialpet, Puducherry, India E. Priyadarshini Centre for Incubation, Innovation, Research and Consultancy (CIIRC), Department of Food Technology, Jyothy Institute of Technology, Bengaluru, India Prateek Rai Department of Chemistry, Amity Institute of Applied Sciences, Amity University, Noida, Uttar Pradesh, India Rampriya Alagarsamy Rajagopal Department of Pharmaceutical Technology, Centre for Excellence in Nanobio Translational Research (CENTRE), University College of Engineering, Anna University, Tiruchirappalli, Tamil Nadu, India Shishir Raut Department of Chemical Engineering, School of Technology, Pandit Deendayal Energy University, Gandhinagar, Gujarat, India Juhi B. Raval Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Science (ARIBAS), Anand, Gujarat, India R. Reshmy Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara; Department of Science and Humanities, Providence College of Engineering, Chengannur, Kerala, India Jigneshkumar V. Rohit Department of Chemistry, National Institute of Technology, Srinagar, Jammu and Kashmir, India Subhasis Roy Department of Chemical Engineering, University of Calcutta, Kolkata, India E.M. Sadek Petrochemical Department, Egyptian Petroleum Research Institute, Cairo, Egypt Ankit Saha Department of Chemical Engineering, University of Calcutta, Kolkata, India Mehtap Sahiner Department of Bioengineering, Faculty of Engineering, Canakkale Onsekiz Mart University, Terzioglu Campus, Canakkale, Turkey Nurettin Sahiner Department of Chemical & Biomedical Engineering, and Materials Science and Engineering Program; Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States; Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey

Contributors

Chirantan Shah Department of Chemical Engineering, School of Technology, Pandit Deendayal Energy University, Gandhinagar, Gujarat, India Manan Shah Department of Chemical Engineering, School of Technology, Pandit Deendayal Energy University, Gandhinagar, Gujarat, India Vraj Shah Department of Chemical Engineering, School of Technology, Pandit Deendayal Energy University, Gandhinagar, Gujarat, India Nandini Sharma Department of Biological Science, Sri Venkateswara College, University of Delhi, Delhi, India Shikha Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Raveendran Sindhu Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Trivandrum, Kerala, India Parinita Singh Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India Sinosh Skariyachan Department of Microbiology, St. Pius X College Rajapuram, Kasaragod, Kerala, India Selin S. Suner Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey Deepa Thomas Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara, Kerala, India Rekha Unni Department of Chemistry, Christian College, Chengannur, Kerala, India P.H. Vaisakh Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara, Kerala, India Sneha Vijayan Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India

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This book is dedicated to my beloved GOD “Meray Pyarey Allah (SWT).” C.M. Hussain This book is dedicated to my wife Mina, my son Iman, my daughters Adeleh and Fereshteh, and my granddaughter Termeh. S. Mallakpour

Editors’ biography

Chaudhery Mustansar Hussain, PhD, is an Adjunct Professor and Director of Laboratories in the Department of Chemistry & Environmental Science at the New Jersey Institute of Technology (NJIT), Newark, New Jersey, United States. His research is focused on the applications of nanotechnology and advanced materials, environmental management, analytical chemistry, smart materials and technologies, and other various industries. Dr. Hussain is the author of numerous papers in peer-reviewed journals as well as a prolific author and editor of approximately 100 books, including scientific monographs and handbooks in his research areas. He has published with Elsevier, the American Chemical Society, the Royal Society of Chemistry, Springer, John Wiley & Sons, and CRC Press. Professor Shadpour Mallakpour is an organic polymer chemist; he graduated from the Department of Chemistry, University of Florida (UF), Gainesville, Florida, United States in 1984, and spent 2 years carrying out postdoctoral work. He joined the Department of Chemistry, Isfahan University of Technology (IUT), Iran in 1986, where he held several positions such as Chairman of the Department of Chemistry and Deputy of Research, Department of Chemistry. From 1994 to 1995, he worked as a visiting professor at the University of Mainz, Germany, and from 2003 to 2004, he was a visiting professor at Virginia Tech, Blacksburg, United States. He has published more than 900 journal papers and book chapters, and more than 440 conference papers; he has also received more than 40 awards. Professor Mallakpour considers the most important of these awards to be First Laureate on Fundamental Research, 21st Khwarizmi International Award, which he received in 2008. He has been listed in the leading 1% of Top Chemistry Scientists in the Institute for Scientific Information (ISI) Essential Science Indicators since 2003. He was selected as an academic guest at

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the 59th Meeting of Nobel Prize Winners in Chemistry, 2009, in Lindau, Germany. He has presented many lectures as an invited or keynote speaker at different national and international conferences and universities. He has been a member of organizing and scientific committees for many national and international conferences. He has also been the chairperson of many national and international meetings. In recent years, he has focused on the preparation and characterization of polymers containing chiral amino acid moieties under green conditions using ionic liquids and microwave irradiation as new technology, and on bringing these aspects to nanotechnology for the preparation of novel chiral bionanocomposite polymers as well as polymer nanocomposites for hazardous materials removal technologies.

Preface

Functionalized carbon nanomaterials (FCNMs) have different mechanical, absorption, optical or electrical properties than original nanomaterials. In fact, most utilization of nanomaterials occurs in their functionalized forms, which are very different from the parent material. FCNMs can be integrated easily into molecular diagnostic methods for promising potential clinical applications. The future of FCNM-based devices is focused on in-body applications where data can be transferred from the patient’s body, eliminating any discomfort and unacceptable body connectors, and precluding the need for connecting wires to the patient’s body. With the focus on providing improved quality of life to patients, there is a demand for extensive development of health monitoring and diagnostic techniques that are rapid and inexpensive. FCNM-based devices are the smallest diagnostic devices that are capable of monitoring and delivering appropriate therapeutic interventions. Future trends in diagnostics are expected to pave the way toward miniaturization to a nanoscale level, providing sensitive assessments of health and disease. This book is intended to give an insight into the developments and trends that are progressing fast in the field of FCNM-based devices as diagnostic tools for early detection of human diseases, and it is aimed at readers from various areas of science (chemistry, biology, physics, and medicine). Overall, this is the first book to discuss functionalized carbon nanomaterial-based diagnostic devices and tools. To present a comprehensive review of theranostic applications of functionalized carbon nanomaterials and to provide readers with a coherent and informative reference, the book is divided into several parts, each comprising several chapters. Section A focuses on FCNMs for therapeutic applications, and Chapters 1–3 discuss next-generation nanomedicine, new perspective in theranostic applications, and application of FCNMs in therapeutic. In Section B, Chapters 4–9 detail the fundamentals and functionalization of carbon nanotubes (CNTs) and other carbon nanomaterials, and summarize their applications. Section C focuses on FCNMs for diagnosis, drug delivery, and stem cell therapy, and Chapters 10–15 discuss advances of FCNMs for drug delivery, promising applications of functionalized carbon nanotubes in therapeutics and diagnostics, potential therapeutic applications of carbon-based nanomaterials, carbon nanomaterial-based nanocrystals for dental applications, carbon nanomaterial-based and metal nanocrystals in modern health care systems, and production and characterization of modified carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy. Section D comprises Chapters 16 and 17, which explore FCNMs for biomedical imaging for diagnostics, and current advancement and development of FCNMs for biomedical therapy. In Section E, Chapter 18 considers functionalization of carbon nanotubes, and investigates

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a multifaceted and upcoming diagnostic approach in the clinical domain. In Section F, Chapter 19 discusses FCNMs for point-of-care applications, innovative progress in FCNMs, their hybrids, and nanocomposites, including fabrication, antibacterial, biomedical, bioactivity, and biosensor applications. In Section G, Chapters 20 and 21 review regulatory and toxicological perspectives of carbon nanomaterials of carbon nanomaterials, and biodegradation of carbonaceous nanomaterials and their hybrids. In Section H, Chapter 22 concludes by describing the role of FCNMs in a green and sustainable vision. Overall, this book is anticipated to be a reference guide for experts, researchers, and scientists who are searching for new and modern developments in applications of nanotechnology in the biomedical industry. The editors and authors are well-known researchers, scientists, and specialists from various universities and industry. On behalf of Elsevier, we are very grateful to all the authors for their exceptional and dedicated efforts in contributing to this book. Particular acknowledgments go to Simon Holt (Publisher), Edward Payne (Acquisition Editor), John Leonard (Editorial Project Manager), and Nirmala Arumugam (Production Manager) at Elsevier, for their dedicated support and help during this project. We express our deepest appreciation to Elsevier for publishing this book. Shadpour Mallakpour (Editor) Chaudhery Mustansar Hussain (Editor)

Acknowledgments

We would like to acknowledge Chaudhery Ghazanfar Hussain for his dedicated support during the compilation of this book. We are also grateful to Dr. Vajiha Behranvand, Dr. Farbod Tabesh, Dr. Iman Mallakpour, Miss Fariba Sirous, and Miss Elham Azadi for their support during the preparation of this book.

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Section A Functionalized carbon nanomaterials for therapeutic applications

CHAPTER 1

Functionalized graphene nanomaterials: Next-generation nanomedicine Annu Pandeya and Priya Chauhanb a

Department of Chemistry, Chandigarh University, Mohali, Punjab, India School of Studies in Environmental Chemistry, Jiwaji University, Gwalior, India

b

1. Introduction The need for better quality and more affordable healthcare is regarded as one of the greatest challenges facing our society. In developed countries, the high proportion of older people is leading to a growing number of so-called “aging population diseases,” such as cancer and cardiovascular, musculoskeletal, and central neural system disorders. However, in developing countries, infections and other pathogens continue to take a substantial toll on the young as well as on the working-age population. All over the world, such factors are gradually increasing the burden on healthcare systems [1,2]. Even though our successes in treating many diseases are inspiring, present cases of antibiotic-resistant superbugs in the United States, the outbreak of the deadly Ebola virus, the new challenge of the Zika virus, and other old unsolved problems including cancer continue to hamper our progress in terms of threat detection, diagnosis, treatment strategies, and development of new drugs. Although functionalized carbon-based nanomaterials have been broadly utilized in the electronics, electrochemistry, spintronics, and electro-mechanical field afterward creating their safety and bio-compatibility in current studies. Furthermore, functionalized carbon-based nanomaterials has been scrutinized for their application in the biomedical field either in diagnosis or as a drug delivery platform [3]. In recent scenarios, nanotechnology has proven to be a swiftly emerging field of scientific research that predominantly encompasses knowledge of manufacturing as well as the structural study, properties, and behavior of materials that are measured in nanometers [4]. Nanotechnology is regarded as one of the most recent and advanced fields of medicine and healthcare, with intriguing implications. It includes multifunctional nanostructures that help in diagnosis and therapy. Carbon-based nanomaterials (NMs) might involve the transferal of electrons directly between functionalized as well as bio-receptor active sites, giving signal amplification and also label-free sensing depriving of any noise

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00020-0

Copyright © 2023 Elsevier Ltd. All rights reserved.

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[5,6]. They possess versatile properties like electrical conductivity, large surface area, and noncovalent anticancer drug loading. Consequently, they are considered to be a favorite material for the application of thermotherapy in cancer treatment. Moreover, the process of PEGylation, where the surface of nanoparticles (NPs) is coated by using polyethylene glycol (PEG) polymer, may be carried out to accomplish stable dispersion in nearinfrared (NIR) absorption of cancer thermal therapy. Alternatively, nanomedicine refers to the field where nanomaterials and nanotechnology are employed to design novel drug delivery systems so as to improve the efficacy of current therapeutics [7]. In cancer research, nanomedicine has shown remarkable potential to overcome the downsides of existing chemotherapeutic agents. The increasing interest in nanomedicine among cancer researchers may be attributed to the exceptionally appealing properties of nanocarriers, viz., their nanoscale size, promising drug release profile, high surface-tovolume ratio, and, most importantly, their capability to discriminate and selectively exterminate malignant cells [8,9]. Undeniably, a great insight has been provided by nanomedicine in terms of the design as well as engineering of a wide range of nano-vehicles of varying sizes so as to improve therapeutic efficacy of the loaded chemotherapeutic agent, and also attaining safety through specific targeting of tumor cells. Cancer nanotechnology, one of the major disciplines of nanomedicine, has evolved enormously over the years, along with advancement in areas of functionalized carbonbased nanomedicine. Prompt detection, good treatment options, and fewer side effects are significant advantages of nanotechnology-mediated innovations in cancer therapy [10,11]. The primary step involved in the confirmation of disease is diagnosed. The detection of an abnormality in the body at an early stage is the best way to prevent it from progressing as well as allow it to be treated if in an advanced stage. With the assistance of nano-devices, modern technology enables the imaging of infectious sites within the body. Because of their fascinating optical and magnetic properties, several types of nanoparticles might be applied for multimodal imaging and also for image-guided cancer therapy. The imaging of drug carriers and allied molecules is essential for determining the fate, distribution, and pharmacokinetics of therapeutic molecules within the system after delivery. “Therapy” in this area refers to the treatment proposed to deal with a disorder after its detection. Methods of therapy will vary depending on the patient’s condition. In the case of cancer, the foremost therapies involve surgery, chemotherapy, radiation, targeted therapy, immune therapy, hyperthermia, stem cell treatment, etc. Conventional treatment methods have numerous limitations like nonspecific targeting, toxicity issues to normal cells, the requirement of high dosage, and long processing time. In addition, they generally involve invasive methods like surgery or biopsy as well as equipment such as catheters and radiation seeds. The application of nanomaterials in various therapeutic procedures like chemotherapy, radiation, and systemic application possesses a wide range of very critical side effects such as immune system suppression and neurotoxicity; these

Functionalized graphene nanomaterials

side effects might be improved by applying nanotechnology which helps in providing good treatment options by frequently noninvasive activities as well as passive targeting methods by providing additional prominence to specific and effective treatment [12–14]. However, it is believed that in the near future, nanomedicines will move the paradigm of cancer management, linking its translational beyond bench-to-bedside gap. Moreover, several methods such as cross-collaborations and multidisciplinary approaches for knowledge exchange among academia, the pharmaceutical industry, and medical specialists have been employed to establish the best option, addressing the various challenges and flaws to increase the chances of success in cancer nanomedicine. This will in turn improve patient survival rates globally, benefiting the wellbeing of society in general. Such materials are multifunctional in nature; they possess high surface area, low density, and multifaceted surface properties. Carbon is considered as one of the readily available samples as well as adaptable elements on the planet and has a wide range of applications [15]. Carbon-based nanomaterials (CNMs) have inimitable and exceptional characteristics, such as excellent mechanical strength, chemical and thermal stability, low density, resistance to corrosion, and hardness, making them highly competitive in a variety of commercial fields, such as drug delivery, energy storage, microelectronics, environmental remediation, biotechnology, packaging, and coating [16]. The synthesis of CNMs for targeted applications is fascinating because of their unique properties, such as high surface area and superior directionality. Carbon nanoallotropes can be categorized into the broad family along with its classification. In chemistry, and applications of fullerenes, carbon dots, nanotubes, graphene, nanodiamonds, has combined remarkable optical properties, and flexibility, making their unique synthesis process is also highly challenging as compared to bulky materials for innovative applications. This chapter provides an overview of functionalized carbon-based materials, specifically graphene counting chemical structures, synthesis routes, and functionalization approaches, as well as their properties [17–19].

2. Carbon-based nanomaterials (CNMs) In the past few years, CNMs have attracted considerable interest from researchers. They are composed of sp2 and sp3-bonded carbon atoms. Carbon-based nanomaterials possess higher electrical, magnetic, mechanical, and thermal stability, electrochemical action, ease of fabrication, chemical variety, and biocompatibility, making them suitable for extensive application as a voltammetric sensor, energy storage, and electrodes with greater performance. Nanomaterials comprise of fullerene, carbon dots (CDs), carbon nanohorns (CNHs), carbon nanotubes (CNTs) and graphene (G) in addition to their consequent derivatives. During scheming synthesis of different forms of carbon nanomaterials, particularly CNTs and G, can be accumulated into films, foams, collections, and

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sponges; these films amplify the electrical conductivity and accessible surface area aid to sensing application. CNMs are classified as: • zero-dimensional (0D), including carbon dots and quantum dots; • one-dimensional (1D), consist of carbon nanotubes (CNTs); and • two-dimensional (2D), i.e., graphene. Prior studies signified that the purposes, characteristics, and applications of carbon nanomaterials are attributed to their aspects, composition, and functionalization. For illustration, 0D carbon nanomaterials have clear benefits in the fields of bioimaging and biomedicine, and 1D CNTs are suitable for application in materials science, nanotechnology, and nanoelectronics because of enhanced surface area, in addition to distinctive mechanical, electrical, and magnetic characteristics. Carbon nanotubes (CNTs) were determined long years ago years before and have drawn remarkable attention from many scientists working in physics, chemistry, and materials science. In these areas, biomedical purposes of nanotechnology have particularly significant potential. These purposes of bio-nanotechnology can be classified as: (i) biomedical analytical methods, (ii) medicine, and (iii) prostheses and implants [20–22].

2.1 Carbon nanotubes A carbon nanotube is a type of carbon allotrope, found in the form of cylindrical carbon molecules embedded in graphene covers in a lattice formation, and has enormous surface areas that are advantageous for therapeutic applications such as therapy, bioimaging, and treatment. CNTs are a type of 1D carbon nanomaterial comparable to G nanosheets and demonstrate outstanding electrical, mechanical, and conductivity properties. They were first isolated in 1991 and have since attracted much attention from researchers. CNTs have been found to offer superior electrical conductivity compared to carbon dots and fullerene as sensing materials. CNTs can be of two types: multiwalled CNTs (MWCNTs) and single-walled CNTs. Their surfaces can be tailored through chemical functional assembly or biomolecules to increase the dispersibility and conductivity, mechanical power, surface area, and optical amalgamation capacity to provide sensors with improved performance. Currently, the application of CNTs in the treatment of cancer by a blend of photothermal therapy and chemotherapy offers synergistic therapeutic effects [23,24].

2.2 Fullerene Fullerene is a compact structured carbon nanomaterial consisting of bundled carbon atoms. Since fullerene is a carbon allotrope with prominent physical, chemical, and electrical characteristics, making it the ultimate contestant for making nanostructures for a range of applications. It was initially discovered by Smalley in 1985 and identified as being

Functionalized graphene nanomaterials

in the carbon family by graphite vaporization, applying laser irradiation beneath a static gaseous environment at low pressure. It has various forms; among them, C60 is the most common structure and reveals 20 hexagonal and 12 pentagonal rings of sp2 hybridized carbon atoms assembled in a symmetrical icosahedral closed cage configuration. The spherical constitution speeds up electron charges. Fullerene can also be functionalized by covalent or noncovalent interfaces to outline a multifunctional material with tunable physical and chemical characteristics, capably in therapeutic applications [25].

2.3 Carbon dots Carbon dots (CDs) are a type of 0D carbon nanomaterials and have received a great deal of attention because of their exceptional optical and electrochemical characteristics. On the basis of their structure, CDs can be categorized into carbon quantum dots (CQDs) and graphene quantum dots (GQDs). CQDs are quasispherical and amorphous, with diameters smaller than 10 nm. GQDs are comparable to the 2D plane of graphene, but the tangential dimensions of GQDs are smaller than 20 nm [26].

2.4 Carbon nanohorns Carbon nanohorns (CNHs) are another carbon nanostructure; they are found in conical form and consist of sp2 and sp3 carbon sheets. Generally, CNHs have diameters of 2–5 nm and their lengths are commonly 40–50 nm. CNHs have the advantage of lower toxicity, because of the lack of toxic catalyst through the preparation, which is considerably better than CNTs and G. They have distinctive electrical characteristics because of their conical structure. Their greater porosity and adsorption potential enable them to act as substrates for therapeutic purposes. Comparable to CNTs and G, CNHs can be moderately oxidized to consist of oxygen-containing groups on their surface during heat or chemical treatment. The presence of nanopores can also boost the surface area and pore volume of CNHs, confirming their potential to be functionalized with biomolecules [27].

2.5 Carbon nanofibers Carbon nanofibers are nanosized in diameter and have filaments like structures. They have very high surface-to-volume ratios, exceptional mechanical stability, greater aspect ratios, and nanoscale-determined characteristics, with a range of purposes. Varieties of methods like electrospinning, chemical vapor deposition (CVD), and templating are applied for carbon nanofibers generation. Among these, electrospinning is the majorly used route to prepare good-quality carbon nanofibers and is low-cost. This technique needs a sol-gel or polymer solution in a syringe pump to be extended under a greater voltage, which results in good filaments of carbon on a conductive electrode collector [28].

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2.6 Nanodiamonds and nanoporous carbon Nanodiamonds (NDs) are one of the newest members of the nanocarbon family, having the structure and characteristics of diamonds in nano size. NDs were discovered by chance in 1963 by the technique of shock firmness of carbon black and graphite in blast compartment rooms. Usually, NDs are prepared by a precursor such as a blend of hydrocarbons, CNTs, and carbon film enclosing Si, graphite, carbon, and ethanol by using various techniques, viz., hydrothermal, ion bombardment, laser bombarding, microwave plasma chemical vapor deposition, detonation, and ball milling. Furthermore, nanoporous carbon (NPC) can be categorized by pore dimensions: microporous (2 nm), mesoporous (2–50 nm), and macroporous (50–1000 nm). Commonly, NPC is prepared by pyrolysis and physical methods, chemical commencement of organic precursors like wood, coal, fruit peel, or polymers, at elevated temperatures. However, the effectiveness of these techniques is limited by the low conductivity, imperfections, graphitization at superior temperatures, and sluggish transfer of the resultant NPC [29,30].

3. Graphene and its derivatives The discovery of graphene has unlocked an innovative opportunity in the area of materials science. The unique qualities of graphene, its derivatives, and graphene-supported nanomaterials have been investigated in depth in the last few years. The simplicity of proliferation of electrons inside the honeycomb structure of graphene through nominal scattering conveys a distinctive quantum result at room temperature. Consequently, graphene-supported nanostructures have been discovered comprehensively as innovative building blocks for several future applications. The optimization of structural constraints, viz., thickness, lateral dimension, morphology, and surface property, indicate the significant potential of graphene nanostructures. Graphene has unique traits like biocompatibility, stiffness, and flexibility. In addition, this 2D nanomaterial has been identified as having widespread applications in biomedicine and electronics due to its fundamental characteristics [31–33]. Graphene (G) is a very significant potential carbon nanomaterial that is compiled of a monolayer of sp2-linked carbon atoms bundled into a honeycomb lattice, has shown a significant role after its discovery in 2004. Graphene can be produced by numerous methods, such as mechanical cleavage, CVD, and mechanical exfoliation of graphite. Usually, the family of G materials comprises single and multilayer graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots. Every category of graphene materials demonstrates diverse and tunable physical, chemical, imperfection density, electrical, and mechanical characteristics, indicating the potential for a range of therapeutic applications. In contrast to CNTs, G has a comparatively greater surface area. Researchers have shown great interest in this recently discovered

Functionalized graphene nanomaterials

material due to its inimitable chemical structure, material, and biomedical characteristics. GO includes a huge quantity of hydrophilic groups in its structure; therefore, sheets of tiny size and lower concentrations should be additionally biocompatible. These characteristics make GO enormously important to many scientists with the most recent applications being in the areas of drug delivery, cancer therapy, imaging, and diagnostics [34–36].

3.1 Graphene oxide GO is a significant hydrophilic derivative of graphene, and is a solitary film of graphite oxide, frequently prepared by exfoliation of graphite oxide. GO is synthesized by acidbase treatment of graphite oxide followed by sonication. Some functional groups like oxygen, epoxide, and carbonyl, hydroxyl, and phenol groups are on the surface of GO. A clear difference between graphene and GO is the subsistence of oxygen atoms linked to carbon. GO is the product of hydrophilic derivative of graphene. GO has aromatic (sp2) and aliphatic (sp3) carbon in their structures which ease the interfaces at the surface. It is produced by Hummer’s technique and has oxygenated sets on the surface of the molecule. There is no definite configuration for GO; however, morphological and structural categorization provide a scheme of the GO structure. Recently, graphene oxide has been frequently employed for therapeutic purposes like targeting organs, drug delivery systems, and chemotherapy and radiation therapy techniques. For example, drugs that are water-insoluble like doxorubicin and docetaxel, embedded with antibodies for discriminating assassination of cancer cells, are placed on graphene oxide using simple physisorption by π-π stacking [37,38].

3.2 Reduced graphene oxide Reduced graphene oxide (rGO) is obtained from chemically or thermally treated graphene oxide. Generally, preparation of rGO occurs between graphite sheets and oxidized graphene oxide. Hydrazine, hydrazine hydrate, L-ascorbic acid, and sodium borohydride are the most prominently used reducing agents for reduction of GO to rGO. Various research studies have demonstrated the utilization of plant and plant extracts for the preparation of rGO, as these are environment friendly and easy to prepare. The preparation of nanoparticles needs reducing and capping representatives, which are offered by plant extracts. Functional groups of rGO oxides cooperate with DNA, proteins, peptides, and enzymes; consequently, they can be easily chemically fabricated. The reason for applying biomolecules for the preparation of rGO is due to their cost effectiveness; in addition, it does not require as much labor and time for the reduction phenomena because of its nontoxic and biocompatible characteristics and that’s why these are

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applied for the preparation of rGO. Additional, low toxicity enables therapeutic applications. These are effective because of the greater surface area of rGO [39,40].

3.3 Graphene quantum dots (GQDs) In recent years, graphene quantum dots (GQDs), as he latest quasi zero-dimensional nanomaterial, have drawn extra attention. In contrast to other graphene derivatives, GQDs demonstrate a number of extra advantages, such as tunable bandgap, exceptional aqueous solubility, high biocompatibility, greater fluorescence quantum product, and the existence of numerous active functional groups; therefore, they present an unprecedented prospect in the area of nanodevices. For example, due to their size-dependent property, GQDs can be employed in LEDs, molecular switches, single-electron transistors, and other electronic devices. Furthermore, due to its capability to modify the physical and chemical characteristics of GQDs with ease during the synthetic process making them further smart and versatile as compared to other allotropes of carbon such as fullerene, graphene, carbon nanotubes (CNTs), etc. Although GQDs have numerous smart properties, their relatively low quantum yield limits their profitable applications in a range of areas. Graphene quantum dots (GQDs) are a graphene sectioned within 20 nm approximately. GQDs are mostly applied in bioimaging. Research has also been carried out based on the cytotoxicity of GQDs [41,42].

4. Functionalization of graphene With their outstanding and advanced properties, such as brilliant electrical and mechanical properties, and higher surface area, carbon-based nanomaterials (CNMs) are regarded as prospective building blocks for developing nano range functionalized materials. Amplified dispersion of CNMs in diverse media and on their interfaces with other inorganic/organic and polymeric molecules is crucial to attaining their full potential in a range of purposes such as water purification, sensing, and biomedical. Surface functionalization of CNMs can boost the interactions. Functionalization of CNMs improves the dispersion, colloidal stability, selectivity, and multifunctional gathering of nanostructures. For example, CNMs can easily be changed to have a hydrophobic, hydrophilic, anticorrosive, anionic, cationic, and zwitterion surface presently by surface functionalization. Depending on the bonding properties between CNMs and functional molecules, functionalized advances are segregated into two classes: covalent and noncovalent functionalization [14].

4.1 Covalent functionalization In covalent functionalization, diverse chemical species are connected to CNMs by making chemical bonds. This modification in CNMs is directed by oxygen/nitrogen-carrying

Functionalized graphene nanomaterials

groups that bond to the π-π conjugated framework of the carbon nanostructures. Covalent functionalization is a generally applied approach for the functionalization of CNMs to optimize their full-scale potential in a wide range of applications [15].

4.2 Noncovalent functionalization Noncovalent functionalization takes place by weak physicochemical interactions—for instance, π-π interfaces, hydrogen interactions, or van der Waals forces. Intended for noncovalent interactions functionalization, vital repulsive forces, and attraction forces are major responsible factor. Unknown molecules can be modified noncovalently on carbon-based nanomaterials via physisorption. Further, in the case of weak interactions, noncovalent functionalization can also take place in structures of polymer packaging, π-π interactions, and electron donor-acceptor ligand schemes. Surface functionalization of carbon-based nanomaterials applying a range of nanostructures including metals, metal oxides, metal sulfides, etc. via managed morphology and crystallinity has been extensively investigated for nanotechnology purposes in several fields, such as nanomedicine, energy storage, and electrocatalysis [43]. Functionalization of unrefined graphene-supported materials is vital in order to increase their aggregation and additionally to support in sustaining their intrinsic properties. It has significant primary advances to modify the physical and chemical characteristics of graphene. Analogous to CNTs, the surface of graphene can be functionalized via covalent or noncovalent functionalization techniques. The functionalization of graphene through covalent techniques can be achieved by numerous methods, including nucleophilic substitution, electrophilic addition, and addition and condensation reactions. In words of covalent functionalization, the mechanism engages in the organization of covalent connections linking the unsaturated carbon π-bond and additional functional groups. Covalent bond modification is constant and stronger when compared to noncovalent modification techniques. In addition, the electronic and chemical characteristics of graphene and its derivatives can be altered simply and efficiently via covalent functionalization. However, their characteristics relayed to the transfer of electrons may be interrupted because of modification of the graphene lattice. A new substitute to remedy this problem is to apply noncovalent functionalization. Noncovalent functionalization of graphene is significantly supported by π-π contacts, ionic interfaces, and van der Waals forces. The present technique would not interrupt the configuration of graphene and its electronic conjugation. Therefore, it would not influence the essential advantages of graphene, such as electrical conductivity and physiochemical and mechanical properties. Various approaches for noncovalent modification of graphene and GO exist, consisting of adding of polymers, biomolecules, and surfactants. Polymers like polyaniline, polysulfone, and polyvinyl can be inserted to graphene to prepare a composite to improve its mechanical power and capacitance [44–46].

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5. Properties of graphene As an essential constituent of additional carbon allotropes, graphene has a 2D configuration compiled of six-atom rings in a honeycomb arrangement with one-atom width. Every carbon atom is linked to three additional carbon atoms. The C-C bond length is ˚ , with a bond angle of 120 degrees. Every carbon atom structures three σ-bonds 1.42 A via three sp2 hybrid orbitals with three carbon atoms; the respite of the p-orbital forms a conjugated system with additional contiguous carbon atoms. In this conjugated system, every carbon atom provides a p-electron; therefore, the carbon skeleton of graphene consists of σ-bonds with paired electron clouds over and below the skeleton. The bonding structure is similar to that in a benzene structure; therefore, graphene could be considered a massive polycyclic aromatic hydrocarbon. Graphene and GO have exceptional physicochemical properties, which have attracted the attention of researchers. The 2D allotropic configuration and biocompatible characteristics of graphene make it suitable for biological purposes. Graphene has attractive properties such as greater surface area of 2630 m2/g, the thermal conductivity of 5000 W/m/K, and electrical conductivity and mechanical force of 1100 GPa (Young’s modulus). These characteristics of graphene have led to its utilization in biomedical and therapeutic applications such as treatment of cancer, bioimaging, and drug delivery [47,48]. The large and planar sp2 linked carbon atoms, greater surface area, and oxygen groups in the GO make it biocompatible. Its solubility with the increased ability of transported drugs and genes on it, make it unique. Consequently, it can be applied as a drug transporter. Graphene and GO demonstrate capable applications in biomedical purposes and have the potential of scrutinizing diverse cells (like cancer cells) and molecules. The oxide and hydroxyl sets in GO encourage propagation and differentiation of pluripotent speeding up of axonal development in hippocampus neurons. The utilization of graphene and its derivatives is regarded as secure and sustained by a range of studies. Graphene-supported nanomaterials have excellent biocompatibility prior to modification, biodegradability, and multifunctionalities that make them appropriate candidates for cancer nanotheragnostics. They can also transport very large quantities of drug molecules on mutually areas of the single-atom layer sheet [49–51].

6. Application of graphene in targeted cancer theragnostics Basically, the structure of a theragnostic agent involves three major components, i.e., imaging agent, therapeutic agent, and a carrier, so as to encompass the imaging and therapeutic agents. In order to ensure specific targeting of the theragnostic system, targeting ligands may be attached to the system. The development of a system includes different

Functionalized graphene nanomaterials

functionalization methods. Nanotheragnostics refers to the combination of nanotechnology, diagnostics, and therapy. The delocalized π electrons and extremely accessible surface area on graphene derivatives offer superior loading capability for a variety of molecules. The main advantages of nanographene as a delivery vector of anticancer drugs and genes have been analyzed in another study [52]. Graphene nanomedicine is known as one of the most recent and advanced fields of medicine and healthcare with outstanding implications. This includes the multifunctional nanostructures that can be used in diagnosis, therapy, and continuous treatment. Cancer is a leading cause of death worldwide, and it continues to be one of the main challenges of our time. In the treatment of cancer, chemotherapy is the intervention most commonly used; however, severe side effects impact patients because of the wide cytostatic action of the obtainable drugs that also affect normal cells. Therefore, merged treatments applying numerous healing agents targeting definite cancer-targeted sites for prompting synergistic effects can be judged as an efficient approach to fighting cancer. For instance, the mixture of peptide ligands, antibodies, and aptamers facilitates nanomaterials. The growth of biomedicine needs innovative materials and development of technologies for accurate therapeutics. Conventional approaches are distant from the vital command of current medicine for their intrinsic inadequacy, particularly shimmering in their imprecise target and low retention competence in pathological areas, as well as lack of synergistic assets in single stage [53–56]. In the last few years, the flourishing growth of nanotechnologies and nanomaterials has brought bright opportunities in the area of biomedicine. Nanomaterials with superior biocompatibility, high-quality physiological stability, appropriate physical and chemical properties, and outstanding biomedical presentation will be vital in the future. Taking advantage of the large, functionalized surface of graphene-supported materials, the analytical and therapeutic tools could be contemplated as parts of an “all-in-one” stage. The synergy purposes of the theragnostic approach aim to provide an accurate diagnosis of disease and individualized treatment of patients, and precise real-time examining of therapeutic effects [17,57–59]. For targeting a gene to cancerous sites, graphene-derived nanomaterials are dynamic candidates. They are employed for conveying DNA and RNA to cancer cells, with other nanomaterials individually two chief arbitrators to improve the DNA/RNA requisite and compression. Among them, graphene-supported materials, mostly GO, have gained huge attention recently, due to their exceptional 2D configuration, especially their great surface area, outstanding stability, simplicity of alteration, surface properties, high-quality biocompatibility, and intense industrialization potential [60,61].

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The single-atom layer configuration is advantageous for the adsorption and attaching of drug molecules in cooperation with the GO surfaces, higher drug loading capabilities. The physiological surroundings involve sophisticated structures, which include plentiful inorganic salt and proteins. In this form, GO devoid of surface functionalization should be uneven. Previous studies have reported that GO is liable to aggregation in an elevated salt solution, and it acquires nondefinite adsorption to a range of proteins that may reduce its stability, leading to side effects. Chemotherapy is the most commonly used approach in clinical anticancer purposes due to its extensive-spectrum and high-competence inhibition properties. However, anticancer drugs, such as doxorubicin, camptothecin, paclitaxel, vincristine, resveratrol, and sanguinarine, are typically insoluble in water, which has caused immense difficulty and deprived bioavailability in clinical applications. In addition, anticancer drugs frequently undergo from their nonspecific tumor ending, to short blood circulation instance, and rapid elimination during metabolism. The application of GO as a transporter for anticancer drugs can considerably improve their physicochemical characteristics and improve the anticancer efficiency [62–64]. Conservative therapeutic alternatives including chemotherapy and radiation therapy are most commonly used in the treatment of cancer. However, these methods have low success rates and have profound undesirable side effects on patients’ physical and mental health. Thus, less harmful treatments, which are more efficiently targeted, need to be developed for analgesic care and improvement of quality of life. Original regimes for instantaneous analysis and therapy, known as theragnostics, have modified the cancer treatment algorithm by the mixture of bioimaging by site-specific and site-selective targeting of tumors, devoid of destructive normal cells. The therapeutic responses of diverse derivatives of graphene like GO and graphene quantum dots indicated them as capable treatment agents and demonstrated the opportunity of utilizing ROS in cancer treatment. An improved perceptive of the position of ROS in the therapeutic method of utilization of graphene, in cancer treatment, will assist the improvement of graphene-based theragnostic stages [65–67].

7. Future prospect In conclusion, an array of carbon-based nanomaterials has been intensively investigated, in view of important developments in the area of theragnostic research. It is evident that carbon-based nanomaterial has unlocked an incredible perspective for the secure, efficient, and diagnosis technologies of cancer in comparison to traditional cancer therapies, even as enlisted nanomaterials has prospective applications in cancer treatment and therapy and continues to increase enormously. In similar cases, the swift advancement of theragnostic research offers deeper hope to cancer researchers on their viewpoints in

Functionalized graphene nanomaterials

developing a drug-carrier-nanosystem that increases the hope of treatment of the disease. Although cancer nanomedicine offers the latest prospect as an original and capable new approach for early detection, obtaining better treatment. It is vital to understand the complications of cancer and to estimate the controllability, reproducibility, and scalable synthesis of nanocarriers. However, it is believed that in the future, nanomedicines will change the cancer treatment technology. The evidence of the application of graphene in cancer theranostics areas yet at a preclinical level. Overall, current research has evaluated the potential applications of graphene in the theragnostic area. Several studies have employed graphene in photothermal therapy and fluorescent imaging for cancer cure. The blend of imaging and therapy could produce synergistic consequences to raise the intended killing with minimal side effects and by the preservation of biocompatibility. The extent of modification and conjugation of graphene can probably produce capable tools of theragnostic agents. Additional in vivo investigation will be needed to understand better the real-world applications of graphene. Furthermore, the phases of graphene generation, toxicity, and probable cancer theragnostic advances for extra derivatives of graphene, viz., graphene nanoribbons, nanoplatelets, three-dimensional foams, nanopores, and porous nanosheets, will need to be investigated.

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[54] S. Stankovich, R.D. Piner, X. Chen, N. Wu, S.T. Nguyen, R.S. Ruoff, Stable aqueous dispersions of graphitic nanoplatelets via the reduction of exfoliated graphite oxide in the presence of poly(sodium 4-styrenesulfonate), J. Mater. Chem. 16 (2006) 155–158. [55] C.M. Santos, J. Mangadlao, F. Ahmed, A. Leon, R.C. Advincula, D.F. Rodrigues, Graphene nanocomposite for biomedical applications: fabrication, antimicrobial and cytotoxic investigations, Nanotechnology 23 (2012) 395101. [56] J. Liu, W. Yang, L. Tao, D. Li, C. Boyer, T.P. Davis, Thermosensitive graphene nanocomposites formed using pyrene-terminal polymers made by RAFT polymerization, J. Polym. Sci. 48 (2010) 425–433. [57] C. Chung, Y.K. Kim, D. Shin, S.-R. Ryoo, B.H. Hong, D.-H. Min, Biomedical applications of graphene and graphene oxide, Acc. Chem. Res. 46 (2013) 2211–2224. [58] P. Rong, K. Yang, A. Srivastan, D.O. Kiesewetter, X. Yue, F. Wang, L. Nie, A. Bhirde, Z. Wang, Z. Liu, G. Niu, W. Wang, X. Chen, Photosensitizer loaded nanographene for multimodality imaging guided tumor photodynamic therapy, Theranostics 4 (2014) 229–239. [59] D. de Melo-Diogo, C. Pais-Silva, E.C. Costa, R.O. Louro, I.J. Correia, D-α-tocopheryl polyethylene glycol 1000 succinate functionalized nanographene oxide for cancer therapy, Nanomedicine 12 (2017) 443–456. [60] H.S. Jung, W.H. Kong, D.K. Sung, M.-Y. Lee, S.E. Beack, D.H. Keum, K.S. Kim, S.H. Yun, S.K. Hahn, Nanographene oxide–hyaluronic acid conjugate for photothermal ablation therapy of skin cancer, ACS Nano 8 (2014) 260–268. [61] J.P. Rourke, P.A. Pandey, J.J. Moore, M. Bates, I.A. Kinloch, R.J. Young, N.R. Wilson, The eeal graphene oxide revealed: stripping the oxidative debris from the graphene like sheets, Angew. Chem. 123 (2011) 3231–3235. [62] D. Ma, L. Dong, M. Zhou, L. Zhu, The influence of oxidation debris containing in graphene oxide on the adsorption and electrochemical properties of 1,10-phenanthroline-5,6-dione, Analyst 141 (2016) 2761–2766. [63] X. Sun, Z. Liu, K. Welsher, J.T. Robinson, A. Goodwin, S. Zaric, H. Dai, Nanographene oxide for cellular imaging and drug delivery, Nano Res. 1 (2008) 203–212. [64] W. Zhang, Z. Guo, D. Huang, Z. Liu, X. Guo, H. Zhong, Synergistic effect of chemophotothermal therapy using PEGylated graphene oxide, Biomaterials 32 (2011) 8555–8561. [65] R. Miao, L. Wang, M. Zhu, D. Deng, S. Li, J. Wang, Effect of hydration forces on protein fouling of ultrafiltration membranes: the role of protein charge, hydrated ion species, and membrane hydrophilicity, Environ. Sci. Technol. 51 (2014) 167–174. [66] X. Liu, X. Zhang, M. Zhu, G. Lin, J. Liu, Z. Zhou, PEGylated Au@Pt nanodendrites as novel theranostic agents for computed tomography imaging and photothermal/ radiation synergistic therapy, ACS Appl. Mater. Interfaces 9 (2014) 279–285. [67] S.H. Hu, Y.W. Chen, W.T. Hung, I.W. Chen, S.Y. Chen, Quantum-dot-tagged reduced graphene oxide nanocomposites for bright fluorescence bioimaging and photothermal therapy monitored in situ, Adv. Mater. 24 (2012) 1748–1754.

CHAPTER 2

Functionalized carbon nanomaterials: Fabrication, properties and potential applications Osman Polata, S. Gorkem Gizera, Mehtap Sahinerb, and Nurettin Sahinera,c,d a

Department of Chemical & Biomedical Engineering, and Materials Science and Engineering Program, University of South Florida, Tampa, FL, United States b Department of Bioengineering, Faculty of Engineering, Canakkale Onsekiz Mart University, Terzioglu Campus, Canakkale, Turkey c Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey d Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

1. Fabrication of functionalized carbon nanomaterials In the last few years, carbon-based nanomaterials have been the subject of focus in the scientific community, which resulted in groundbreaking achievements in energy storage [1–7], renewable energy [1,8–10], biomedical applications [11–14], aerospace [15,16], and sensor applications [17,18]. A search of the Web of Science database in December 2021 was used to illustrate the publications containing the words “carbon nanotubes” and “graphene” (Fig. 1). These two materials showed the greatest number of publications for carbon nanomaterials and demonstrate the growing interest in the scientific community. This section of the book will briefly touch the methods of fabrication of some carbon nanomaterials, namely graphene, carbon nanotubes (CNTs), carbon dots (CDs) and graphitic carbon nitride (g-C3N4).

1.1 Functionalization of functionalized carbon nanomaterials Functionalization is the process of introducing specific functional groups or molecules to the surface of materials to change their properties in a manner that is fit for the specific application needed without altering the essence of the material. Despite the amazing characteristics of carbon nanomaterials, surface functionalization is essential, for example, for biomedical applications. This is due to the fact that most carbon nanomaterials have high toxicity and low biocompatibility if used without the appropriate modifications. Furthermore, some carbon nanomaterials with low oxygen content such as graphene are hydrophobic in polar solvents and aggregate quickly. Additionally, low dispersion and aggregation due to strong van der Waals forces are associated with carbon nanomaterials. To overcome these drawbacks, modifications and functionalization of these Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00012-1

Copyright © 2023 Elsevier Ltd. All rights reserved.

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materials are necessary. For example, introducing polyethylene glycol (PEG) [19], polyethylenimine (PEI) [20], polyvinyl alcohol [21], and chitosan [22] to the surface can be beneficial. As a result, research into the functionalization of carbon nanomaterials has grown exponentially in the last decade [1]. The functionalization methods used for graphene and other carbon layered nanomaterials, such as CNTs, can be divided into covalent and noncovalent approaches. The latter method depends on physical bonding and intermolecular interactions such as van der Waals interactions, electrostatic interactions, H-bonds, π-stacking interactions, etc. [11,12]. Covalent functionalization is achieved through the covalent linkage between functional groups and the carbon skeleton of the material [11,23,24]. For example, the functionalization of graphene can take place on the two faces, the edges, and at the defect sides. If comparing the exposed specific surface areas of CNTs and graphene, the latter is higher but less reactive due to the missing bond tension that is caused by the curvature on CNTs [25].

Functionalized carbon nanomaterials: Fabrication, properties and potential applications

Covalent modification introduces functional groups such as carboxyl, hydroxyl, or epoxy groups to the surface of the material. In the process, the hybridization of carbon atoms is changed from sp2 to sp3. Direct covalent sidewall functionalization and indirect covalent sidewall functionalization are two types of covalent functionalization of CNTs [26]. Whereas the former is equal to the covalent modification of graphene, the latter takes advantage of chemical transformation of carboxylic groups at the open ends and holes in the sidewalls [26]. On the other hand, noncovalent modifications avoid this change of hybridization, allowing the intrinsic characteristics to be preserved. Instead, the functionalization is achieved through adsorption forces. CDs often have low quantum yield, which has led to extensive research on improving their fluorescence properties via surface functionalization and doping with heteroatoms [17]. In addition, studies on how to lower the cytotoxicity and improve biocompatibility show that modification with different functional groups on graphene quantum dots (GQDs) has little effect [17,27]. However, the removal of oxygen function groups could enhance the photostability and decrease the cytotoxicity [17,28]. Due to its high biocompatibility and facile synthesis, g-C3N4 is a fascinating material for therapeutic applications. For example, it can be utilized in cancer-directed photodynamic therapy [29]. Additionally, its optical properties, low cytotoxicity, and easy functionalization make it a promising new imaging agent.

1.2 Graphene Generally speaking, there are two pathways for the synthesis of graphene: the “top-down” and the “bottom-up” methods [8,30–33]. The first approach makes use of the fact that graphite is nothing else than stacked up graphene layers; the objective is to separate these stacked up layers into single layers, namely graphene. The oldest known graphene synthesis method is a top-down approach, first published in 2004 by Kostantin Novoselov and Andre Geim, who were later awarded the Nobel Prize. The procedure is simple: put graphite between two tapes and strip away layer for layer until you are left with a single layer of graphene. This process is also called exfoliation. The top-down approach can be grouped into mechanical exfoliation [8,30–33], chemical exfoliation [8,30–33], electrochemical exfoliation [30–32], chemical fabrication/reduction [30,33], and arc discharge [32]. On the other hand, the bottom-up approach utilizes carbon molecules from alternative sources [31] such as carbonaceous gas [33]. They can be separated in chemical vapor deposition (CVD) [30,32–34], epitaxial growth [30,32,33], chemical synthesis [30], pyrolysis [30,33], and plasma synthesis [33]. Fig. 2 displays the groupings of graphene synthesis. 1.2.1 Top-down approaches Chemical exfoliation Chemical exfoliation is the preferred top-down method to produce graphene, since it is a quick, two-step procedure [33]. First, the van der Waals forces between the layers are

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reduced, then the solution is heated in a fast manner or sonicated to carry out the exfoliation of graphene into single or few layers [33]. When using such a system, the synthesized graphene tends to stack back together. To prevent this problem, surfactants or dispersing agents can be added before the exfoliation process [31]. Electrochemical exfoliation The setup for this synthesis method consists of a graphite-based working electrode, a reference electrode, electrolyte, and a power source. Depending on the type of potential applied, the exfoliation can be categorized into anodic and cathodic exfoliation [35]. Anodic exfoliation happens when the positive current draws electrons from the working electrode, creating a positive charged graphite anode. This encourages the intercalation of negatively charged ions from the electrolyte, which increases the interlayered spacing and subsequently results in exfoliation. Cathodic exfoliation happens when the working electrode is negatively charged, attracting positively charged ions. As in the anodic exfoliation, this leads to a separation in single and limited layered graphene. The electrolyte can also be treated with functionalizing agents, which results in functionalized graphene after the exfoliation process. Chemical fabrication Another way to synthesize graphene is through the reduction of graphite oxide. Graphite is oxidized via oxidants such as nitric acid, potassium permanganate, and concentrated sulfuric acid [33]. Afterwards, the same procedure as described for the chemical

Functionalized carbon nanomaterials: Fabrication, properties and potential applications

exfoliation is carried out (fast heating or sonication), and reducing agents such as hydrazine are used to remove the oxygen groups. Arc discharge The arc discharge method uses high purity graphite electrodes in the presence of a buffer gas [32]. Different buffer gases have different advantages; for example, H2 can hinder the rolling of graphene into nanotubes, because of the termination of “dangling bonds” [36]. Helium, on the other hand, results in graphene with a high crystallinity [37]. The diameters of the electrodes vary between 6 and 12 mm; they are placed with a 1–2 mm spacing in a chamber filled with the buffer gas [38]. Additionally, the chamber contains evaporated carbon molecules and a certain amount of metal catalyst particles (e.g., cobalt, nickel, iron) [38]. The arcing happens when a direct current is passed through the chamber, the pressure builds up, and the temperature rises. Through this process, the evaporated carbon molecules solidify on the negative electrode tip; at the same time, the positive electrode is consumed. The solidified carbon molecules consist of CNTs and graphene. 1.2.2 Bottom-up approaches Pyrolysis Choucair et al. [39] presented a gram-scale production through pyrolysis for graphene based on a solvothermal synthesis. Sodium and ethanol are mixed at a 1:1 M ratio in a reactor vessel at 220 °C for 72 h to yield a solid solvothermal product. This graphene base material is then pyrolyzed, and the remains are washed with deionized water, vacuum filtered, and dried in a vacuum oven at 100 °C for 24 h. This process results in a yield of graphene of approximately 0.1 g per 1 ml of ethanol. Epitaxial growth In this method silicon carbide (SiC), the carbon precursor, is heated to high temperatures,
1100 °C [31], resulting in a single or bi-layer graphene on the Si face of the crystal and few-layer graphene on the C face [33]. It results in high-quality graphene but is strongly affected by the process parameters such as temperature and pressure heating rate [33]. Since the cost of SiC is relatively high in relation to the low yield, this method is not suitable for industrial manufacturing [31]. Chemical vapor deposition CVD can simply be described as the deposition of gaseous reactants onto a substrate. First, the reaction chamber with the substrate will be heated in a controlled atmosphere. When a certain temperature is reached, it will be maintained to reduce (or, in other words, to clean) the surface of the substrate and modify its surface morphology as far as possible. During this process, the evaporation of the metal substrate should be avoided [34].

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Afterwards, the precursors for the graphene growth are introduced into the chamber. There are many different methods of CVD such as low-pressure chemical vapor deposition (LPCVD), ultra-high vacuum chemical vapor deposition (UHVCVD), etc. Depending on the CVD method and the catalyst used, substrate graphene may grow during this step or during the cooling process [33,34]. After the chamber is cooled in a proper atmosphere, it is filled with inert gas before being opened. Plasma synthesis The plasma synthesis of graphene involves plasma-enhanced chemical vapor deposition (PECVD) and plasma doping. It requires precise controller over the process parameters such as temperature, pressure, deposition time, type of precursors) [30]. In this method, the different types of plasma such as energetic ions, highly reactive radicals, electrons, a fraction of the undissociated source gas, and photons affect the progression [33]. PECVD can further be divided into direct current plasma-enhanced chemical vapor deposition (DC-PECVD), inductively coupled plasma-enhanced chemical vapor deposition (ICP-PECVD), and microwave plasma-enhanced chemical vapor deposition (MW-PECVD). In DC-PECVD, the plasma is sustained through the secondary electrons, which are formed by the accelerated ions; ICP-PECVD and MW-PECVD, on the other hand, form plasma through wave heating with the absence of electrodes [33]. The choice of method affects the purity of the synthesized graphene. In addition to PECVD, plasma doping is being used to dope graphene with other substances to achieve a product with different electrical properties. Chemical synthesis The research on chemical synthesis of graphene has shown promising results in recent years. Moreno et al. [40] presented a bottom-up method to synthesize multifunctional nanoporous graphene. It can roughly be summarized into two steps: first graphene nanoribbons are synthesized from a monomer precursor labeled DP-DBBA (diphenyl–10,100 -dibromo-9,90 -bianthracene), then these nanoribbons are interconnected to form nanoporous graphene. This method demonstrates a single-pot synthesis for the chemical production of graphene without the need for expensive devices.

1.3 Carbon nanotubes Carbon nanotubes (CNTs) are practically rolled up graphene and can be divided into single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs) [38,41,42]. Different forms of SWCNTs exist, differentiated by the arrangement of carbon atoms in the molecule. Depending on the vector coordinates, they are divided into armchair, zig-zag, and chiral SWCNTs [38,41,42]. In the past few years, many techniques have been employed to synthesize CNTs, but the main three methods are laser ablation, arc discharge and chemical vapor deposition [38,41,42].

Functionalized carbon nanomaterials: Fabrication, properties and potential applications

Whereas the first two are rather high-temperature techniques, operating at 1200 °C and 1700 °C, respectively, CVD methods are usually utilized at 20 of carbon atoms on any spherical substrate is one of the most unique features observed in fullerenes. The carbon atoms in fullerenes are sp2 hybridized and covalently bonded with each other. Fullerenes are more often found on the surfaces of spheres occupying the

Fig. 2 (A) Various defects in graphene. (B) SWCNTs, having defects like vacancies, edge/ends, sp3 defects, and pentagon/heptagon [34]. Reprinted with permission of the American Chemical Society.

Fundamentals and functionalization of CNTs

vertices of the corresponding hexagons and pentagons. Fullerene with the molecular formula C60 has been studied and investigated in great detail. It comprises symmetric and spherical molecules containing around 60 carbon atoms, occupying the vertices of 12 pentagons and 20 hexagons or 60 such carbon atoms consisting of 20 six-member rings and 12 five-member rings [35]. Fullerenes are now extensively used in biomedical applications such as for gynecological malignancies, MRI, and cancer therapies [36–40] (Fig. 3).

5. Carbon nanofibers Graphene sheet stacked cylindrical nanostructures with numerous configurations are termed as carbon nanofibers (CNFs). These possess the same electric properties and mechanical strength as CNTs. Due to the stacking of graphene sheets with different shapes and placing them in different orientations, CNFs are expected to possess extra edge sites on their outer walls in contrast to CNTs. As a result of these edged sites, it becomes feasible for CNFs to transfer electrons in solution and subsequently in the detector substrate. Due to their properties such as considerable electrical conductivity, increased surface area, biocompatibility, and ease of fabrication, CNFs are ideal candidates for use in electrochemical sensing devices. In addition, they are easily functionalized for a particular detection mechanism.

Fig. 3 (A) Formation of C60 molecule with graphene sheets. (B) Truncated icosahedral structure of fullerene. (C) Schematic portrayal of C60 molecule [34]. Reprinted with permission of the American Chemical Society.

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6. Synthesis of different carbon nanomaterials 6.1 Carbon nanotubes (CNTs) CNTs may be synthesized in various methods. In this chapter we have described one of the most used synthesis methods, chemical vapor deposition (CVD). The following subsection is dedicated to this synthesis route. 6.1.1 Chemical vapor deposition (CVD) In CVD, carbon nanotubes are synthesized by utilizing various hydrocarbon gasses as the basic source of carbon. It is carried out inside a furnace at a temperature range of 500–900 °C. An inert gas is made to fill the contents of a quartz tube inside which the substrate containing crucible already coated with the catalyst nanoparticle is kept. The hydrocarbon gas being fed into the quartz tube is pyrolyzed to produce vapors of carbon atoms. The presence of inherent Van der Waals attractive forces causes the carbon atoms to get attached to the substrate, forming multiwalled carbon nanotubes (MWCNTs) [41]. Fe, Co, and Ni catalyst nanoparticles are utilized to make singlewalled carbon nanotubes. CVD is considered to be a relatively economic and simple technique for the synthesis of carbon nanotubes at atmospheric pressure and relatively low temperatures, as compared to the other two synthesis techniques. In the arc discharge and laser ablation techniques, the synthesized CNTs are comparatively better than the CNTs grown by CVD. However, the purity and yield in the case of CVD are better than those of the arc and laser methods. In tuning the CNT architecture, CVD is considered to be a superior technique.

6.2 Synthesis of graphene The method outlined by Giem and Novaselov [29] has been efficient in producing defect-free graphene. Despite its successful production in the laboratory, its small size has kept it from being used for commercial applications. The same peeling-off technique has been carried out in solvents like sodium dodecylbenzenesulfonate solution [42] and N-methyl pyrrolidone [43], and has been reported. Numerous techniques have been used for the effective synthesis of graphene, which include CVD, solvothermal production, liquid-phase exfoliation, and several other oxidation methods [29,44]. The reduction of graphene oxide has proved to be an effective process for the synthesis of graphene. However, the associated defects are greater in such synthesis as reported [45]. The method of CVD has been employed for the effective fabrication of devices with graphene-modified electrodes for the fabrication of electrochemical sensors.

6.3 Synthesis of fullerene Fullerenes can be classified as a 0D form in the family of carbon allotropes. Moreover, they can be envisaged as graphene sheets being made into a sphere. These allotropes

Fundamentals and functionalization of CNTs

can be found in various sizes and forms. They can be synthesized by using various techniques, namely electron beam ablation, arc discharge and sputtering [46,47]. The first synthesis of fullerenes was carried out by the evaporation of graphite electrodes in the presence of helium [48,49]. The soot of combustion flames is also reported to contain fullerenes [50–52].

6.4 Synthesis of carbon nanofibers Typically, CNFs are synthesized from a mixture of C2H5OC2H5, Zn powder, and Fe powder. Firstly, 7.5 mL of C2H5OC2H5 along with 1 g of Zn powder and 0.5 g of Fe powder are placed in a stainless-steel autoclave 20 mL. After sealing the autoclave, the mixture is heated for 10 h at 650 °C. The mixture is then cooled at room temperature and washed sequentially with dilute HCl, distilled water, and ethanol. Finally, the product is dried in a vacuum at 50 °C for 4 h [53].

7. Functionalization of carbon nanomaterials 7.1 Functionalization of carbon nanotubes Due to the complex structure of CNTs, their solubility in most organic and aqueous solutions gets affected. To mitigate this problem, surface functionalization of CNTs was proposed [54,55]. This is mainly divided into covalent and noncovalent functionalization, based on the bonds formed between CNTs and the introduced functional groups [55]. 7.1.1 Covalent functionalization In the covalent functionalization technique, the functional groups are made to stick to the surface of the CNTs with the help of a covalent bond. In these bonds, at least one pair of electrons is shared between introduced functional groups and the synthesized carbon nanotubes, which in turn help in increasing dispersibility and reactivity. For covalent functionalization, functional groups such as CH3NH2 and COOH are attached to the surface of CNTs [56,57]. These surface modifications eventually result in increased solubility of CNTs in standard solvents. CNTs were functionalized with the help of porphyrindendrons by Palacin et al., by the formation of a covalent linkage between ZnP and SWNT [58]. 7.1.2 Noncovalent functionalization Van der Waals force, mainly π-π interactions, is the main reason behind noncovalent functionalization [59]. The noncovalent modification of CNTs with pyrenefunctionalized nickel complexion was reported by Tran et al. [60]. Additionally, a thermodynamic study reporting the relation between porphyrin molecules and nanotubes diameter was reported, showing that the strong binding of tetraphenyl-porphyrin molecules is preferable in nanotubes with large diameters.

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7.1.3 Direct side-wall functionalization Direct side-wall functionalization is primarily the change of hybridization of a carbon atom from sp2 state to sp3 state through a nucleophilic or electrophilic type attack and cycloaddition onto the aromatic rings [61,62]. 7.1.4 Endohedral functionalization Many reactions take place in the nano space, which is located in the inner environment of the carbon nanotubes. This nano space can be exploited with the help of endohedral functionalization [63]. Various synthetic methods can be used to encapsulate molecules and atoms in this nano space of CNTs. 7.1.5 Exohedral functionalization To solubilize, purify, and improve the properties of CNTs, exohedral functionalization is regarded as a prospective approach. It is considered to have fewer limitations than endohedral functionalization. 7.1.6 Advancements in functionalization of CNTs The conventional techniques of functionalization of carbon nanotubes have been discussed in the earlier subsections. This subsection is dedicated to recent advancements in the domain of CNT functionalization. Amino functionalized CNTs can be achieved by introducing carboxyl groups on the surface of the CNTs. An oxidative procedure is followed in the amidation of CNTs [64]. Additionally, the synthesis of functionalized SWCNTs was studied by Abjameh et al. [65]. The inherent presence of amide groups and subsequent carboxylic acid was confirmed by FTIR analysis.

7.2 Functionalization of graphene nanomaterials One of the extensively used methods of functionalizing graphene is a surface modification where cohesive force between the graphene sheets is manipulated physically and chemically [66]. There are two approaches of surface functionalization, covalent and noncovalent, which are directly dependent on van der Waals forces [67].

7.3 Functionalization of CNFs Mechanical modification and chemical treatment are the most well-known processes of CNF functionalization [68]. Mechanical modification is done in an attrition mill with a perpendicular ceramic bar which is placed in a container filled with a 2 mm diameter alumina medium and the material (CNFs) utilizing anhydrous 99.97% ethanol as the solvent. After applying a rotation speed of 350 rpm for 1 h, the speed is reduced to 50 rpm. The produced slurry is then dried until a cake of nanofiber is formed.

Fundamentals and functionalization of CNTs

Chemical reagents such as HCl, HNO3, and H2SO4 are commonly used for surface modification. Generally, CNFs and a typical solvent are taken in a 1:100 weight ratio and are heated at 80 °C for 1 h. After drying the produced slurry, functionalized CNFs are obtained. Table 1 lists some recent developments in the domain of carbon nanomaterials.

8. Important organizations, companies, and research groups working on functionalization of CNTs There has been enough research on the domain of carbon nanotubes and its allied nanomaterials. However, there have been few works which has specified the works undertaken by various organizations working on the commercialization of functionalized CNTs. In this section we have listed such organizations and provided their website links for the readers easy access and subsequent reference. • NanoIntegris: https://nanointegris.com • Base Pair Biotechnology: https://www.basepairbio.com • Birad Research: https://birad.biz • Nopo: https://nopo.in/web • Biois: http://www.biois.co.kr • Carbon Nanomaterial Laboratory: https://english.nsu.ru/research/divisions/ materials-and-technologies/23857 Table 1 Recent developments on functionalization of carbon nanomaterials. Year

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In this work, carboxylated MWCNTs were reacted with ethylenediamine (EDA); subsequently, on performing Michael addition reactions with acryloyl morpholine (ACMO), hydroxyethyl acrylate (HEA), and acrylamide (AM), a series of hydrophilic MWCNTs was synthesized. Here, a reliable one-step mechanism for fixing substantial amounts of HBPEI on the graphenic domains of MWCNTs, not only in defects, has been presented. This work describes a scalable, single-step electrochemical exfoliation of graphite to produce highly solution-processable fluorine-modified graphene (FG) for flexible and high-performance ionogel-based MSCs (FG-MSCs). The aim of this study was to use various procedures to functionalize CNFs that have already been synthesized, and to improve their ultimate qualities in order to boost their appeal as a high-tech material. The direct fluorination approach was used to test the inherent conductivity of SWCNTs.

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• BARC-http://www.barc.gov.in/technologies/cnt/index.html • The University of Sydney Nano institute: https://www.sydney.edu.au/nano/ our-research/research-programs/tailoring-carbon-nanomaterials.html

9. Conclusion In this chapter, we have listed some of the recent developments and advances in the synthesis and the various applications of carbon nanomaterials in numerous domains. The functionalization of CNTs has been keenly addressed due to their capacity to make the already available carbon nanomaterials gain increased efficacy. The covalent and noncovalent functionalizations of CNTs have been efficient in enhancing their electrochemical sensing performance. CNTs have also been able to accentuate the electrochemical reactions of various biomolecules. The inherently increased surface area of these CNTs renders them suitable for attaching the functional groups. Graphene inherently is a monolayer of the sp2 hybridized carbon atoms in the honeycomb structure. As a material, it has created a huge upsurge in research activities over the last decades, due to its high current density, thermal conductivity, and optical transmittance. Graphene is considered to be more effective and attractive than its allotropic counterpart, carbon nanotubes, as its 2D form is superior, concerning synthesis, to the low-dimensional CNTs. Graphene is an eligible candidate for the effective replacement of ITO in the form of transparent electrodes. Graphene can achieve transparency of more than 90%; congruently its low resistance provides an added feature to its novel properties. The photoluminescence phenomenon of carbon-based nanomaterials is due to the inherent quantum, confinement effect, surface defects, and various functionalization techniques. The strategy of quantum confinement and several intrinsic defect-based strategies are key factors in generating novel imaging properties which render these materials critical for their use in theragnostic applications. Additionally, carbon-based nanomaterials may support several diagnostic purposes with the help of chemical integration with therapeutics delivery for the effective and efficient treatment of traumas and diseases.

Acknowledgments Teachers Associateship for Research Excellence (TAR/2018/000195) funding with the support from the Science and Engineering Research Board (SERB) was used to assist this research, which was financed by the Department of Science and Technology (DST) Central, Government of India (S. Roy). We would particularly like to thank the Department of Science and Technology (DST), Ministry of Science and Technology, Government of India, for supporting this work through the MI IC#5 “Conversion of Sunlight to Storable Fuels” issued by DBT-DST Joint Funding Opportunity, Central Government of India through the Mission Innovation Programme DST(DST/TMD(EWO)/IC5-2018/06(G)) (S. Roy).

Fundamentals and functionalization of CNTs

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CHAPTER 5

Carbon nanomaterials: Fundamentals, functionalization, and applications Shikha Gulati, Kartika Goyal, and Sneha Vijayan Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India

1. Introduction Carbon nanotubes (CNTs) are made of carbon with diameters typically measured in nanometers. These are considered one of the strongest materials known to humans. Carbon nanotubes possess unique structural and electrical properties that make them ideal for a wide variety of applications [1]. Carbon nanotubes come in two principal forms (as shown in Fig. 1): • single-walled carbon nanotubes (SWCNTs); and • multiwalled carbon nanotubes (MWCNTs). In a typical CNT, the carbon is sp2 hybridized with a tubular structure having rolled-up sheets of graphene, as shown in Fig. 1. In addition to unique nanostructures, they display significant properties, some derived from the similar properties of graphite and some from their one-dimensional aspects. Depending on their chirality, CNTs can be either semiconductors or metals [2]. In the literature, metallic CNTs can carry an electric current density of 4  109 A/cm2, which is more than 1000 times greater than that of metals such as copper. Because of their 1D conductivity, CNTs exhibit ballistic transport along the tube direction, resulting in high intrinsic mobility, exceeding that of many semiconductors. These advantages make CNTs a potential and novel candidate for many applications: electronic devices including transistors, electron-field emitters, chemical/electrochemical sensors, biosensors, lithium-ion batteries, hydrogen storage cells, supercapacitors, and electrical shielding devices [3]. The other carbon nanomaterials discussed in this chapter include fullerenes, carbon quantum dots, and graphene. Fullerenes are hollow spherical molecules composed of layers of graphite, having zero-dimensional geometry. They are better and more economical alternatives to carbon nanotubes and graphene [4]. They find wide applications in lubricant materials, superconductors, and photoconductors, among others [5]. Carbon quantum dots are a novel class of carbon nanoparticles possessing stellar optical absorption capacity and stability and can be considered as an alternative to the conventional quantum dots based on toxic heavy metals [6]. Owing to their remarkable luminescence and photoelectric properties, they are used extensively in chemical sensing, bioimaging and Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00006-6

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Fig. 1 Types of CNTs.

sensing, optronics, and photovoltaic systems [7]. Surface functionalization helps improve their physicochemical properties, fostering better performance in the aforementioned applications. Graphene is a two-dimensional single-atom-thick allotrope of carbon, with an exceptional set of properties such as high mechanical strength and superior electrical and thermal conductivity [8]. It is often dubbed the “wonder material,” and finds applications in a plethora of fields such as catalysis, biomedicine, and energy storage. In this chapter, we elaborate on the fundamentals and synthetic strategies of the various carbon nanomaterials, and strategies for their functionalization, with special emphasis on the applications of functionalized carbon nanomaterials.

2. General characteristics of carbon nanomaterials Carbon is a versatile element capable of existing in various orbital hybridizations, namely sp., sp2, and sp3, which confer it with the phenomenal ability to arrange with other carbon atoms/other elements, giving rise to an endless list of molecules, compounds, and nanostructures. The discovery of Buckminsterfullerene C60 in 1985 established a breakthrough in materials science, paving way for a new class of nanomaterials called carbon nanomaterials (CNMs). This novel class became more popular after the discovery of carbon nanotubes in 1991 [9], and has witnessed tremendous progress in the last few decades, with the extraordinary graphene being the latest addition. CNMs include fullerenes, carbon nanotubes, carbon quantum dots, nanodiamonds, graphene, nano-onions, and nano-fibers, among others [10,11]. These nanomaterials have a size range of 1–100 nm and differ in properties including the structure and chemical reactivity [12]. The various carbon nanomaterials dealt with in this chapter are presented in Fig. 2.

Carbon nanomaterials

Fig. 2 Various carbon nanomaterials.

2.1 Insights into different carbon nanomaterials 2.1.1 Carbon nanotubes (CNTs) Ever since its serendipitous discovery in 1991 by Iijima [9], CNTs have garnered the greatest attention among all CNMs, due to their tunable physical properties, functionalization potential, and unique electrochemical and optical properties. They are onedimensional CNMs, members of the fullerene structural family, and have an immaculate cylindrical structure made of rolled-up sheets of graphene with capped or open ends [13]. CNTs are categorized into single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs), depending on the number of layers of graphene rolled up to form the tubular structure [14]. The lengths of CNTs range from micrometers to centimeters, and the outer diameter is up to 2 nm in the case of SWCNTs and between 5 and 20 nm for multiwalled CNTs [15]. Owing to the strong sp2 bonding, they possess excellent mechanical strength with extraordinary flexibility and rigidity (the Young’s modulus for SWCNTs is as high as 1 TPa) [10,16]. One of the unique features of SWCNTs is their variable thermal conductivity—SWCNTs function as insulators when the thermal conductivity is measured at right angles to the axis, while the conductivity along the axis exceeds that of copper 10-fold [14]. CNTs are employed in a plethora of applications including biosensing, environmental remediation, and nanomedicine. 2.1.2 Fullerenes This zero-dimensional allotrope of carbon was first synthesized by Kroto and coworkers in 1985 [17]. Due to the structural resemblance with geodesic domes designed by the eminent

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architect, R. Buckminister Fuller, the nanomaterial was named Buckminister fullerene (C60) [17]. C60 is a single-atom-thick, hollow sphere consisting of 60 sp2-hybridized carbon atoms, arranged as 12 pentagons and 20 hexagons. The most important noteworthy characteristic of this molecule is its exceptional symmetry. With a whopping 120 symmetry operations, it holds the title of the molecule with the highest number of symmetry operations [18]. Over the years, many members of the fullerene family have been reported, including C70, C72, C76, C80, C84, C240, and C540, all of them consisting of different numbers of fused hexagons and 12 pentagons. These are collectively called buckyballs due to their spherical shape [19]. They can be represented by the general formula Cn, where n is the total number of carbons [12]. The strained structure arising due to bent sp2 hybridized carbon-carbon bonding is responsible for the high reactivity of fullerenes [20], and they can undergo a broad range of reactions including halogenation, oxidation, reduction, etc. Since the caged structures are wholly composed of sp2-hybridized carbon atoms, fullerenes function as electron acceptors due to the more electronegative nature of these carbon atoms [20]. They are soluble in organic solvents and the solubility is found to decrease with an increase in size [21]. Their unusual structure endows them with remarkable magnetic, optical, electronic, and superconducting properties, among others [22]. 2.1.3 Carbon quantum dots (CQDs) Carbon quantum dots (CQDs) are also known as carbon dots (C-dots/CDs), carbon nanodots (CNDs), and fluorescent carbon nanoparticles [7,23]; they are a relatively new class of quantum dots, adventitiously discovered by Xu et al. in 2004 [24]. They are quasispherical nanoparticles smaller than 10 nm, possessing incredible photoluminescence, outstanding water dispersibility, chemical stability, and inertness, and are often dubbed as “carbon nanolights” [25]. The presence of a large number of oxygenic functional groups on the surface makes them soluble in aqueous media and offers enormous functionalization potential [23]. Their ability to function as electron acceptors or donors, combined with the excellent luminescence properties, fosters them in applications of chemical sensing and optronics. Their application in biomedicine can be attributed to their low levels of toxicity and significant biocompatibility, which set them apart from other quantum dots [7]. Furthermore, owing to effective solar light absorption capability and photoinduced charge transfer, CQDs find application in photocatalysis and photovoltaic systems [26]. 2.1.4 Graphene Graphene is a two-dimensional nanomaterial that consists of a single layer of sp2-hybridized carbon atoms forming hexagonal rings, and is only as thick as an atom [11,27]. It serves as the building unit for graphite and all other graphitic allotropes [28]. It is one of the most researched materials of recent times due to its fascinating properties. Graphene has a high specific surface area (up to 2630 m2/g) and is the lightest yet strongest material discovered to

Carbon nanomaterials

date [29,30]. It has the most flexible crystal and is incredibly impermeable to gases [31]. It exhibits a marvelous thermal conductivity of more than 5000 W/mK [32] and outstanding electrical conductivity. The charge carriers in graphene function as relativistic quasiparticles having no mass, with unparalleled intrinsic mobility (200,000 cm2/Vs), and can be explained based on the Dirac equation [27,29,33].

3. Synthesis of various carbon nanomaterials 3.1 Carbon nanotubes Two types of carbon nanotubes can be prepared: single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs). The general techniques for the synthesis of carbon nanotubes are as follows: • Arc discharge method: This is the oldest and one of the widely employed methods for the synthesis of CNTs. In a chamber containing inert gas like He, two graphite electrodes of high purity are separated by 1–2 mm. By the arc evaporation of the graphite electrode at temperatures above 3000°C, CNTs are obtained in soot-like deposits [34]. SWCNTs are prepared using arc discharge in an H/Ar atmosphere wherein the anode is composed of graphite and transition metal catalysts such as Ni, Ag, Fe, Pt, Co, etc., or a combination of elements like Co-Cu, Fe-Ni, Ni-Ti, among others [35]. On the other hand, the use of transition metal catalysts is not required for the production of MWCNTs. Though this technique produces superior-quality CNTs, the crude product is often contaminated with undesirable impurities such as residual catalyst particles or amorphous carbon. Furthermore, the difficulties in scaling up the process and the exorbitant cost of production limit the use of this technique [36]. • Laser ablation: This method produces high-quality SWCNTs by the vaporization of a graphite target doped with a metal catalyst in an inert gas atmosphere using a laser (119). The system is generally heated in a furnace at high temperatures, above 1000°C. The different factors that determine the properties of carbon nanotubes prepared by this technique include laser energy fluence, the wavelength of oscillation, the chemical composition of the substrate, the graphite target, and the buffer gas [34]. Despite the benefits of obtaining carbon nanotubes of excellent quality and purity, whose diameters can be regulated, the laser ablation method is not economical and not feasible to scale up. • Chemical vapor deposition (CVD): In this method, CNTs are formed by the decomposition of hydrocarbons such as methane, ethane, ethene, ethyne, ethanol, etc. over transition metal catalysts [35]. The operating temperature is in the range of 650–900°C. This method results in a low yield of CNTs, but of very high purity, and favors large-scale production economically. In addition to catalytic CVD, other variants include plasma-enhanced CVD (PECVD), hot filament CVD, oxygenassisted CVD, and radio-frequency CVD [34].

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3.2 Fullerenes • Laser vaporization of carbon: This was the first synthetic route for the production of fullerenes, but has the drawback of minuscule yields. In this method, a pulsed laser is focused on a rotating disc of graphite in a helium (inert) atmosphere. The process is carried out at elevated temperatures and causes the cooling of the plasma to form stable clusters of fullerene [20]. • Electric Arc method: This technique was conceived by Huttman and Kratchmer in 1990 [18], and makes use of the benchtop reactor designed by Wudl and his group in 1991 [37]. The apparatus consists of two graphite rods (one slightly thicker than the other), a copper electrode, a pyrex bell jar, a vacuum system, and a manometer [20]. In an inert atmosphere, an electric arc is generated between the two graphite rods by passing an AC/DC current to the thin rod attached to the copper electrode, which causes its evaporation until it has no contact with the other rod. The fullerenes are extracted from the soot with toluene, and separated and purified by liquid chromatography [37]. • Resistive Arc heating of graphite: This method was established as an alternative to the electric arc method by Haufler and coworkers in 1991. Herein, in a partial helium atmosphere, fullerenes are obtained in grayish-white soot-like deposits by the resistive heating of graphite rods [18]. Unlike in the electric arc method, the two graphite rods are not in direct contact with each other but are very close. This method produces a slightly better yield (15%) than the electric arc method (5%–10%) [20]. • Pyrolysis of polycyclic aromatic hydrocarbons (PAHs): In this method, PAHs having the requisite framework of C60 structure are “rolled up” to produce various homologs of fullerenes [18]. One of the first examples of fullerene synthesis via this method is the pyrolysis of naphthalene in argon steam at a temperature of 1000°C [38]. Boorum et al. produced fullerene C60 by the laser irradiation (337 nm) of a PAH comprising 60 carbon atoms [39].

3.3 Carbon quantum dots (CQDs) • Chemical ablation: CQDs can be prepared by carbonizing small organic molecules using strong oxidizing acids like H2SO4 followed by controlled oxidation with HNO3 to break down the carbonaceous materials obtained to discrete carbon quantum dots. This method offers the advantage of the availability of a wide variety of carbon sources. However, harsh reaction conditions and drastic multistep processes involved limit the use of the method [7]. • Electrochemical carbonization: This is a hassle-free one-step process wherein CQDs are prepared from bulky carbon molecule precursors. The size and structure of the CQDs can be precisely controlled by changing the potential applied. The major drawback of this method is that very few small molecules can be used as precursors in this synthetic route. Hou et al. demonstrated a one-pot electrochemical synthesis of

Carbon nanomaterials

water-dispersible fluorescent CQDs from sodium citrate and urea as precursors, using Pt electrodes at a potential of 5 V for an hour. The as-synthesized CQDs had an average size of 2.4 nm and could effectively detect Hg2+ in water samples [40]. • Laser ablation: In this technique, carbon quantum dots are prepared in organic solvents using a laser pulse of high energy [12]. Although it is a rapid technique, it results in low quantum yield (QY) of the product, and the size of the QDs cannot be precisely controlled. Advances in research have been focused on solving these shortcomings. Recently, Cui et al. employed dual-beam pulsed laser ablation to produce homogeneous CQDs with significant QY, from cheap carbon cloth. The as-prepared CQDs exhibited remarkable photoluminescence (PL) emission and find application in cell bioimaging [41]. • Microwave pyrolysis: Synthesis of CQDs by microwave irradiation of organic compounds is a quick, cost-effective, environmentally friendly technique suitable for large-scale production [7,12]. The CQDs prepared by this method are dispersible in aqueous media. In recent work, Yu, Wang, and coworkers successfully synthesized green-emissive CQDs via microwave pyrolysis in just 60 s. The prepared CQDs could be employed in cell imaging, optoelectronic devices, and pH sensing applications [42]. • Hydrothermal/solvothermal carbonization: In hydrothermal carbonization (HTC), a solution of organic precursor in water/organic solvent is subjected to high temperature in an autoclave. This method yields CQDs smaller than 10 nm [12]. CQDs of uniform size distribution can be prepared from various precursors like citric acid, banana juice, orange juice, glucose, etc. In recent work, Shen et al. studied the effects of precursors (number of carbon atoms, length of the carbon chain, etc.) on the properties of carbon quantum dots. They synthesized CQDs via the hydrothermal method using glucose and citric acid as precursors. The experimental results indicated that the CQDs prepared from citric acid were smaller in size (2–4 nm) than those prepared from glucose (3–6 nm). Furthermore, the latter had better crystallinity which revealed the difference in completion of the carbonization process [43]. In solvothermal carbonization, the precursor is heated in high-boiling organic solvents. The product is then extracted from the solvent.

3.4 Graphene • Mechanical exfoliation: High-quality graphene can be obtained by this top-down technique of repeatedly peeling layers from graphite or graphitic materials including single-crystal graphite and highly ordered pyrolytic graphite (HOPG), using an electric field or ultrasonication or adhesive tapes [44]. However, being a daunting process, it is difficult to scale up for mass production. • Chemical exfoliation: This synthetic route involves two steps. In the first step, graphene-intercalated compounds (GICs) are formed by increasing the spacing between

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layers of graphite (by chemical oxidation). In the second step, sonication or rapid heating is done to exfoliate graphene [45]. Zhang and coworkers employed chemical exfoliation for the large-scale synthesis of few-layered graphene (FG) having three or four layers. By regulating the degree of oxidation of graphite, followed by sonication and reduction, they produced graphene as well as few-layered graphene [46]. • Thermal chemical vapor deposition (CVD): This is a relatively new technique. In this method, the substrate is diffused on gaseous precursor molecules at high temperatures. The growth of graphene is usually done on transition metal substrates such as Ni and Cu. The limitations of this technique include difficulty in controlling the number of layers, reducing the folds, and the growth of graphene is possible only on centimeter-scale substrates [45]. Other methods for the synthesis of graphene include chemical synthesis, plasma-enhanced CVD, epitaxial growth, and pyrolysis, among others.

4. Strategies for functionalization In addition to the phenomenal properties of CNTs, two main problems restrict their practical applications: • the dispersion of CNTs into matrices; and • the surface of CNTs does not provide physical interaction between CNTs and the matrix. Thus, in the face of such limitations, the reported modification of CNTs with other materials makes it more interesting and a novel candidate for a wide range of applications. Hence, CNTs are frequently functionalized with different polymers to improve the properties of the end product. The general principle forces involved in these methods are discussed in Table 1.

4.1 Covalent functionalization (chemical method) This method is based on the formation of the covalent bond between the functional groups and carbon forms of CNTs. It can be done at the end caps of nanotubes or at their sidewalls which have many defects. This direct sidewall functionalization cause two significant changes in the CNT system [47]: Table 1 General overview for the method of functionalization and principle involved. Method

Principle

Chemical method

(a) (b) (a) (b)

Physical method/polymer wrapping

A change in hybridization from sp2 to sp3 Defect transformation Van der Waals force π-π stacking

Carbon nanomaterials

• a change in hybridization from sp2 to sp3; and • a simultaneous loss of p-conjugation. In this process, generally, a reaction is carried out with molecules of high reactivity. In the earlier studies, fluorination of CNTs has gained significant attention due to the fact that CNT walls are inert. Many researchers reported the successful accomplishment of the replacement of fluorine atoms by amino, alkyl, and hydroxyl groups [47]. Other successful covalent methods that were reported include: (i) cycloaddition, e.g., Diels-Alder reaction, carbene and nitrene addition [48]; (ii) chlorination, bromination [49]; (iii) hydrogenation [50]; and (iv) azomethineylides [51] These methods are known significantly for their good results. In addition, it was stated that on exposure of CNTs with a strong acid like HNO3 or H2SO4, or with strong oxidants such as KMnO4 or ozone, they open up their tube-like structure; as a result, they produce the oxygenated functional groups such as carboxylic acid, ketone, alcohol, and ester groups. These functional groups have rich chemistry and the CNTs can be used as precursors for further chemical reactions [51]. The CNTs functionalized by this method have an edge, i.e., they are soluble in a plethora of organic solvents due to many attached functional groups that are either polar or nonpolar.

4.2 Noncovalent functionalization (physical method) The above-discussed method of covalent functionalization often creates a large number of defects in CNTs, and this damage further degrade the mechanical properties of CNTs as well as disruption of π electron system in nanotubes. This significantly affects the transport properties of the system. Moreover, the strong acids used in the method are not environmentally friendly, hence more emphasis is shifted to methods that do not disrupt the CNT system [47]. In view of this concern, noncovalent functionalization emerges with the advantage that it does not destroy the conjugated system in CNT sidewalls, and subsequently, it does not affect the corresponding properties of CNTs. The CNTs are functionalized noncovalently by aromatic compounds, and polymers, utilizing π-π stacking or hydrophobic interactions. These methods are reported to improve the solubilities of CNTs remarkably [47]. 4.2.1 Noncovalent functionalization by aromatic compounds Dai and coworkers have reported the noncovalent functionalization of CNTs sidewalls and the immobilization of biological molecules onto CNTs under controlled manner and specificity [36]. In another study, CNTs/FET devices were fabricated and subsequently functionalized noncovalently with a zinc porphyrin derivative. This was utilized to detect directly

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a photo-induced electron transferring within the zinc porphyrin derivative-CNTs system [30]. 4.2.2 Noncovalent functionalization by polymers The conjugated polymer chains containing aromatic rings possesses van der Waals interactions with the surfaces of CNTs and simultaneously exhibit π-π stacking, due to which conjugated polymers work as potential wrapping materials for noncovalent functionalization. Some organic-soluble conjugated systems like poly(m-phenylenevinylene)-co-(2,5-dioctoxy-pphenylene) vinylene (PmPV) [52], poly(2,6-pyridin lenevinylene)-co-(2,5-dioctoxy-p-phenylene) vinylene (PPyPV), poly-(5-alkoxy-mphenylenevinylene)-co-(2,5-dioctoxy-p-phenylene)-vinylene (PAmPV), and stilbene-like dendrimers are reported for their significant role in noncovalent functionalization of CNTs (Star et al. 2001).

4.3 Alternative routes for functionalization The above methods are sometimes reported to cause detrimental effects hampering the potential of CNTs for practical applications. To eliminate the existing problems, there is a need to look for some alternatives that can offer homogenous surface functional groups, while enhancing the compatibility between CNTs and the foreign matrix, and causing no structural damage to the CNTs, thus computing their properties for wider practical applications. To look into some of these needs, a study has reported a novel route to covalently functionalize CNTs through the direct Friedel-Crafts acylation technique. On the whole, this type of grafting enhances the reactivity, simultaneously improves the specificity, and provides a place for further chemical modification of CNTs [53].

5. Applications of functionalized carbon nanomaterials Functional CNTs display a unique set of properties that enables their utilization in various applications including the diagnosis and treatment of cancer, infectious diseases, and central nervous system disorders, and applications in tissue engineering [54]. In a study, Moy et al. [55] reported that CNTs could be valuable nano-additives for the fuels where they carry out the following functions [56]: (1) Enhance the burning rate of the fuel (2) Act as an antiknock additive (3) Promote clean burning; and (4) Suppress smoke formation Singh reported the effective fabrication of polysaccharide (functionalized with alginate and chitosan) single-walled CNTs to function as carriers for delivery of curcumin in human lung adenocarcinoma (A549) cells [57].

Carbon nanomaterials

Table 2 The major impacts of CNTs on the treatment of cancer. Type of CNTs

Cell line

Single-walled CNTs Human breast cancer cells (MCF-7) Single-walled CNTs MDA-MB231 human breast cancer cells Single-walled CNTs A549 and NIH 3T3 cells

CNTs dosage

Results

References

12.67 and 5.49 μg/mL

Higher cytotoxic action toward cancer cells

[59]

3.125, 6.25, 12.5, and 25 μg/mL

Induction of death of cancer cells under NIRirradiation Delivery of curcumin to cancer cells; induction death and apoptosis in cancer cells Delivery of curcumin to splenic lymphocytes Enhancement of curcumin antitumor activity; inhibition of cancer cells

[60]

4, 8, 12, 16, and 20 μg/mL

Single-walled CNTs Splenic lymphocytes

36.8 and 123 μg/L

Single-walled CNTs PC-3 tumor cells

5, 15, 40 μM

[57]

[61]

[62]

Karimi et al. reported the use of methotrexate in the combination with carboxylated functionalized multiwalled CNTs for the elimination of cancer breast cancer cells via photo-thermal therapy. For this, folic acid and methotrexate were conjugated through ethylenediamine to the surface of multiwalled CNTs. Cancer cell death was achieved via thermal ablation induced by CNTs [58]. The major impacts of CNTs on the treatment of cancer are summarized in Table 2. CNTs have evolved over the decades as promising delivery systems for chemotherapies and cancer treatment. McFadden and coworkers fabricated a drug delivery system for the anticancer drugs DOX and mitoxantrone loaded on CNTs, exhibiting high chemical and biological stability, and selective cancer treatment through an active targeting scheme [63].

6. Conclusion and future outlook Over the last two decades, CNT-based materials have opened new pathways for developing novel functional materials. This led to continuous and evolving developments in the areas of nanotechnology and material science. In a nutshell, CNTs with their unique

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set of properties, especially surface interactions, have been utilized for various energy and electronic applications. While many studies have been carried out regarding their potential in drug delivery and other biomedical applications, on the whole, there is room for exploration in energy-oriented areas, such as supercapacitors. Furthermore, the extension of these functional methods to the 2D forms of carbon, namely graphene-based materials, is also now a fast-growing area. While the quest for new materials always continues, the research on CNT-based materials in special fields such as doping is still open for investigation and discussion.

Important websites https://www.ch.ic.ac.uk/local/projects/unwin/Fullerenes.html https://www.britannica.com/science/carbon-nanotube https://www.bbc.co.uk/bitesize/guides/zpvfk2p/revision/3 https://www.nanowerk.com/nanotechnology/introduction/introduction_to_ nanotechnology_22.php (5) https://nano-c.com/technology-platform/what-is-a-nanotube (6) https://www.sciencedirect.com/topics/materials-science/carbon-nanotubes (1) (2) (3) (4)

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CHAPTER 6

Carbon nanotubes and other carbon nanomaterials: Prospects for functionalization E.M. Sadek, S.M. Ahmed, and N.A. Mansour Petrochemical Department, Egyptian Petroleum Research Institute, Cairo, Egypt

1. CNTs bases Carbon nanotubes (CNTs), the 1-dimensional (1D) allotropes of carbon, have become a focus of attention in chemistry, physics, and material science since their discovery in 1991 by Sumio Ijima via the arc discharge method [1]. The produced helical microtubules of graphitic carbon are known as multiwall carbon nanotubes, whereas single-walled carbon nanotubes of 1-nm diameter were made in 1993 [2]. CNTs are hexagonally arranged, honeycombed lattice of carbon atoms formed by the rolling of graphene into cylindrical tube with a diameter in nanometer and length in micrometer scales. CNTs are classified as single-walled CNTs (SWCNTs), double-walled CNTs (DWCNTs), and multiwalled CNTs (MWCNTs) depending on the number of graphene walls in their structure [3]. A SWCNT is formed from a single graphene sheet with diameter
0.5–1.5 nm and length of
100 μm [4]. While a MWCNT consists of multiple concentric walls of carbons around the core of a SWCNT (i.e., coaxial stacking of SWCNTs), the outer diameter of MWCNTs ranges from 5 to 50 nm and their length ranges from 100 nm to several centimeters depending on the preparation conditions [4,5]. MWCNTs are less expensive and abundantly available than SWCNTs. CNTs ends are normally capped by a fullerene-like structure [3]. CNTs have different chiralities which affect their structures, properties, and applications. The armchair chirality has similar properties to metals, while the zigzag and chiral chiralities are more likely to be semiconductors [6]. CNTs have stable tubular surface morphology, extraordinary electronic structure, outstanding aspect ratio, high surface area, unique strength, remarkable flexibility, superior Young’s modulus, high electrical and thermal conductivities, as well as light weight [7–10]. Because of these appealing characteristics, CNTs can be used as reinforcing fillers in composite materials with improved properties. CNTs can be produced by various techniques such as arc discharge and laser ablation, which include the condensation of vapor carbon atoms from the vaporization of solid carbon, while chemical vapor deposition is based on hydrocarbons decomposition [11]. Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00004-2

Copyright © 2023 Elsevier Ltd. All rights reserved.

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2. Synthesis of CNTs 2.1 Arc discharge method This method is the oldest and most common technique to produce CNTs, especially SWCNTs on a large scale. The advantage of this method is the formation of high-quality CNTs with minimal structural defects compared with other techniques. The disadvantages are the requirements of high temperature, low pressure, and expensive noble gases [12]. This method produces metallic impurities from a metal catalyst and carbon-soot impurities at high temperature as by-products, meaning that further purification is required. In addition, it is difficult to achieve expected nanosized particles with this method [13].

2.2 Laser ablation (LA) This method is an efficient technique to produce SWNTs; however, it is not a superior method to synthesize MWNTs because of its expensive cost [9]. Smalley’s group showed the efficiency of this method to produce SWCNTs with narrow distribution [14]. The advantage of this method is the production of crystalline CNTs of the best quality with low defect content and high aspect ratio (length/diameter), when compared with other synthesis approaches [15]. High yield and high purity of SWCNT could be produced within a few minutes by this method [16]. The disadvantages of this method are the high energy consumption and adhering impurities, requiring further purification. In addition, it is difficult to retain control over the surface chemistry and size and structure of nanoparticles with this method [17].

2.3 Chemical vapor deposition (CVD) This method is the most applicable method to produce CNTs in comparison to the arc discharge and laser ablation methods. Various CVD techniques for CNTs production include plasma-enhanced (PECVD), microwave plasma-enhanced (MPECVD) or radiofrequency (RFCVD), hot-filament (HFCVD), oxygen-assisted CVD, waterassisted CVD, and floating catalyst (FCCVD) [18]. The main advantages of this method are easy control of CNTs’ growth, large scale of CNT production in vertical alignment, few impurities, and low cost of CNTs compared to the above mentioned methods. In addition, this simple technique consumes less energy with an operating temperature lower than 1200 °C [19]. The disadvantages of this method are the production of CNTs with many structural defects, and production of higher toxic and corrosive gases. The selection of the catalyst is one of the most important parameters influencing the growth and morphology of the CNTs. Transition metal nanoparticles are considered as effective catalysts [20,21]. Bhongade et al. [22] reported that hydrocarbons are not the only source for CNTs production. They used waste toner

Carbon nanotubes and other carbon nanomaterials

powder as a carbon source by the CVD method and proved that this source is a good carbon source for synthesis of CNTs.

2.4 Green methods Recently, Hakim et al. [23] developed a one-step water assisted (quenching) synthesis method to produce carbon nanotubes for Pb (II) ions adsorption. This method was based on coconut shell wastes. Adorinni et al. [24] described the green approaches that have been developed to produce and functionalize carbon nanomaterials for biomedical applications. Tripathi et al. [25] prepared carbon nanotubes using green plant extract (e.g., wall-nut extract) as a catalyst. Using green methods means that grown CNTs are free from toxic metal catalysts, and thus can be applied in medical applications and the textile industry.

3. Carbon nanotubes functionalization The fundamental problem with the above mentioned synthetic methods of CNTs is the production of different diameters and chiralities of nanotubes that are normally polluted with metallic and amorphous impurities. In addition, commercial CNTs are supplied as heavily entangled bundles via van der Waals forces and π-π interaction among the nanotubes, causing a dispersion problem for CNTs when being used as reinforcing fillers in a polymeric matrix. All these problems hinder the dispersion and interfacial interaction between CNTs and polymeric matrix, and ultimately aggregation formation which in turn inhibits the load transfer of CNTs to the polymer matrix [26,27]. Therefore, treatment protocols with intensive research works have been employed to separate the tube bundles according to diameter and chirality, taking into account the favorable properties of these materials. These protocols modify the surface properties of CNTs via chemical (covalent) and physical (noncovalent) bonding between nanotubes and active molecules [28].

3.1 Covalent functionalization Covalent functionalization is based on the chemical bond formation between functional groups and carbon atoms of nanotube at side walls or at tube ends [29,30]. The end caps of CNTs are highly reactive compared with the side walls, since they are composed of highly curved fullerene-like hemispheres. The presence of carboxylic and pentagon groups, five- and seven-membered rings instead of six-membered rings, and the rehybridization of carbon atoms from sp2 to sp3 are examples of defects. All these defects are formed on the ends and side walls of CNTs during their preparation and purification [31].

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3.1.1 Oxidation functionalization Oxidation functionalization is another method for covalent functionalization of CNTs. In this method, defects are created by oxidation treatment of CNTs with various oxidizing agents [32]. Using strong acids is the most common method of oxidation covalent functionalization, producing oxygenated groups such as carboxylic, carbonyl, and hydroxyl groups as defect sites on the ends and side walls of CNTs [33]. CNTs can be refluxed with a solution of nitric acid [34], or a mixture of sulfuric acid/nitric acid (HNO3/H2SO4) (1:3 by volume) under ultrasonication for 6 h [35]. The drawback of this method on using concentrated acid is the rehybridization of carbon atoms from a strong sp2 hybrid graphite structure to a weak sp3 hybrid carbon structure, producing a large number of defects on the CNTs with a simultaneous loss of π-π conjugation system. These defects can contribute to changes in the mechanical, electrical, and thermal properties of CNTs [36]. In addition, using concentrated acid with high power sonication shortens the length of CNTs, which in turn decreases the aspect ratio. The benefit of this functionalization approach is the introduction of carboxyl groups, which are useful for further functionalization reaction. Another benefit is that it provides high solubility of acid functionalized CNTs both in water and in nonaqueous solvents [37]. 3.1.2 Plasma treatment The hydrophilicity of the CNT surface can be improved via covalent plasma treatment by introducing large number of oxygenated groups, which enhances the CNTs’ dispersion and stability in aqueous solutions [38,39]. Kim et al. [40] investigated the effects of ambient plasma treatment on SWCNTs in increasing the interfacial interaction between CNTs and epoxy/fabrics matrix with improving dispersion. They found that the prepared light weight composites with improved fraction toughness and high electromagnetic shielding were efficient materials in modern devices. The benefits of this method are that it is a time-saving, nontoxic method, and does not change the structural physical properties of CNTs. 3.1.3 Covalent functionalization approach The covalent functionalization approach is still an efficient method, although it has drawbacks, to introduce functional groups on carboxylic groups or other oxidized moieties as well as on sp2 carbon lattice via different chemical reactions such as 1,3-dipolar cycloaddition (DC) [41–43]. Lu et al. [44] have functionalized arm chair SWCNTs through covalent approach via [2+1] cycloaddition of dichlorocarbene, silylene, germylene, and oxycarbonyl nitrene. Diazonium chemistry is considered as an efficient route for the functionalization of CNTs and graphene-based materials with aryl diazonium salt [45,46]. The in situ generated diazonium aromatic salt based on aniline precursor

Carbon nanotubes and other carbon nanomaterials

undergoes reductive dissociation with loss of nitrogen and formation of an aryl radical that reacts with double bonds of the carbon nanostructure. Fedoseeva et al. [47] have functionalized oxygenated DWCNT using BrF3 at room temperature, confirming physical and chemical properties changing via fluorine and oxygen groups. Bulusheva et al. [48] have developed chlorinated holey DWCNTs for relative humidity sensors. Morales-Lara et al. [49] performed covalent bromination of MWCNTs via a reaction with CH3Br cold plasma, giving 4.9% bromination degree within 10 min with 99% bromine covalent bonds. Kazemi et al. [50] studied the effect of side wall hydrogenation on the structure and wettability of spaghetti MWCNTs. The formed carboxylic groups via oxidation reaction can react with amine or alcohol groups, forming amide or ester bonds, respectively [51]. These new functional groups can be used as precursors for further chemical reactions. Jian and Lau [52] found that highly reactive amine functional groups in CNTs can react with an epoxy matrix for epoxy-based nanocomposites forming more than one covalent bond during the cross-linking process. Zhang et al. [53] proved that aminated MWCNTs participated more efficiently in the cross-linking reaction with the epoxy matrix compared with carboxylated functionalized MWCNTs. They found that carboxylated MWCNTs showed reaggregation during the fabrication process, whereas the NH2-MWCNTs had dispersion stability due to amine-curing agents. Sapiai et al. [54] studied the effect of acid functionalized MWCNTs with 3-aminopropyl triethoxy silane on enhancing the dispersion of MWCNTs in an unsaturated polyester matrix. 3.1.4 Polymer grafting of CNTs This approach involves the “grafting” of polymeric segments to CNTs, and can be performed via “grafting to” or “grafting from” approaches. Polymer-grafted CNTs exhibit unique thermal stability, excellent electromagnetic interference shielding properties, outstanding mechanical properties, and high electrical resistance in comparison to pristine CNTs [55]. Polymer grafting allows CNTs to be soluble in many solvents and in water, which in turn can be applied in biomedical areas, especially in biosensors and drug delivery [56,57]. “Grafting to” approach In this approach, the functionalized CNTs react with the prepared modified polymer chains terminated groups, via addition reactions [58]. The advantage of this approach is using preformed commercial polymers with a known mass. The drawback is the formation of few grafting bonds and consequently low grafting degree percentages. This can be attributed to the steric hindrance of the used low reactive polymer chains. This approach is restricted to polymers with reactive groups [59]. As examples of “grafting to,” Zhang et al. [60] performed a thiolene addition reaction to graft polyethylene onto MWCNTs. The reactions were efficient with a grafting degree of 18 wt%. DiezPascual and Naffakh [61] grafted an aminated poly(phenylene sulfide) derivative to

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epoxy-functionalized SWCNTs via epoxy ring opening, which causes bonding to hydroxyl or amine modified polymers. Li et al. [62] grafted polystyrene derivatives with azide end groups to alkyne functionalized SWCNTs by “click” coupling. The cycloaddition reaction resulted in 45% grafting degree. For the esterification reaction, Wang and Tseng [63] grafted the synthesized polyurethane (PU) with carboxylic groups in the chain extender onto activated MWCNTs by acyl chloride. For amidation reaction, Zhang et al. [64] grafted carboxy-functionalized MWCNTs to polyethyleneimine (PEI), giving grafting ratios of 25–36%. Wie and Kim [65] grafted aminated MWCNTs onto poly (methyl methacylate) (PMMA). They observed an increase in diameters of PMMA-g-MWCNTs which was about two to three times larger than those of pristine MWCNTs. In addition, the surface roughness of the MWCNTs increased with PMMA grafting. Zhang et al. [66] grafted MWCNTs with poly (amidoamine)PAMAM dendrimers DEN. The prepared CNTs/DEN can be applied for cancer cell detection and imaging. Mallakpour and Zadehnazari [67] functionalized MWCNTs with amino acid molecules via microwave irradiation. They studied the influence of the prepared amido functionalized MWCNTs on the properties of thiadiazol-bearing poly (amide-thioester-imide) PATEI composition. Jafer et al. [68] covalently functionalized MWCNTs using 5,10,15,20-tetra (4-amino-phenyl) porphyrinatonickel (II) via an amide linkage. Soubaneh et al. [69] prepared amide MWCNTs by amidation of the chloroacylated carboxylated functionalized MWCNTs. “Grafting from” approach In this approach, in situ polymerization of the monomer was performed in the presence of an initiator to initiate functionality onto nanotubes. This approach eliminates the drawbacks of the “grafting to” technique, producing a higher grafting degree percentage. While it needs reaction conditions control as well as the contents of initiator and substrate. Examples of “grafting from” approach Based on the atom transfer radical polymerization (ATRP) approach, Wang et al. [70] grafted the synthesized functionalized MWCNTs (e.g., MWCNTs-Br) onto MMA monomer, yielding 32–82% grafting degrees depending on the weight ratio of CNTs to polymer. Hong et al. [71] grafted poly (N-isopropyl acrylamide) (PNIPAAm) onto MWCNTs via reversible addition fragmentation chain transfer (RAFT). The grafted product exhibited good solubility in water, chloroform, and tetrahydrofuran with debundling character. By the same technique, Xu et al. [72] fabricated MWCNTs grafted with polymer shells. Yang and coworkers [73] grafted polyamide 6 onto isocyanate functionalized MWCNTs via an ionic ring opening polymerization. The polymer grafting percentage was found to be 65% after increasing the polymerization time to 6 h. Based on free radical polymerization, Yue et al. [74] reported the in situ polymerization of MMA in supercritical CO2 to improve the monomer diffusion and enhance PMMA chains growth onto functionalized SWCNTs.

Carbon nanotubes and other carbon nanomaterials

3.1.5 Biomolecules Recently, specific attention has been paid to the further functionalization of carboxylated CNTs with biological molecules to improve their poor solubility and biocompatibility. For instance, amino acids are natural organic compounds with amino and carboxyl functional groups. Covalent surface functionalization of carboxylated MWCNTs with seven different amino acids (l-leucine, l-isoleucine, S-valine, l-alanine, S-methionine, l-phenylalanine, and tyrosine) was successfully performed under microwave irradiation with a high degree of functionalization and dispersibility in organic solvents [75]. Starch is one of the most applied biopolymers due to its biocompatibility, biodegradability, and low cost. Starch with hydroxyl functional groups can be covalently attached to carboxylated MWCNTs [76]. Mallakpour and Khodadadzadeh [77] found that D-glucose, as a low-cost and environmentally friendly biomolecule, is an efficient carbohydrate to increase the hydrophilicity of functionalized MWCNTs. They found that covalent functionalization of carboxylated MWCNTs with D-glucose improved CNTs’ dispersion in a starch matrix and the prepared nanocomposites were efficient for drug delivery [77]. They also found that carboxylated MWCNTs functionalized with D-fructose improved the compatibility between MWCNTs-fructose and the starch matrix with a uniform distribution in the starch. The prepared nanocomposites were applied for dyes removal from water because of the performance of both fructose functionalized MWCNTs and plasticized starch in water [78]. Vitamin B1 or thiamine acts as a coenzyme for metabolization of food for energy and to maintain heart and nerve cells. The carboxylated MWCNTs’ surfaces were chemically functionalized with B1 creating ester and amide linkages via hydroxyl and amine moieties in the B1 structure. It was found that the obtained MWCNTs-B1 improved the thermal and mechanical properties of poly(vinyl alcohol) PVA matrix [79]. Vitamin B2 [80] and vitamin C [81] have been used as modifiers for improving the biocompatibility and dispersion of MWCNTs in a PVA matrix. The prepared MWCNT-vitamin C-PVA nanocomposites were applied for removal of methylene blue [81]. Riboflavin as a low-cost and environmentally friendly biomolecule was also used to functionalize MWCNTs further through ester groups formation, improving the dispersion and compatibility of MWCNTs in the poly (vinyl chloride) PVC matrix [82]. Dopamine was used as an example of hormone chemical modification of carboxylated MWCNTs. Dopamine functions as a neurotransmitter in the human brain. Mallakpour and Madani [83] prepared chitosan nanocomposites based on covalent surface modification of MWCNTs by dopamine via a solution casting method as a simple route. They found an enhancement in the mechanical and thermal properties of the nanocomposite films compared with the pure chitosan.

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3.2 Noncovalent functionalization Noncovalent functionalization of external CNT surface is an efficient and attractive approach due to its possibility to absorb various ordered structure groups on the CNT surface under a mild reaction condition involving sonication of CNTs with amphiphilic molecules in a solvent at room temperature. Therefore, this approach does not disturb the π-π conjugation of the nanotubes [84]. While covalent functionalization is one of the most efficient methods, based on a stable linkage providing good stability and efficient electron transfer processes, its drawbacks in comparison to noncovalent functionalization is that this approach may damage the π-π conjugated electronic structure of the carbon nanotubes, leading to changes in their properties as mentioned earlier [36,85]. A wide range of compounds have been used to noncovalently functionalize CNTs by electrostatic adsorption interactions, π-π stacking interactions, and hydrophobic interaction [6,86]. These compounds include polymers, polyaromatic compounds, surfactants, and biomolecules. 3.2.1 Conjugated aromatic polymers It has been reported that some conjugated polymers have significantly higher energy of interaction with nanotubes than small molecules. In conjugated systems, intermolecular overlap of p-orbitals leads to strong π-π interaction, which in turn increases nanotubes dispersion [87]. A noncovalent functionalization method based on π-π stacking interaction between conjugated aromatic polymers and CNTs has attracted considerable attention [88–90]. For instance, using the prepared poly thiophene-g-poly (dimethylaminoethylmethacrylate) (PDMAEMA) as a compatibilizer for nanocomposites based on CNTs/poly (vinylidene) fluoride (PVDF), it was found that the polythiophene backbone interacted with CNTs via π-π interaction and the (PDMAEMA) side chain interacted with PVDF, enhancing a good dispersion of CNTs in the PVDF matrix, and consequently improving the reinforcement and conductivity of PVDF films [91]. Aromatic ring-containing polymers were also reported to interact with CNTs via π-π interaction with a high efficiency in dispersing CNTs in a polymeric matrix. As examples, Kim and Jo [92] prepared poly (styrene-co-acrylonitrile) (SAN)/MWCNTs composites and poly(vinyl benzyl oxyethylnaphthalene)-g-poly(methyl methacrylate) as a compatibilizer. In the dispersion process, they found that a naphthalene unit in the backbone of the compatibilizer interacted with MWCNTs via π-π interaction and the the PMMA graft of the compatibilizer was miscible with the poly (styrene-co-acrylonitrile) matrix with an enhancement in matrix properties. Liu et al. [93] prepared copolymer of glycidyl methacrylate (GMA) and vinylcarbazole (VCz) as a compatibilizer for MWCNTs/epoxy resin composite. They found that the conjugated carbazole groups in P(GMA-co-VCz) interacted with MWCNTs surface via π-π interaction, whereas epoxide rings in GMA matrix chemically reacted with the

Carbon nanotubes and other carbon nanomaterials

epoxy matrix, increasing MWCNTs dispersion and enhancing interfacial interaction between MWCNTs and epoxy, which in turn improved the reinforcement and conductivity of epoxy composites. 3.2.2 Polyaromatic molecules Polyaromatic molecules with hydrophilic moieties have been used to produce aqueous dispersible CNTs or to link CNTs with other molecules via π-π stacking interaction [94,95]. As examples, pyrene is the most efficient polyaromatic compound since the prepared functionalized pyrene with polymers are always adequate for noncovalent interaction [96,97]. Other classes of polyaromatic molecules such as substituted anthracenes, heterocyclic polyaromatic porphyrins, and phthalocyanines disperse CNTs via the same mechanism. Roquelet et al. [98] investigated stacking functionalization of SWCNTs with porphyrin via a micelle-swelling technique in the presence of an organic solvent. Orellana and Correa [99] reported functionalization of SWCNTs with tetraphenylporphyrin (TPP). They studied the stability and optical absorption of π-stacked TPP in comparison to the singular isolated TPP. They found that the stacked TPP and its singular structure are at nearly the same position in the optical spectra, indicating that the TPP absorption properties were preserved in the complex. Tetraphenylporphyrin macrocycles were functionalized with sulfonate groups to enhance their water solubility and processability for deposition on the prepared CNTs electrodes. The produced materials were characterized for capacitive charge storage [100]. 3.2.3 Water soluble polymers Noncovalent functionalization of CNTs with water soluble polymers is an important approach to improve the poor solubility of CNTs in aqueous and organic media. The benefit of this technique is the formation of a thermodynamically stable coating of wrapped polymer, and any unbound polymer can be removed via any separation techniques such as dialysis, ultra-centrifugation, or chromatographic separation methods [6]. For example, polyvinyl pyrrolidone (PVP): in the water dispersion process a hydrophobic alkyl backbone of PVP attached to the nanotube surface by hydrophobic interaction and its hydrophilic pyrrolidone pendant groups directed to water repelling each other. The electrostatic repulsion stabilizes CNTs suspension against van der Waals interaction, resulting in steric stabilization [101]. As another example of water soluble polymers, Cao et al. [84] functionalized SWCNTs with polyethylene glycol in aqueous media through Diels-Alder (DA) click reaction. The hybrid materials were efficient nanocarrier for doxorubicin delivery. In addition, Gan et al. [102] functionalized CNTs with tannins (TA) via mussel-inspired chemistry. The functionalized CNT-TA materials were applied in the removal of methylene blue with high adsorption capacity. Another benefit of using

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water soluble polymers is the reduction of micelle formation instead of small molecular surfactants [103]. 3.2.4 Surfactants Noncovalent adsorption of amphiphilic molecules, such as surfactants, amphiphilic copolymer or others onto CNT surfaces, is the most effective and simplest way to disperse CNTs without damaging their sp2 hybridization. Generally, the interaction of carbon nanotubes with surfactants takes place via a sonication process. Throughout the sonication technique, the mechanical energy overcomes the van der Waals interaction between CNTs and prevents the CNTs aggregation into bundles; the hydrophobic part of surfactants is oriented toward the surface of CNTs, whereas the hydrophilic moiety interacts with solvent molecules in the outer region [104]. The colloidal stability of CNTs dispersion with adsorbed surfactant molecules on their surface is originated by electrostatic and/or steric repulsion. This depends on the surfactant type. For example, in the case of sodium dodecyl sulfate (SDS) [105] or sodium cholate as an anionic surfactant [106], or cetyltrimethylammonium bromide (CTAB) as cationic surfactant [107], the stabilization of the dispersion is due to electrostatic repulsion between the surfactant molecules. The ionic surfactants based on alkyl-substituted imidazolium cationic surfactants can disperse CNTs in organic solvents or water by counter anions [108]. Nonionic surfactants (e.g., Tween and Triton X-100) have been used due to their availability and low cost. Nonionic surfactants stabilized CNT by steric hindrance: the nonionic part attaches to the surface of CNTs whereas the polar moiety imparts solubility of CNTs in water or a solvent [109]. When the hydrophobic parts based on aromatic or a naphthenic group, strong π-π stacking interaction with the CNTs takes place. Sodium dodecyl benzene sulfonate (SDBS) surfactant [110] is more effective for improving CNTs dispersion in comparison to SDS surfactant, although the two surfactants have the same length of alkyl chain. This can be attributed to the presence of a phenyl ring attached between the alkyl chain and the hydrophilic group. Yamamoto et al. [111] studied the effect of a triphenylene-based surfactant, “C10” on SWNTs dispersion in water. They found that C10 stabilizes SWCNTs via its triphenylene core. C10 also disperses SWNTs below its critical micelle concentration (CMC), indicating that micelle formation is not important to SWNTs stabilization. Thus, C10 is different from common surfactant stabilizers. In comparison to conventional alkyl chain surfactants, silicone polymer surfactants have excellent properties such as very high wettability and low surface tension [112]. Siloxane polyether copolymer (PSPEO) is a new amphiphilic macromolecule surfactant with a comb-polymer molecular structure. Its structure consists of -Si-O-Si- main chain as hydrophobic part and polyethylene oxide as hydrophilic pendant groups. PSPEO surfactants have been used successfully for CNTs dispersion in water [113].

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Sadek et al. [114] found that CNTs treatment with gimini surfactant (e.g., N,-decyldiqunoliniumdodecylate) can greatly improve the dispersion and stabilization in PVA matrix compared with its monomer. Abreu et al. [115] investigated the ability of different types of polymer/surfactant mixtures (P/S) to debundle MWCNTs in water under controlled conditions. They used two types of P/S: nonionic polymer/ionic surfactant and ionic polymer/nonionic surfactant. Poly (vinyl pyrrolidone) as nonionic polymer and poly (diallyl dimethyl ammonium chloride) (PDDA) as well as sodium polyacrylate (PAS) as ionic polymers were used. They used SDBS and CTBA as ionic surfactants and triton X-100 as a nonionic one. They observed synergistic effects in nanotube dispersibility in all P/S mixtures compared to individual components. Although surfactants are efficient as solubilizers and dispersants for CNTs, they are known to permeabilize plasma membranes and become toxic. Therefore, the use of surfactant-stabilized CNTs complexes is limited for biomedical applications. 3.2.5 Biomolecules The noncovalent functionalization approach is widely adopted for binding biologically active molecules by wrapping the CNTs surface via π-π stacking interactions. The used biomolecules including proteins, peptides, nucleic acids (DNA), polyaromatic compounds, and monosaccharides as well as polysaccharides [116–118]. Proteins are natural poly ampholytes containing both hydrophobic and hydrophilic domains. Their hydrophilicity depends on the amino acid sequence and pH conditions. Proteins have a high affinity toward CNTs’ side walls. Breitwieser et al. [119] investigated the noncovalent functionalization of MWCNTs using two types of regularly arranged S-layer proteins (SbpA and SbsB) as a new method for dispersing pristine CNTs. The functionalized MWCNTs were reacted with tetramethoxysilane (TMOS) using a mild biogenic approach. The products can act as catalytic sites in biomineralization processes. Peptides are efficient dispersants of CNTs via π-π stacking interactions between the aromatic moieties of a peptide and CNT graphitic surface [120]. Nucleic acids (DNA) consist of hydrophilic sugar phosphate as a backbone and hydrophobic aromatic nucleotide bases present as pendant groups. Such a structure facilitates CNTs dispersion by the hydrophobic bases wrapping to the CNTs and the hydrophilic sugar phosphate groups extending to the water phase [121]. Noncovalent functionalization of CNTs with polyaromatic compounds (e.g., pyrene, anthracene, and porphyrin) has been studied extensively to bind biomolecules such as proteins, polysaccharides, peptides, and polyethylene glycols (PEGs) to CNTs [122–125]. Phospholipid-polyethylene glycol (PL-PEG) has been used to functionalize CNTs; the products were effective in various medical applications such as drug delivery, biomedical imaging, detection, and biosensors [126]. Yeniyurt et al. [127] developed a novel SWCNTs-based drug delivery system by conjugation of N-(fluorenyl–9-methoxy carbonyl) (FMOC)-amino acids bearing PEG chains with different molecular weights.

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4. Noble metal nanoparticles (NPs)/CNTs nanohybrids CNTs nanohybrids based on noble metals such as silver, gold, platinum, and palladium have attracted much attention [128]. They successfully show the unique properties of both CNTs and noble metals, with some new functions due to the interaction between the CNTs and noble metals [129–131].Therefore, noble metal/CNT nanohybrids have shown promising applications in many fields, especially in catalysis, electrochemical, fuel cells, sensors, surface enhanced Raman scattering (SERS), hydrogen storage, and chemical and biological applications [132–139]. Ag nanoparticles (Ag NPs) have gained particular attention based on their promising properties such as optical, electrical, and thermal properties, as well as chemical stability and antibacterial activity [140–145]. Furthermore, silver is used as a doping nanoparticle for various matrixes to produce antibacterial membranes used in water filtration and desalination [146–148]. Silver nanoparticles have also been applied for the fabrication of efficient antibacterial nanocomposites based on CNTs [132,138,149–151].

4.1 Synthesis of noble metal nanoparticles (NPs)/CNTs nanohybrids Various synthetic routes have been applied for the preparation of noble metal NPs/CNTs nanohybrids. These routes can be divided into four approaches: electrochemical deposition, electroless deposition, dispersion of noble metal NPs on the functionalized CNTs, and the physical method [152]. Based on the electrochemical deposition method, noble metal nanoparticles (e.g., Au, Ag, Pt, Pd, and bimetallic PtdRu) are deposited on CNTs’ surfaces with good adhesion and high purity as well as control over metals’ NPs growth. This method depends on reduction of noble metal precursor complexes by electrons such as H(AuCl4), H2(PtCl4), and (NH4)2(PdCl4). In this method, functionalization of CNTs’ surfaces is not required; CNTs act only as molecular conducting wire for supporting the deposition of noble metal NPs [152–154]. Tsai et al. [155,156] successfully used an improved electrochemical deposition technique to deposit platinum and platinum-ruthenium NPs with small size on CNTs directly grown on carbon cloth in the presence of ethylene glycol (EG) containing H2SO4 aqueous solution. The products were effective for methanol oxidation. Chen et al. [157] deposited Pt NPs with smaller particle size on CNTs via the pulsed electrochemical deposition approach using glycerol electrolytes. Brandao [137] deposited Ag NPs on MWCNTs through pulsed reversed current electrochemical deposition using a deep eutectic solvent based on choline chloride and glycerol as an electrolyte. The products were evaluated for energy storage applications. With respect to the electroless deposition method, this approach is based on the redox reaction between metal ions and CNTs. Metal ions can be transformed to metal NPs on the CNT support only when their redox potential is higher than that of CNTs. Therefore, this process is limited compared to the electrodeposition method. Consequently,

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Cu2+ and Ag+ with lower redox potentials cannot be reduced into metal NPs on CNTs via this method. To solve this problem, Qu and Dai [158] developed a process called substrate-enhanced electroless deposition (SEED). This method is applied for deposition of Au, Pt, and Pd metal NPs and some metals with lower redox potential (e.g., Cu and Ag). In this method, CNTs are not the reducing agent. Lorencon et al. [159] reported a one-pot method for synthesis of noble metal NPs/CNTs nanohybrids by a redox reaction between metal ions and reduced CNTs. By this method, they supported Au and Pd NPs to the surface of MWCNTs and SWCNTs without CNTs surface functionalization. The benefit of this method is that it does not require metal ions with a redox potential higher than that of CNTs. Chen et al. [160] used this approach to deposit Ni NPs on CNTs with the aid of supercritical CO2 fluid. The products were effective for hydrogen storage. Zhou et al. [161] used this technique to deposit Pd NPs on nitrogen-doped carbon nanotubes as an excellent substrate. The produced material was used with a high efficiency toward the hydrogen evolution reaction. On the other hand, covalent surface functionalization of CNTs is carried out to introduce more sufficient binding sites for supporting the precursor metal ions or metal nanoparticles. For example, carboxyl functionalized CNTs can anchor and disperse noble metal NPs on CNTs surface. However, it is difficult to anchor a noble metal with small particle size and fine dispersion. To solve this problem, the carboxyl-functionalized CNTs could be further grafted with functional molecules which can effectively control the particles size and dispersion of noble metal NPs on CNTs’ surfaces. As examples, MWCNTs grafted to poly (amido amine) (PAMAM) dendrimers (CNT/DEN) have been used as support for Au NPs [162]. Furthermore, Ag, Cu, Pt, and AgdAu NPs were synthesized in situ on the surface of CNT/DEN with controllable particle size. Pd NPs were also deposited on thiol group [163], benzene sulfonic [164], and ionic liquid functionalized MWCNTs [165], and Au NPs were dispersed on the amine functionalized MWCNTs [166]. Dobrzanski and coworkers [167] synthesized carbon nanotubes decorated with platinum nanoparticles Pt NPs by an organic colloidal process. First, a mixture of concentrated HNO3-H2SO4 and H2O2 as reducing agent was applied to improve metal deposited onto CNTs grown in the CVD method. Then, a CNT-nanocrystal composite was produced by direct deposition of Pt NPs onto CNTs’ surfaces without aggregation of these particles. Many other noble metals such as palladium, gold, and iridium can be used for deposition onto CNTs via this method. The obtained material can be used in construction of various electrochemical sensors with high sensitivity. Sommitsch et al. [168] deposited rhodium nanoparticles and/or palladium noble metals onto MWCNTs surface using the two-step indirect method. First, acid functionalization of MWCNTs’ surfaces in a mixture of H2SO4 and HNO3 was used. Then, a chemical reduction using RhCl3 and PdCl2 as noble metal precursors was performed. The produced materials may be used as the active layer of biosensors. Ag NPs were also

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decorated on carboxylated MWCNT by reducing Ag ions in AgNO3 with N,N dimethyl formamide. The produced PVC composites with CNTs-Ag can be used in electrostatic dissipation applications and for antimicrobial coating during water treatment, filtration, and purification processes [169]. Yadav et al. [170] reported a facile and cost-effective procedure to decorate nitric acid functionalized MWCNTs with silver nanoparticles. The prepared nanocomposites based on decorated MWCNTs with Ag NPs exhibited high performance as electronic and photovoltaic devices compared with unfilled polymer devices. Tambur et al. [150] successfully deposited silver nanoparticles based on AgNO3 on oxygen functionalized MWCNTs using a mixture of concentrated H2SO4 and HNO3 in a molar ratio of 3:1. They concluded that Ag-MWCNTs with high inhibition zone can be used for antibacterial application, especially in Gram-positive bacteria. Hamouda et al. [139] have decorated silver nanoparticles on acid-functionalized MWCNTs using a wet impregnation technique. In this technique, ultrasonication inhibits agglomeration formation in the liquid mixture. Silver nanoparticles were deposited on the carboxylated MWCNTs by reducing Ag ions in AgNO3 with ethanol. The prepared Ag-MWCNT nanocomposites can be used in medical applications. By the noncovalent linkage method, noble metal NPs were also deposited on CNTs’ surfaces with no structural damage and thus their electrical conductivity was maintained. For example, modifying CNTs with 1-aminopyrene by π-π stacking increased binding sites and consequently anchored Pt NPs with uniform dispersion onto the surfaces of CNTs [171,172]. Compared to the abovementioned synthetic methods of noble metal NPs/CNTs nanohybrids, the microwave method as a physical technique is a fast and widely accepted technology because of homogeneous heating and easy nucleation of noble metal nanoparticles. For example, decoration of noble metals on CNTs wrapped with carboxy methyl cellulose (CMC) at 100 °C for 5 min was performed by the microwave method. CMC disperses NTs in the solution, and also acts as a reducing agent for the binding of metal ions (i.e., Pt, Au, Ag, and Pd) [173]. Various physical methods such as plasma irradiation and gamma irradiation have also been reported for CNT surface functionalization. It was found that plasma irradiation of CNTs introduced various chemical groups into CNT surfaces. These functional groups (i.e., carboxyl and amine groups) can bind with the precursor metal ions [174]. Pulsed laser ablation in liquid media was used as the most significant, successful, fast, and eco-friendly method for producing metal or metal oxide-CNTs nanocomposites. The benefits of this method compared to physical and chemical approaches included cleanliness, stability of the produced NPs colloids, ease of chemical preparation, and the lack of a vacuum chamber. In addition, this technique is considered to be the most versatile since changing the particles shape/size is controllable by optimizing operational laser variables such as irradiation time, pulse duration, energy density, wave length, and ablation time [175–180]. This clean method produces decorated CNTs materials with catalytic reduction against

Carbon nanotubes and other carbon nanomaterials

different hazardous organic compounds [181,182]. Alamro et al. [183] decorated CNTs with different amounts of Ag NPs via the laser-assisted method based on generation of Ag NPs via the ablation of Ag plate immersed in functionalized CNT solution. The amount of decorated Ag NPs was controlled by optimizing the laser ablation time. It was noted that the amount of Ag NPs coating onto CNTs was increased as the ablation time increased. The produced Ag NPs/CNTs samples exhibited outstanding photocatalytic adsorption efficiency in removing naphthalene from water.

5. Graphene-based materials (GBMs) Graphene-based materials were classified based on number of layers, oxygen content (O/C atomic ratio), lateral size of sheets, and surface modification [184]. The most common GBMs are graphene, graphene nanoplatelets, graphene oxide (GO), reduced graphene (rGO), and graphite nanomaterials. The graphene 2D structure is crucial to all carbon allotropes: a graphene sheet can be wrapped to form 0D fullerenes, rolled to form 1D nanotubes, or stacked to form a graphite 3D structure [185–187].

5.1 Graphite Graphite is one of the most important carbon allotropes; it is cost effective as a raw material since it is naturally occurring. Its layered structure of parallel graphene layers has a 3D structure in which adjacent graphene sheets, separated by 0.337 nm, are held together by weak van der Waals force. Graphite is a thermally and electrically good conductor due to the presence of π-π orbital on the graphene sheet. Various chemical species can be intercalated between graphite layers, giving graphite intercalated compounds. Expansion or exfoliation of the intercalated graphite by rapid heating leads to the formation of wormlike structures, which can be transformed to graphene via an ultrasonication strategy [188].

5.2 Graphene Since the synthesis of graphene by Geim and his coworkers in 2004 via mechanical exfoliation of graphite [189], graphene has been studied comprehensively in chemistry, physics, materials science, and nanotechnology [190–192]. Graphene is a single monolayer sheets of conjugated sp2 carbon atoms packed together in a 2-dimensional (2D) honeycomb hexagonal crystal lattice [193]. Nowadays, much work is focused on the synthesis of single-layer and few-layer graphene because it has been cited as a promising candidate for possible applications. Among the main manufacturing methods, scotch-tope cleavage [189], liquid phase/ mechanical exfoliation of graphite [194], chemical vapor deposition (CVD) [195], and reduction of graphene oxide [196] are the most popular for graphene synthesis.

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The chemical exfoliation method is the most common route to prepare the grapheme at low cost and high quality. In this method, graphite is oxidized to increase the d-spacing and intercalation between graphite layers, producing graphene oxide (GO) which is reduced by chemical or thermal treatment to obtain reduced graphene oxide (r GO) [197]. Because of its distinctive one atom-thick structure, graphene exhibits a broad spectrum of outstanding properties such as extremely high mechanical strength [198], excellent flexibility [199], high transparency [200], exceptionally high thermal and electrical conductivities [201], as well as rich electronic properties [202]. Due to these attractive properties, much interest has been focused on graphene and its wide applications. Graphene is widely used in energy storage and conversion [203], catalysis [204], gas adsorption and separation [205], drug delivery [206], as well as green chemistry and environmental applications [207].

5.3 Graphene nanoplatelets (GNPs) Graphene nanoplatelets (GNPs) with no more than 10 layers and a low content of defects are an important branch in the graphene family. GNPs are easy to aggregate in water and other organic media due to strong van der Waals forces and π-π stacking interactions between the large sp2 conjugated structures, which in turn hinder its applications. This leads to great challenges during preparation and manufacturing processes. To overcome these barriers, GNPs functionalization with suitable functional materials has been suggested. Generally, graphene functionalization can be performed through either covalent bonds or noncovalent interactions [208,209]. 5.3.1 Covalent functionalization approach This approach is based on a stable strong bond formation between GNPs and functional units. Although covalent functionalization may change the electronic properties of GNPs [210], it is still a suitable way to introduce amino, carboxylic, and hydroxyl terminal groups onto GNPs via various chemical reactions such as 1,3 dipolar cycloaddition with azomethine ylide [211,212], an amide condensation reaction [212], Friedel–Crafts reaction [213], thiolene click reaction [214], ball milling reaction [215], azide addition [216], nitrene addition [217], modified Birch reduction [218], ester reaction [219], one-pot microwave assisted electrophilic reaction [220], and free radical reaction of hydrogen peroxide [221]. These terminal groups can also be further functionalized, introducing other functional moieties and consequently enhancing further applications of GNPs. Basta et al. [222] investigated the covalent functionalization of both GNPs and reduced graphene oxide with azomethine ylide via 1,3 dipolar cycloaddition reaction as a more selective and controlled method in comparison to the use of diazonium salts. They compared between 1-methyl-2-pyrrolidinone and N,N-dimethyl formamide as dispersant solvents and between sonication and homogenization as dispersion techniques. They found that N,N-dimethyl formamide and homogenization were the most effective choices.

Carbon nanotubes and other carbon nanomaterials

Polymer grafting covalent functionalization This approach is an effective method for graphene surface modification with polymeric segments via either “grafting from” or “grafting to” [223,224]. Until now, graphene functionalized with various polymers has been produced by the “grafting from” approach based on the following polymerization methods: single electron-transfer living radical polymerization [225], surface initiated atom transfer radical polymerization (ATP) [226], reversible addition–fragmentation chains transfer (RAFT) [227], controlled radical polymerization [228], nitroxide mediated radical polymerization (NMP) [229], and photo-induced copper-mediated polymerization (SI-photo, CMP) [230]. The activator regenerated electron transfer-atom transfer radical polymerization (ARGET-ATRP) technique is a more industrially attractive method than ATRP. Although many different polymers have been grafted from various substrates via the best ARGET-ATRP technique [231–235], grafting polymer brushes from graphene materials by this technique is still rarely reported. Wang et al. [236,237] first reported polymer brushes grafted from graphene via polydopamine chemistry (noncovalent functionalization) and the ARGET-ATRP technique (covalent functionalization). Wang et al. [238] functionalized GO with polymer brushes. First, they prepared hybrid materials by coating GO with polydopamine (PDA) as a reactive layer and reducing agent for GO; then, methyl methacrylate and styrene monomers were polymerized via the ARGET-ATRP approach. Finally, the polymer brush-modified graphene materials (e.g., rGO-g-PMMA and rGO-g-PS) were incorporated into the PMMA or PS matrix, giving polymer nanocomposites (e.g., PMMA/rGO-g-PMMA and PS/rGO-g-PS) with better thermal properties than the PMMA or PS matrix. 5.3.2 Noncovalent functionalization approach In noncovalent functionalization, one can avoid the drawbacks of covalent functionalization such as causing defects and disrupting the conjugated electronic structure of graphene sheet surface. In this approach, various compounds have been used including polymer, surfactant, or conjugated aromatic small molecules and biomolecules. The hydrophobic part of the modified agent is attached to the graphene surface via π-π stacking, hydrophobic interactions, or electrostatic adsorption interactions [239,240]. GNPs with a large π system were noncovalent functionalized with aromatic molecules via π-π stacking to introduce hydroxyl, carboxylic acid, and amino groups onto GNPs, which in turn enhanced GNPs’ dispersibility [241–243]. Yu and coworkers [244] as well as Vazquez et al. [245] introduced amino groups by exfoliation of graphene with amino acid [244] and triazine [245] via the ball-milling method. A large number of surfactant types, with an amphiphilic nature, such as cationic, anionic, and nonionic, have been used in exfoliation and dispersion of graphene, as illustrated in detail in the following examples. Anionic surfactants stabilize graphene via electrostatic repulsion or intermolecular force. However, nonionic surfactants lead to steric hindrance; the nonionic part attaches to the surface of graphene whereas the polar moiety

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leads to uniform dispersion and prevents agglomeration [246]. Ma et al. [247] studied the effect of three different ionic surfactants on the Hansen solubility parameters (HSPs) of rGO. The surfactants used were sodium dodecyl benzene sulfonate (SDBS), tetradecyl dimethyl betaine (BS14), and cetylpyridinium chloride (CPC) as an anionic, zwitterionic, and cationic surfactant, respectively. They found that both the dispersion and the calculated HSPs of the functionalized rGO in different solvents were changed compared to rGO. Feng et al. [248] investigated the dispersion of graphene in aqueous solution of mixed SDS and CTAB surfactants at different ratios. They obtained a uniform and stable dispersion solution of graphene with the mixtures of SDS and CTAB at lower concentrations compared to the pure one. The SDS-based surfactant exhibited better dispersion compared to the CTAB-based surfactant. Poorsargol et al. [249] used molecular dynamics simultaneous study to investigate the structure of assemblies formed by SDS/CTAB mixed surfactants on graphene surface in an electrolyte containing aqueous solution. They found that surfactant charged head groups approach each other by the screening effect of the electrolyte and hence electrostatic repulsion between surfactant head groups and a more compact assembly formation of surfactants on the graphene’s surface. The steric repulsion between the micelles was increased, and consequently the reaggregation of graphene sheets covered with surfactants was inhibited. Kim et al. [250] found that perylene diimide amino N-oxide (PDI-NO) is an efficient surfactant for enhancing graphene dispersibility in aqueous media regardless of the pH levels via the noncovalent zwitterion functionalization approach. They found that a perylene diimide (PDI) surfactant with large π-π area can adsorb on the graphene’s surface via π-π interaction. Moreover, zwitterionic NO side terminal groups were found to improve the dispersibility of graphene in an aqueous solution with different pH levels via hydration repulsion effects. The PDI-NO functionalized graphene was successfully used in the oxygen evolution reaction. Hussein et al. [251] functionalized GNPs with various surfactants such as Tween 80 (Tw-80), sodium dodecyl sulfonate (SDS), Triton X-100 (TX-100), and cetyltrimethyl ammonium bromide (CTAB) with different weight percentages of 0.02–0.1 wt%. They investigated the thermal conductivity of GNP-based nanofluid with the used surfactant and compared it with their thermal conductivity after covalent functionalization with sulfuric acid. They found that acid covalent functionalized GNPs exhibited the highest thermal conductivity, followed by GNPs functionalized with Tw-80, TX-100, CTAB, and SDS-GNP. Amran et al. [252] treated GNPs with amino dodecanoic acid via covalent interaction and with (TX-100) via noncovalent interaction, and investigated the functionalized GNPs’ effect on the chemical, mechanical, and electrical properties of polylactic acid/liquid natural rubber blend. It was found that TX-100 wrapped around the surface of the GNPs via π-π stacking interaction enhances the interfacial interaction between the GNPs and matrix with a remarkable improvement in the nanocomposite properties based on covalent interaction. Baig et al. [253] used ethyl

Carbon nanotubes and other carbon nanomaterials

cellulose [EC] as a nonionic surfactant and sodium dodecyl benzene sulfonate SDBS as an anionic surfactant to disperse graphite in an aluminum (AL) matrix. They found that EC-based nanocomposites exhibited better hardness and lower wear rate than SDBSbased nanocomposites. Moradi et al. [254] investigated the effect of different loadings of EC on GNPs’ dispersion in the Al matrix. They found that AL/GNPs nanocomposites exhibited the best mechanical properties at 1.5 wt% EC. Sadek et al. [255] used Tween 80 as a nonionic surfactant to disperse expanded graphite (EG) in a nitrile rubber (NBR) matrix. They found that modified expanded graphite (MEG) with surfactant exhibited good dispersion in NBR matrix at 6 phr. In addition, they found improvements in the cure rate, mechanical properties, and electrical conductivity for nanocomposites based on MEG (6 phr) in comparison to nanocomposites based on EG at the same loading and unfilled NBR. The data reflected a promising application of these nanocomposites as antistatic materials. As an example of noncovalent functional molecules, amphiphilic pyrene-based molecules have been investigated for graphene functionalization via π-π stacking [256,257]. These amphiphilic molecules with aromatic structure can absorb onto the graphene surface, enhancing the graphene dispersion in a solvent [258]. In addition, the presence of hydrophilic groups can further functionalize, or allow the detection of biomolecules. As example, Lin et al. and Park et al. [259,260] studied the pyrene polyglucose-based graphene biosensors, which exhibited good sensitivity and selectivity for concanavalin A (Con A) molecules detection. Han et al. [261] used the pyrene maltose for the noncovalent functionalization of graphene via π-π stacking interactions. They successfully confirmed the self-assembled formation of pyrene maltose layer on the graphene surface. Based on the atomic force microscopy (AFM) adhesion measurements, they could detect the lectin protein concanavalin A (Con A) molecule through selective absorption.

5.4 Graphene oxide (GO) Graphene oxide (GO) is a single layer of carbon atoms arranged in a honeycomb structure. It can be produced by the oxidation and exfoliation of graphite with strong oxidative reagents. GO exhibits outstanding properties due to the presence of oxygenated groups (e.g., epoxy and hydroxyl groups on the basal plane, whereas carbonyl and carboxylic acid groups are at the edges) [262]. GO shows colloidal stability in aqueous medium because of the highly negative charge on its surface compared with graphene [205]. Until now, GO has been considered as an excellent precursor to various graphene-based materials because of its large scale, cost-efficiency, and easy processing. 5.4.1 Covalent functionalization of GO Carboxylic acid and epoxide groups constitute the highest concentration of functional groups in GO layers. The presence of these oxygenated groups in GO serves as sites for its covalent modification and the tunability of its physicochemical properties for a

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wide range of applications [263,264]. For example, the electronic properties such as conductivity sheets depend strongly on their chemical and atomic structures that can be modified via chemical and thermal treatment. Thus, GO can be made into insulating, semiconductive, or semimetallic material [265]. This approach may occur on the edges or basal plane of GO nanosheets. Examples of covalent functionalization of GO on edges In this category, carboxylic acid groups can be activated by a coupling agent (e.g., thionyl chloride) producing acyl chloride, a reactive intermediate for further condensation reactions with excess alcohols or amines, forming esters or amides [266,267]. Furthermore, polymers can be used for the edgefunctionalization of GO nanosheets [268,269]. In addition, the hydroxyl groups on GO can act as nucleophiles and condense with the carboxylic acid via coupling chemistry. Furthermore, the hydroxyl groups can react with trialkoxy silanes or alkyltrichloro silanes, forming siloxy bonds [270,271].

Examples of covalent functionalization on GO basal plane This approach is based on ring-opening reactions of epoxy functional group with strong nucleophiles in polar solvents [272]. Furthermore, the aromatic basal plane of GO can be functionalized by reactive intermediates such as aryl diazonium salts, carbenes, and nitrenes [273]. Especially, diazonium chemistry has been widely employed to functionalize the surface of graphene with aryl diazonium salt. Under acidic conditions, the diazonium salt forms an aryl cation by releasing N2 gas, while the graphene lattice provides an electron for the aryl diazonium ion that is readily incorporated to the sp2-carbon network. Through this reaction, the sp2 hybridization of basal plane could be changed to sp3 upon functionalization [274]. Based on “chick” chemistry, a wide range of polymers and block copolymers have been anchored to graphene nanosheets with high selectivity and good yield under mild conditions [275–278]. Based on the thiol-ene “chick” reaction, Carcia et al. [279] functionalized GO with cysteamine (CA) via thiolene radical addition (TERA) based on photo-initiation instead of using thermal radical initiators, producing high yields without by-products. Using the thermal radical initiators led to GO reduction on long periods of heating and losing functional groups such as carboxylic and/or epoxide groups [280].

Carcı´a et al. [281] functionalized GO via thiol-ene Michael addition (TEMA) using a base catalyst, producing two by-products based on epoxy ring opening reaction by NH2 and epoxy ring opening reaction by SH. Thus, TEMA and thiol-epoxide ring opening reaction (TEROR) can occur simultaneously in the presence of a base catalyst. They also functionalized reduced graphene oxide (rGO) with cysteamine (CA) under the same conditions, producing no by-products. 5.4.2 Noncovalent functionalization of GO Wang et al. [282] used two cationic surfactants, cetyl trimethyl ammonium bromide (CTAB) and gemini surfactant (GS), to noncovalently functionalize the prepared modified GO surface via polyaniline nanofiber GO-PANI. They found that GS is more

Carbon nanotubes and other carbon nanomaterials

effective in improving the water dispersibility and corrosion resistance of GO-PANI in waterborne alkyd resin. They also found that GS is functionalized as a dopant to improve the electrochemical properties of PANI. Thus, the products can be used in waterborne alkyd anticorrosive coatings. In comparison with surfactant molecules, graphene oxide (GO) contains large π-conjugated areas as well as various oxygenated functional groups [262]. Because of its amphiphilic nature, GO can be dispersed stably in an aqueous solution and attach to and activate the interface. Therefore, GO could be expected to function as a special surfactant to disperse graphene in an aqueous solution via π-π interaction between the π-conjugated basal planes [283]. Song et al. [284] prepared pyrene block copolymer (e.g., poly (methyl methacrylate)block-polymethyl siloxane copolymer via the ARGET-ATRP polymerization method. GO was then functionalized with the prepared copolymer via the π-π interaction between pyrene and carbon sheets, enhancing the physical properties of poly (methyl methacylate). The noncovalent functionalization of graphene with conjugated aromatic polymer (e.g., polythiophene-graft-poly(methyl methacrylate) (PT-g.-PMMA) is another example. This reaction was based on oxidation of graphite into GO by Hummer’s technique, then reduction of GO into rGO, and finally attachment of the (PT-g-PMMA) to rGO via noncovalent interaction [285]. Recently, great attention has been focused on the unique biological properties of graphene and its derivatives by incorporating biological molecules to be applicable in many medical fields. Peptides with aromatic functional groups may be immobilized on graphene by a noncovalent approach via π-π stacking interactions [286]. Graphene may also noncovalently functionalize with peptides via van der Waals forces because of its hydrophobic nature [287]. GO exhibits biocompatibility with various biomolecules due to the presence of many oxygenated functional groups on its surface [288]. GO can be functionalized with peptides via both covalent and noncovalent interactions by π-stacking interaction, electrostatic adsorption, and hydrophobic interactions [289]. Joshi et al. [290] indicated that the functionalized graphene and GO with peptides are considered as nanotools for sensing and imaging medical applications. In addition, these compounds can be used to detect cancer cells and protease enzyme activity as well as determination of environmental pollutants and pathogenic microorganisms. Kundu and coworkers [291] functionalized GO with lignin (L) as a plant-derived biomacromolecule and a green phosphorus compound like phytic acid (PA). The produced materials were used to improve the flame retardancy of polyamide 66 fabrics via a one-pot deposition method. The objective of this study was to discover the best formulation based on chitosan (CS) as a new charring agent in preparing flame-retardant coatings for a thermoplastic polyamide 66 textile. Sapner et al. [292] have functionalized GO with L-cysteine as a biomolecule via a chemical approach. The produced L-cysteine functionalized graphene oxide (L-Cy-rGO) was evaluated as an electrocatalyst. The product

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exhibited a bifunctional nature for fuel-cell oxidation and reduction reactions since it was used for enhancing the oxygen reduction reaction (ORR) and hydrazine oxidation reaction (HOR). The enhanced electrocatalytic activity of L-Cy-rGO for both ORR and HOR reactions is due to the presence of the sulfur (S) and nitrogen (N) heteroatomcontaining surface of GO.

5.5 Reduced graphene oxide (rGO) The structural defects generated via the oxidation process of graphite disrupt the conjugated electronic structure of graphite producing GO with low conductivity and cannot be applied for electrical applications. In addition, the oxygenated functional groups onto GO’s surface hinder its compatibility with most nonpolar matrices. Thus, chemical reduction of GO sheets with hydrazine leads to a partial recovery of conductivity through a revival of sp2 hybridization. In addition, reduction methods eliminate the oxygenated functional groups and consequently improve GO compatibility in a nonpolar polymer. Ren et al. [293] efficiently replaced hydrophilic groups of GO and rGO by alkyl groups via nucleophilic substitution and amidation reaction with dodecyl amine (DA). The produced functionalized (DA-GO) and (DA-rGO) exhibited homogeneous dispersion in a high-density polyethylene (HDPE) matrix with improved composite properties.

6. Metal nanoparticles (NPs)/graphene nanohybrids Recently, metal NP-decorated graphene or graphene derivatives have been of interest due to their various potential applications such as catalysis, optics, and nanomedicine. Graphene and graphene oxide (GO) have been considered as attractive catalytic supports because they usually improve the catalytic properties of metal and metal oxide NPs. This can be attributed to their very high surface area (
2600 m2/g) and unique properties such as high thermal and electrical conductivities as well as chemical stability. They also exhibit high performance to protect the catalyst through the sp2 hybrid 2D carbon network [294]. Metal NPs exhibit physical and chemical properties; they act as model building blocks for modifying carbon nanoscale material, leading to a hybrid structure with both the unique properties of the carbon nanoscale material and the elements of single nanosized metal particles. Darabdhara et al. [295] introduced noble metals (e.g., Ag and Au) in reduced graphene oxide via in situ and ex situ techniques. In the in situ approach, metal salts and GO were simultaneously reduced, obtaining rGO/NPs nanocomposite materials, while in the ex situ process, the metal NPs were first synthesized and then added to a GO or rGO matrix. The prepared nanocomposite materials can be applied in drug delivery, photothermal therapy, and biosensing. Hsuch et al. [296] deposited nanosilver and zinc oxide NPs on rGO’s surface at different weight percentages via microwave-assisted chemical reduction. The products were tested for antibacterial activity. They proved that these nanocomposites could be applied not only as antibacterial agents but also in various

Carbon nanotubes and other carbon nanomaterials

biomedical materials such as sensors, photothermal therapy, drug delivery, and catalysis. Thangamuthu et al. [297] prepared graphene and graphene derivative (e.g., GO and rGO) nanocomposites based on metal semiconductor NPs, metal oxides, quantum dots, and polymers. Such nanocomposites are becoming increasingly useful as electrochemical biosensing platforms (e.g., enzymatic biosensors, nonenzymatic biosensors, and immunosensors) for biomedical cell capture. Behi et al. [298] found that SnO₂-decorated graphene displayed high sensitivity toward benzene, toluene, and xylene, with the lowest tested concentrations of 2 ppm, 1.5 ppm, and 0.2 ppm, respectively. The prepared nanomaterials can be used to identify the presence of benzene vapors for monitoring occupational exposure in the textiles, painting, and adhesives industries, or in fuel stations. For the nonnoble transition metal including cobalt (CO), nickel (Ni), and iron (Fe), it is hard to reduce these metals to their zerovalent metallic state compared to noble metals. Many authors have developed crumbled graphene based on oxides of these transition metals [299,300]. Recently, Mohammadi et al. [301] introduced a general approach for producing nanocomposites based on metal-decorated crumpled reduced graphene oxide using a one-step continuous process, which is known as a flame-driven hightemperature reducing jet (HTRJ) process. Crumpled reduced graphene oxide balls (CGBs) were synthesized from graphene oxide (GO). The produced CGBs were decorated with various transition metal nanoparticles (e.g., Co, Ni, Fe, and palladium (Pd)), and also with various metal alloys including CoPd-, CoNi-, CoPdNi-, and CoNiFe-CGBs. Thus, by using this technique, various transition metal nanoparticles can be decorated on the CGBs and used for particular applications. With respect to graphene decoration with copper, there are two different methods to prepare graphene- or GO-supported copper-based nanocomposites. In the first method, copper NPs and graphene are prepared separately and the decoration is performed via various methods such as CVD [302], ultrasonication [303], and/or hydrothermal procedures [304]. The second method is based on mixing a solution of GO and copper salt to reduce both of them simultaneously [305]. The mixture produced is composed of decorated graphene oxide with mixed oxidation states of Cu (e.g., copper nanoparticles, copper oxide nanoparticles, and cuprous oxide nanoparticles). Zhu et al. [306] and Darvishi et al. [307] used microwave methods for the decoration of graphene materials with cuprous oxide NPs [306] and copper oxide nanoparticles [307]. Recently, Shabestari et al. [308] developed a novel procedure for simultaneous synthesis and decoration with a copper double salt (DS) using a microwave energy source. First, they prepared a copper double salt (i.e., copper hydroxy nitrate, Cu ₂(OH)3 NO3 DS), which was deposited on graphene oxide (DS/GO). Then, the DS acted as an intermediate for the preparation of GO decorated with various states of copper including copper nanoparticles (Cu/GO), copper oxide nanoparticles (CuO/GO), or cuprous oxide nanoparticle (Cu₂O/GO). They found that the copper-based nanomaterials exhibited excellent catalytic efficiency in oxidation and coupling reactions.

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7. Graphene and CNT hybrid nanofiller-reinforced polymer composites Although CNTs and graphene are similar in their properties, graphene is more useful than CNTs. Graphene is more biocompatible material, since it is free from metallic impurities [309]. It can be synthesized from graphite as a cheaper raw material than methane as a carbon source for CNTs production. Graphene has a higher surface area than single-walled carbon nanotube (SWCNTs), which in turn enhances its electroactivity and immobilization capability. Graphene has high strength due to its wrinkled surface caused by more surface defects contents (e.g., single, multiple, and Stone-ThrowerWales defects), causing more contact with polymeric material than CNTs [294]. Thus, graphene has attracted considerable interest compared to CNTs, although it is considered a relatively new member of the carbon allotrope family. Recently, hybrid nanofillers with 1D MWCNTs and 2D GNPs have proved to be promising reinforcements to fabricate hybrid nanocomposite. In this process, 3D hybrid networks are formed, in which the long and flexible MWCNTs act as a bridge between the GNP layers and inhibit the agglomeration of nanofillers [310,311]. The synergistic effects of the nanofillers on the properties of the polymeric matrix depend on the particle size and the ratio of the nanofillers. For example, Wang et al. [312] compared the effects of CNTs and GNPs on the electrical conductivity and electromagnetic interference shielding EMI properties of poly (lactic acid)-based nanocomposites in both segregated and random structures. They concluded that EMI and electrical conductivity mechanisms are completely different. Qi et al. [313] developed the synergistic effect of a functionalized graphene oxide and carbon nanotube hybrid on mechanical properties of epoxy composites. The improvement in composite properties was achieved via the π-π stacking interaction between CNTs and conjugated aromatic regions of GO sheets. He et al. [314] constructed the synergetic effect of CNT-graphene and CNT-graphite on the electric and thermal performance of poly(phenylene oxide) (PPO)-based nanocomposites. They found that CNT-graphene improved the above mentioned properties of composites more than CNT-graphite at the same weight percentage. This may be due to the larger surface area and wrinkled surface texture of graphene, which in turn formed good interactions with polymer and achieved interlocking of polymer chain. Shukla et al. [315] prepared an epoxy composite with enhanced mechanical and thermal properties based on a hybrid of MWCNTs and amino functionalized graphene via the sonication method. Han et al. [316] studied the synergistic effect of graphene and CNTs on enhancing the lap shear strength and electrical conductivity of epoxy adhesives compared to pure epoxy, CNT/epoxy composites, and GNP/epoxy composites. They demonstrated that a hybrid of CNTs (1D) and GNPs (2D) formed a 3D network in the epoxy matrix due to their large contact surface area between the fillers and the matrix. Bisht et al. [317] studied the synergistic effect of graphene/CNT hybrid on the mechanical properties of epoxy composites in the presence of nanodiamond (ND). They concluded that the addition of ND improved the dispersion and interfacial interaction with

Carbon nanotubes and other carbon nanomaterials

the matrix compared to the graphene/CNT hybrid filler. Rostami and Moosavi [318] investigated the hybrid effect of functionalized graphene and CNTs on the tensile strength and tensile modulus of thermoplastic polyurethane (TPU) nanocomposites. Navidfar and Trabzon [311] studied the synergetic effect of MWCNTs/GNPs on enhancing the hardness and tensile strength of thermoplastic polyurethane nanocomposites compared with pure PU. Again, larger surface area and more defects of GNPs imply a greater ability to fit together with MWCNTs, which in turn shows a better synergistic effect in reinforcing PU. Bagotia et al. [319] observed an enhancement in tensile strength of polycarbonate/ethylene methylacrylate (PCE) nanocomposites reinforced by a MWCNT/graphene hybrid filler via the melt blending method compared to graphene/PEC and MWCNT/PCE nanocomposites. This improvement may be due to the bridging of MWCNTs between graphene layers, which leads to homogeneous dispersion and interfacial adhesion between the matrix and fillers that helps the load transfer to MWCNT/graphene. Min et al. [320] studied the unique synergistic effects of GO and functionalized f-CNT hybrids on the tribological properties of polyimide (PI) nanocomposites. They found that incorporation of 3D structured filler enhanced the interaction between GO, f-CNTs, and PI matrix with a reduction in stress concentration. Abreu et al. [321] prepared 3D nanocomposites based on noncovalent functionalized MWCNTs (1D) and GNPs (2D) with surfactant and polymer/surfactant combinations as the dispersants for the initial carbon nanomaterials. The nanocomposites with enhanced properties were evaluated as electrocatalysts for the oxygen reduction reaction (ORR). Rao et al. [322] studied the synergy effects of MWCNTs and GNPs dispersed in epoxy adhesive on mode I fracture toughness of unidirectional composite bonded joints. They found that MWCNT/GNP (1:4) hybrid had the highest toughening effect (286%) compared with pure adhesives. They also found that using polyvinyl pyrrolidone (PVP) as a functional polymeric surfactant had a positive effect on improving fracture toughness for single nanofillers, while it decreased the toughness of MWCNT/GNP hybrids.

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CHAPTER 7

Carbon nanotubes and their biomedical applications Kulkarni Akshay Narayanrao, E. Priyadarshini, and Ravi-Kumar Kadeppagari Centre for Incubation, Innovation, Research and Consultancy (CIIRC), Department of Food Technology, Jyothy Institute of Technology, Bengaluru, India

1. Introduction The interesting physicochemical characteristics of carbon nanotubes (CNTs) are their thermal and electrical conductivities, higher aspect ratio, and good mechanical strength [1,2]. Bioactivities of CNTs are heavily based on their surface chemistry, which determines critical parameters like hydrophobicity or oxidation power [3]. Concentrated acids are used during purification and pretreatment of CNTs, which will change the surface chemistry and morphology of CNTs. During their synthesis, covalent or noncovalent functionalization is carried out, which will also influence the activities of CNTs. The CNTs’ dispersion in aqueous phase is also important since it will affect the surface contact and the availability of biological agents. Hence, some additive molecules should be introduced on the surface of CNTs in order to stabilize hydrophobic CNTs in the aqueous phase [4]. The CNTs will get bundled and entangled due to their higher aspect ratio which makes their dispersion a difficult problem. Hence, their surface needs to be changed by introducing functional groups through a covalent or noncovalent way. Noncovalent functionalization will be better since CNT structure and graphene π-π system will not be affected during this process. More suitable noncovalent functionalization for dispersing CNTs will be through the usage of surfactant since it is simple process and includes easy steps, i.e., probe sonification, centrifugation and filtration. Hydrophobic chains of surfactants will anchor to the side walls of CNTs and their hydrophilic heads will remain interacting with aqueous phase. Surfactant molecules will get adsorbed strongly on to the surface of CNTs, thereby preventing the reaccumulation of CNTs. Hence, CNTs’ dispersion will maintain colloidal stability for a longer time. The CNTs will show effective biological activities in their dispersed form compared to bundle which could be due to the increased surface contact with biological molecule or system [5,6]. CNTs are increasingly used for biomedical applications since they are stable and have better electrical and mechanical characteristics. They can impart on the composite better biocompatibility, photothermal conversion power, conductivity, shape memory, Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00016-9

Copyright © 2023 Elsevier Ltd. All rights reserved.

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antimicrobial properties, etc. However, CNTs should be used in lower concentrations to reduce or avoid their cytotoxicity. Their various biomedical applications are discussed in the following sections.

2. Antimicrobial applications Microbes have been developing antibiotic resistance due to the extensive and inappropriate use of antibiotics. In this context, CNT-based materials are promising for therapeutic and other biomedical applications. Double-walled CNTs (DWCNTs) and multiwalled CNTs (MWCNTs) are noncovalently modified by treating with sodium dodecyl benzene sulfonate (surfactant) and used against Gram-positive and Gramnegative bacteria, and also against fungus. The MWCNTs showed higher activity against the pathogens compared to DWCNTs [7]. Silver nanowire composites were prepared with single-walled CNTs (SWCNTs) through polyol method [8]. These composites exhibited antimicrobial activity against Staphylococcus aureus, E.coli, S. saprophyticus, and MRSA. Wound healing will be prevented once a bacterial biofilm is formed, since the biofilm will protect the pathogens from antibiotics and antiseptics. The biofilm will also prevent epithelialization, inflammatory processes, and granular cell development. The MWCNTs were incorporated with hetero atoms like N, P/B, and F, and used for destroying biofilms and wound healing [9]. Hetero atoms had been incorporated into the CNTs by using ionic liquids like BMIM-BF4 and BMIM-PF6, which will selfassemble with MWCNTs (acid functionalized). The suspension was then subjected to the process of pyrolysis with nitrogen. Electronegativity differences among the hetero atoms will generate the charge on the surface of CNTs, which will prevent biofilm formation, and hetero atoms will act as a mineral source, which will facilitate granulation and regeneration of fibroblasts.

3. Drug delivery and therapy The Diels-Alder reaction was used in order to introduce OH groups on CNTs’ surfaces under milder conditions [10]. Carboxyl-rich poly acrylic acid and poly ethylene glycol (PEG) methyl ether methacrylate were crafted on CNTs for delivering cis platinum (anticancer agent). This agent was loaded on the composite by coordinating through carboxyl groups and its release was controlled by changing pH. These composites exhibited low toxicity [10]. Anticancerous drugs like doxorubicin and paclitaxel were delivered by using functionalized CNTs. They can be utilized for delivering small molecules, proteins, DNA, and vaccines. Therapeutic molecules may also be incorporated inside the cavities of CNTs while delivering them.

Biomedical applications of carbon nanotubes

Various functional groups can be added on to the CNTs, and they may be simultaneously used for targeting, therapy, and imaging. One example of such multimodal functionalized CNTs is those CNTs carrying amphotericin B (antifungal drug) or methotrexate (antitumor agent) along with a fluorescein probe [11]. The CNTs can passively cross the cell membranes of many kinds of cells by a nanoneedle mechanism, opening the possibilities for delivering drugs to the intracellular targets that are difficult to reach [11]. Vertically arranged CNT arrays were asymmetrically modified by using thermoresponsive hydrogel for the delivery of molecules in a controlled manner [12]. In another study, the CNTs modified with PEG were utilized as sonosensitizers for treating solid tumors [13].

4. Tissue engineering and neural regeneration New materials need to be explored for tissue engineering, and CNTs can become potential materials for this purpose with improved cell tracking, transfectant delivery, microenvironmental sensing, and scaffolding in order to integrate with the host [14]. In addition, tissue formation can be evaluated better by utilizing CNTs for optical, radio tracer, and magnetic resonance contrasting. In addition to structural reinforcement, they impart electrical conductivity to the scaffolds and help in directing the cell growth. They will play a comprehensive role in monitoring and creating the engineered tissue. Biofunctionalized CNTs were utilized for promoting neural regeneration [15]. They can act as matrices in order to support the growth of neurons. Neuronal growth is modulated in a graded manner by functionalized CNTs. Hippocampal neurons will outgrow on positive CNTs compared to zero or negative CNTs. Mechanical and conducting properties of CNTs will also affect the morphology of neurons. Glial and stem cells can be grown on substrates containing CNTs [16]. However, CNTs can interact with ion channels and might affect the neuronal function [17]. CNTs were also used as scaffolds for the regeneration of bone [18]. The most common cause for the death of heart patients is myocardial infarction, i.e., death of cardiac tissue. This condition is caused due to the inability of cardiac tissues to self-repair the tissues. In this context, CNTs are promising since incorporation of SWCNTs or MWCNTs into fibrous, elastomeric, or polymeric scaffolds could significantly improve the signal transduction or electrical stimulation within cardiomyocytes [19]. In addition, the presence of CNTs within scaffolds improved the proliferation, maturation, differentiation, and synchronous beating of cardiomyocytes [19]. Amyloid proteins those misfolded will lead to the generation of amyloid fibrils, which are related to pathogenesis of neurodegenerative disorders like Huntington’s, Alzheimer’s and Parkinson’s. In one study, it was shown that SWCNTs will partially disintegrate the amyloid β-fibrils those are preformed and reduce β sheet-like structures. In this

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process, amyloid β–SWCNT conjugates are formed [20]. Hence, SWCNTs will become potential candidates in the development of drugs for the above neurodegenerative disorders.

5. Gene delivery Ammonium functionalized SWCNTs could penetrate murine and human cells for facilitating plasmid DNA delivery and expressing marker genes [21]. Ammonium functionalized SWCNTs and MWCNTs and lysine functionalized SWCNTs were condensed with plasmid DNA. Condensation of DNA varies in the above synthesized CNTs. Charge density and CNT surface area will determine the electrostatic interaction between CNTs and DNA. All the above three CNT-DNA complexes could upregulate the marker gene expression compared to naked DNA in human cell line, but to different levels. In another study, SWCNTs or MWCNTs were functionalized with polyamidoamine dendrimers by covalent linking and used as transfection agents for the plasmid containing a green fluorescent gene [22]. Both could transfect HeLa cells, but the efficiency of transfection of MWCNTs was higher than that of SWCNTs. In yet another study, SWCNTs were functionalized with polyethyleneimine in a noncovalent manner through phospholipid or hydrophobic alkyl groups [23]. These SWCNTs showed around a 19-fold increase in the efficiency of transfection.

6. Imaging and diagnosis Acid functionalized CNTs are linked with poly (p-phenylene) in a noncovalent manner and poly (p-phenylene) is decorated with PEG before linking to CNTs. The obtained complexes are conjugated with antiestrogen antibodies through the carboxyl groups available on CNT side walls. The final conjugates were efficiently used for imaging cancer cells (MCF-7) over expressing estrogen receptors in a targeted manner [24]. One low-cost and low-dose imaging technique that can capture the information in depth is digital tomosynthesis (DT). Currently, it is used for breast imaging in hospitals. However, the approved DT resolution is limited and many projection views need to be collected by swinging the source of X-ray. The CNT-based X-ray sources were arranged in order to provide a solution and stationary DT equipment was constructed for imaging breasts, teeth, and lungs [25].

7. Biosensors SWCNTs were used in the development of immunosensors that detect histamine, a food-borne toxicant related to scombroid poisoning [26]. This toxin originates from the amino acid histidine, due to its decarboxylation by microbes. This immunosensor

Biomedical applications of carbon nanotubes

was developed by coating SWCNTs on screen-printed silver electrode. Then, antibodies against histamine were immobilized on SWCNTs. This immunosensor was utilized for detecting histamine in fish samples. A nanocomposite film containing MWCNTs was utilized in the development of electrochemical biosensors which can detect the dementia marker protein tau-441 [27]. Graphene oxide (reduced) was utilized in the film for enhancing MWCNT dispersibility and improving overall conductivity. Chitosan was utilized in the composite for immobilizing specific antibodies. The biosensor could detect the biomarker up to 0.46 fM and was successfully used for analyzing human serum samples. A nanocomposite containing functionalized MWCNTs, nanogold, and PEDOT was synthesized by the electropolymerization method. This composite was utilized in the development of electrochemical sensors for detecting xanthine, hypoxanthine, and uric acid simultaneously in human serum and urine [28]. An ethanol biosensor was constructed by using SWCNTs that are modified by using poly cresyl blue. Here, carrageenan and ethanol dehydrogenase were also immobilized on the electrode surface [29]. In yet another study, a composite film containing MWCNTs and three enzymes (creatinine amidohydrolase, sarcosine oxidase, and creatine amidinohydrolase) was immobilized on a Pt electrode for detecting creatinine in human serum by amperometry [30]. The MWCNTs also improved the response time and sensitivity of an enzymatic ammonia biosensor [31].

Acknowledgment The authors are grateful to Sri Sharada Peetham, Sringeri and Jyothy Charitable Trust, Bengaluru, Karnataka, India for their support and facilities.

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Biomedical applications of carbon nanotubes

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CHAPTER 8

Molecular interaction modeling of carbon nanotubes and fullerene toward prioritized targets of SARSCoV-2 by computer-aided screening and docking studies Dharshini Gopala, Sinosh Skariyachanb,*, and Govindappa Melappac a

Grenoble Institut Neurosciences, Univ. Grenoble Alpes, Inserm U1216, Grenoble, France Department of Microbiology, St. Pius X College Rajapuram, Kasaragod, Kerala, India c Department of Studies of Botany, Davenegere University, Davanagere, Karnataka, India *Corresponding author: e-mail address: [email protected] b

1. Introduction The COVID-19 pandemic, which the lives of hundreds of thousands of people and affected millions of others around the world for about 2 years now, which is continuing to be an evolving threat to mankind [1]. Severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2) is the formidable pathogen that caused this global pandemic. The main reason that the pandemic is very challenging to control is that the infection begins with mild flu-like symptoms in most individuals and then spreads through nasal discharge droplets and aerosols, affecting people of all age groups. Several research institutions, industries, and private sectors are working hard to develop therapeutic strategies to tackle the situation [1]. Although various agents are in the human trial phase, an effective solution is yet to be achieved. To speed up the process, computational biology is being adopted for aiding the drug development process, as it provides profound insights about molecular interactions and important structural aspects by molecular modeling and docking approaches. Additionally, combining carbon nanoparticles, such as nanotubes and fullerene, with computational biology can help to predict the binding interaction of nanoparticles on the putative targets of SARS-CoV-2. Therefore, in this chapter, we illustrate different computational approaches and methods to predict the binding potential of carbon nanoparticles against the SARS-CoV-2 targets which could serve as an alternative therapeutic solution.

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00015-7

Copyright © 2023 Elsevier Ltd. All rights reserved.

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2. Overview of COVID-19 Coronavirus disease – 2019, also known as COVID-19, which has shaken the world, is caused by severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2) initially known as novel coronavirus – 2019 (nCoV-19) [2]. The first country to witness the outbreak of SARS-CoV-2 was China; the disease was reported to have originated in the city of Wuhan during December 2019 [3]. Although attempts were made to contain the infection within the country for more than 2 months, it was reported throughout the world in a very short time due to international traveling, contact, and the time delay before symptoms become visible [4–6]. The WHO declared a pandemic on March 12, 2020 to promote awareness about the situation and develop strategies to contain the infection [1]. This global outbreak has affected almost all countries, and countries are still fighting against the COVID-19 infection. Symptoms of the SARS-CoV-2 infection could take about 14 days to occur; however, there are reported cases which have taken about 28 days for symptoms to occur [7]. Symptoms range from mild flu-like symptoms such as fever, dry cough, sore throat, chest congestion, difficulty in breathing, conjunctivitis, discoloration of fingers and toes, and diarrhea, which are observed between 2 and 14 days after exposure, to lethal symptoms, which include severe pneumonia in people with compromised immunity [8]. Cases have been reported with victims showing no sign of infection, i.e., asymptomatic carriers, which makes it much more challenging to combat the infection and ensure national prevention, as screening would eliminate asymptomatic patients and they would transmit the infection [9,10]. The risk of SARS-CoV-2 infection in patients with cardiovascular diseases is reported to increase the incidence and severity [11]. The virus also has a neurological effect due to the limited supply of oxygen to the cells, leading to intracranial invasion and neurological manifestation, which remains unclear [12]. Cases are also reported with the possibility of depression, anxiety, posttraumatic stress disorder, and rare neuropsychiatric syndromes [13]. Reports have stated that some patients showed neurological signs such as headache, nausea, loss of taste and smell, dizziness, and impaired consciousness, which could be due to the invasion of the virus directly or indirectly on the central nervous system; this is yet to be clarified [14]. Major challenges for fighting COVID-19 include scarcity of medical supplies as the demand constantly increases whereas production has fallen behind due to social distancing, which is a suggested precautionary measure [15], the negligence of people [16], impact on mental health [17], and the fact that this is the first such pandemic witnessed in recent world history, which is the main reason for the unpreparedness of the world.

3. Overview of SARS-CoV-2 Severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2) was named after severe acute respiratory syndrome coronavirus (SARS-CoV) as they exhibited 89%

Molecular interaction modeling of carbon nanotubes and fullerene

Fig. 1 Structural overview of SARS-CoV-2 depicting prominent structural features.

genetic identity [18]. It has a diameter of about 200 nm [19]. It has large positive, single-stranded, RNA genome with a methylated 50 end and adenylated 30 end that accounts to 30 kilobases of genome length [20]. It is a type of β-CoV (beta-coronavirus) which is contagious to human beings. The first whole-genome sequence was released on January 12, 2020 [18], after which several genomes of SARS-CoV-2 across the globe were sequenced and released into the public domain, which led researchers to understand the pathogenicity at the genomic level and initiate the development of an alternative solution to combat COVID-19. The genome-wide structure of SARS-CoV-2 predominantly comprises of four important structural proteins: spike glycoproteins (S), which appear as protrusions emerging outwards from the envelope; membrane proteins (M), which appear as rough patchy regions on the envelope; small envelope proteins (E), which appear as deposited spots on the envelope; and nucleocapsid phosphoproteins (N), which are primarily involved in replication and translation processes (Fig. 1) [21,22]. Additionally, the genome comprises of 16 nonstructural proteins (NSP) and at least 13 open reading frames (ORF) [20]. Targeting and inhibiting such proteins would suppress the virus, which is discussed in the following sections.

4. Current therapies, vaccines, and limitations Currently, there are no specific antiviral drugs for the treatment of COVID-19. Therefore, the clinical therapeutic options that were used in the earlier outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), antivirals used against Ebola, influenza, and human immunodeficiency virus, are being

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employed to treat COVID-19 infection [23–25], which include lopinavir, ribavirin, remdesivir, chloroquine, hydroxychloroquine, and ritonavir [21,26,27]. Other treatment options include nucleoside analogs, viral vector vaccines, neutralizing antibodies, monoclonal antibodies, neuraminidase inhibitors, interferons, RNA synthesis inhibitor, and antiinflammatory drugs such as hormones [28–32]. Despite these options, the massive health crisis caused due to SARS-CoV-2 infection and occurrence of newer symptoms is yet to be tackled successfully.

5. Need for an immediate therapeutic strategies—Role of computational biology Although several therapeutic options are being explored for the treatment of COVID19, the emerging infections are critically challenging in terms of national prevention. The recovery rate has been increasing with the aforementioned treatment options, but an effective and potent drug is yet to be developed. Since this process needs to be faster, adopting computational biology in assisting the drug development process could be effective, as this approach contributes to reducing time and infrastructure required compared to that of conventional drug discovery approaches. Therefore, computational biology probably applied for developing effective strategies for the treatment of COVID-19. With advancements in computational biology in recent years and the development in genomic and proteomic technologies, the drug development process has been revolutionized. It helps in the genome sequence analysis, variant analysis, structural annotation, repurposing of antiviral drugs, and development of data-driven models that need to be experimentally tested. Prediction of 3D structures of putative targets by molecular modeling and identification of small molecules with good binding potential by virtual screening and molecular docking aid the drug discovery process. Molecular dynamic simulation studies could be performed to confirm the stability and dynamics of the molecular models and docked complexes, which have to be verified experimentally.

6. Overview of computer-aided drug discovery (CADD) Collaboration between different study fields such as computer science, mathematics, biostatistics, biology, and chemistry amount to the interdisciplinary sector called computeraided drug discovery involves computation, mathematical calculations, and biological experiments to support computational predictions. Understanding the mechanisms of the infection and pathogen responsible for causing the infection is essential, as the molecular drug targets need to be identified and validated. The experimentally solved structures deposited in the structural databases could be retrieved and used for further analysis, whereas the 3D structures of those that are not experimentally available are to be computationally predicted by molecular modeling approaches and the modeled structures are

Molecular interaction modeling of carbon nanotubes and fullerene

Fig. 2 A brief overview of CADD protocol.

validated. Thereafter, small compounds need to be virtually screened based on drug likeliness and pharmacokinetic properties using various computational tools. The qualified molecules are then studied against the identified targets by molecular docking studies and interaction analysis. A brief overview of CADD protocol is represented in Fig. 2. 3D structure prediction of the SARS-CoV-2 targets that do not possess experimentally solved structures is a crucial step in computer-aided drug discovery. Approaches for computational modeling of structures are homology-based comparative modeling, ab initio modeling, and modeling by recognition of folds. Comparative modeling involves homologous template structure selection, which is extensively used to predict the structures of protein targets; the bioinformatics tools include SWISS-MODEL [33], MODELER [34], RaptorX [35], and 3D-JIGSAW [36]. Ab initio modeling includes exploring the conformational space by formulating scoring functions and search algorithms; tools used for this approach are I-TASSER [37], C-I-TASSER [38], QUARK [39], and CABS-FOLD [40]. Fold recognition is modeling based on identifying similar folds from the previously solved experimentally structures; tools used include GenTHREADER [41], MUSTER [42], and DescFold [43]. Once the target structures

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are modeled, they need to be refined and validated; tools used for this purpose include ModRefiner [44], QMEAN [45], ANOLEA [46], Verify3D [47], ProCheck [48], ProSA [49], ERRAT [50], and WHATIF [51]. Screening and validation of small compounds are achieved using molecular descriptors of geometry, composition, thermodynamics, water-solubility, lipophilicity, and bioavailability for drug likeliness and pharmacokinetic features prediction. Prediction of drug likeliness is based on the descriptors of Lipinski’s rule of five [52], the Ghose rule [53], Egan’s rule [54], the World Drug Index (WDI) like rule, Comprehensive Medicinal Chemistry (CMC) rule, lead-like rule [55], and MDL Drug Data Report (MDDR) like rule [56]. Prediction of carbon nanotube and carbon nanofullerene adsorption, distribution, metabolism, and excretion (ADME) properties uses descriptors based on statistical models such as the blood-brain barrier (BBB) [57], human intestinal absorption (HIA), heterogeneous human epithelial colorectal adenocarcinoma (caco-2) cell permeability [58], plasma protein binding [59], lipophilicity [60], Madin Darby canine kidney (MDCK) cell permeability [61], water solubility [62], and skin permeability [63]. Prediction of the toxicity properties include models of mutagenicity (Ames test), rodent (mouse and rat) carcinogenicity, acute fish (minnow and medaka) toxicity, and hERG gene inhibition. Computational tools used for the prediction of these features include PreADMET [64], SwissADME [65], ADMEWORKS Model Builder [66], QikProp [67], AdmetSAR [68], and ADMET Predictor [69]. The predicted putative targets (experimentally solved structures or predicted hypothetical models) are subjected to binding with the small molecules by performing molecular docking studies. This step is crucial in CADD as the inhibitory effect of the molecule on the target can be predicted based on the conformation and interaction analysis [70]. Different types of molecular docking approaches involve either a ligand or receptor to be flexible or rigid. Docking methods are classified into shape complementarity-based and simulation-based. The shape complementarity-based method involves molecular interaction based on the complementarity between the receptor and ligand surfaces, whereas in the widely used simulation-based method, the ligand separated by physical distance from the receptor binds to the binding cavity of the receptor, releasing energy with rotations and translations of torsion angle. Molecular docking includes preparation of the receptor and prediction of its binding sites, preparation of ligands, grid box parameters assignment, and docking estimations. Interaction analysis of the docked complexes is based on the total number of contacts between the ligands and the receptor, among which hydrogen bonds account for the stable interaction profile and the binding affinity obtained help in understanding the effect of ligand interaction with the protein. Binding site prediction could be achieved using tools such as DEPTH server [71], CASTp [72], Q-SiteFinder [73], and MetaPocket [74], and docking tools include Autodock vina [75], iGEMdock [76], SwissDock [77], GOLD [78], and Molecular Operating

Molecular interaction modeling of carbon nanotubes and fullerene

Environment (MOE) [79]. In order to confirm the stability and dynamic nature of the interactions, the docked complexes could be simulated by molecular dynamic studies that are carried out using force fields such as Assisted Model Building with Energy Refinement (AMBER) [80], GROningen MAchine for Chemical Simulations (GROMACS) [81], Nanoscale Molecular Dynamics (NAMD) [82], and Chemistry at HARvard Macromolecular Mechanics (CHARMM) [83].

7. Major drug targets of COVID-19 The genome-wide structural characterization of SARS-CoV-2 revealed that it consists of 25 probable putative targets, which includes four main structural proteins, 16 nonstructural proteins (nsp) and several accessory proteins [84–86]. Structural proteins include spike glycoprotein (S) (Fig. 3A), nucleocapsid phosphoprotein (N), membrane protein (M), and envelope protein (E). Major nonstructural proteins include RNA-directed RNA polymerase (RdRp)—nsp12 (Fig. 3B), papain-like protease (PLpro)—nsp3 (Fig. 3C), 3C-like protease (3CLpro)—nsp5 (Fig. 3D), endoribonuclease—nsp15 (Fig. 3E), RNA binding protein—nsp9 (Fig. 3F), and ADP ribose phosphatase (Fig. 3G). The outermost spike protein, S, which is a homotrimer protruding on the surface, plays a vital role in the transmission and host mediation initiating the infection. Nucleocapsid protein, N, is a highly phosphorylated protein that is structurally bound to the genomic RNA, and is therefore involved in processes such as viral replication and cellular host responses to the infections associated with the virus. The N- and C-terminals of nucleoprotein are shown in Fig. 3H and Fig. 3I, respectively. Membrane protein, M, determines the shape of the viral envelope and is bound to all the structural proteins, thereby stabilizing them. Envelope protein, E, is the smallest structural protein and is involved in the maturation of the virus [84]. Other important accessory proteins include helicase, guanine-N7 methyltransferase, uridylate-specific endoribonuclease, and 20 -O-methyltransferase [85,86]. The Research Collaboratory for Structural Bioinformatics, Protein Data Bank (RCSB PDB) hosts 401 experimentally solved structures of SARS-CoV-2 proteins as of July 15, 2022 [87]. The experimental techniques using which the structures were solved include X-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, and electron microscopy (EM). 3D structures of all the target proteins are available in the database including free forms, associated with cofactors, ligands, and other receptor proteins. The retrievable PDB format of the target structures is used for the computational prediction of the binding potency of the small molecules selected toward the target by molecular docking and analysis of binding events and interaction profiles.

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Fig. 3 Major drug targets of SARS-CoV-2: (A) spike glycoprotein, (B) RNA-directed RNA polymerase, (C) papain-like protease, (D) 3CL-protease, (E) endoribonuclease, (F) RNA binding protein, (G) ADP ribose phosphatase, (H) nucleocapsid protein N-terminal domain, and (I) nucleocapsid protein C-terminal domain.

8. Functionalized carbon nanomaterials as potential lead molecules Low magnitude carbon nanomaterials (CNMs) are carbonaceous materials that have been developed for various applications due to their unique shapes, sizes, and porous structures. One of the most challenging approaches includes target-specific drug delivery, controllable drug dispensation, and prevention of opsonization. In recent decades, the biomedical applications of CNMs have been flourishing due to their potential in gene-targeted therapy, drug delivery, bioimaging, tissue engineering, biosensing, tissue scaffolding, and antibacterial function [4–6,88]. The exclusive properties of CNMs such as mechanical, thermal, electrical, chemical, and optical properties have made them very useful in biomedicine. Prominent CNMs

Molecular interaction modeling of carbon nanotubes and fullerene

include fullerene, graphene, carbon nanotubes, carbon dots, and nanodiamonds. Recent applications of CNMs include cancer therapy, targeted drug delivery, cell and tissue imaging, and regenerative medicine [4–6]. Recent studies have revealed that the implausible capability of the CNMs aids in overcoming the challenges of several therapeutic strategies. The porous nature of CNMs paves a path for advanced drug delivery and gene-targeting techniques [89]. Most studies present the use of CNMs in cancer therapies and other life-threatening disorders as noninvasive compared to other treatment methods employed to address the same illnesses. They are also used in photothermal, photodynamic, and combined phototherapies [90]. Studies revealed that surface functionalization of CNMs facilitate adequate and efficient delivery of drugs or therapeutic and siRNA therapy. CNMs serve as nano drug carriers that are flexible depending on the drug solubility and bioavailability. Different routes of administration such as transdermal drug delivery, blood-brain barrier drug delivery, intravenous administration, oral administration, and inhalation routes for carbon nanomaterials are consistent [91]. In this chapter, we focus on the molecular interaction of carbon nanotubes and carbon fullerene and major prospective targets of SARS-CoV-2 targets by computational modeling and molecular docking studies.

9. Carbon nano fullerene and carbon nanotubes Carbon nano fullerene (C60) (Fig. 4A), also known as buckminsterfullerene, is a CNM that is responsible for the advancement of nanotechnology whose spectacular invention was honored with a Nobel Prize in 1996. It is represented as an ellipsoid or a hollow sphere comprising of 60 carbon atoms in 20 hexagonal and 12 pentagonal rings [92]. It is chemically synthesized by evaporating graphite and further functionalized and encapsulated using amphiphilic host molecules [88,93]. Functionalization and encapsulation improve biocompatibility and fluorescence quantum yield, and enable selective targeting to biomarkers. C60 treated with tetra-ethylene glycol and lithium hydroxide becomes soluble in water, which increases the photoluminescence. The acute toxicity of

Fig. 4 3D structures of (A) carbon nanotube and (B) carbon nano fullerene.

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Table 1 Physical, chemical, and biological properties of carbon fullerene and carbon nanotubes. Properties

Carbon nano fullerene

Carbon nanotubes

Average particle size Appearance Flexibility Thermal conductivity Electrical conductivity Tensile strength Melting point (°C) Solubility in water Boiling point (°C) LogP Flash point (°C) Density (g/cm3) Molecular weight (g/mol) Total surface area Hydrogen bond donor count Hydrogen bond acceptor count Rotatable bond count Exact mass (g/mol) Monoisotopic mass (g/mol) Topological polar surface area Heavy atom count Atom stereo–center count Bond stereo–center count Covalently bonded unit count Compound is canonicalized CCRIS mutagenicity studies AntiHIV activity (EC50) Systematic circulation Biodegradability

50–100 μm Shiny black needle-like crystals Good Low Low High 600 Insoluble 500–600 13.44 94 1.68 720.6 305.6 0 0

95%, and eye corrosion was 60% toxic. Daphina, algae, honeybee, minnow, and medaka fish toxicities of the nanoparticles were mild according to the predictions, as shown in Table 2.

Table 2 Drug likeliness, pharmacokinetics, and toxicity features prediction of carbon fullerene and nanotubes using PreADMET and admetSAR tools. Name of the properties

Carbon nano fullerene

Carbon nanotube

Drug likeness

Not qualified Violated Mid-structure Violated Out of 90% cutoff 28.2401 22.1611 100.0000

Not qualified Violated Mid-structure Violated Out of 90% cutoff 31.3645 23.2743 96.1654

100.0000 5.0254 Positive Mutagen Positive Negative Medium risk 2.62308e-006 3.8803e-010 3.89314e-008 0.0017 72.50 71.75 58.00 98.19

100.0000 5.0309 Positive Mutagen Positive Negative Medium risk 7.81067e-018 6.97767e-030 1.21979e-022 2.57772e-098 70.00 73.42 60.00 96.22

ADME

Toxicity

CMC like rule Lead like rule MDDR like rule Rule of Five WDI like rule Blood-brain barrier caco-2 (nm/sec) Human intestinal absorption (%) Plasma protein binding (%) Skin permeability (cm/h) Human oral bioavailability Ames test Carcinogen test Mouse Rat hERG inhibition Daphnia test Fish toxicity Medaka Minnow Algae test Hepatotoxicity (%) Honeybee toxicity (%) Eye corrosion (%) Eye irritation (%)

Molecular interaction modeling of carbon nanotubes and fullerene

11. Application of carbon nanotubes and carbon fullerene toward various viral infections Recently, several studies have reported the use of nanoparticles for the treatment of various viral infections. In 2018, a study reported that single-walled carbon nanotubes (SWCNTs) administered by bathing and injecting were used as carriers of SWCNTspET32a-G subunit to treat carp infections. These carriers improved the immunity by >15%, and could represent an efficient immersion vaccine against viral pathogens [95]. Another study was conducted using carbon nanotubes embedded with metallic Co/Ni nanomaterials against the human immunodeficiency virus 1 (HIV-1). This composite exhibited high electrochemical activity, good biocompatibility, high tensile strength, and strong bio-affinity toward the HIV DNA with high reproducibility; therefore, it was widely applied for biosensing [96]. Similarly, the pandemic of influenza virus employed detection techniques using antibody and aptamer attachments which showed high performance; this was supported by adequate specificity and reproducibility [97]. Carbon nano fullerene was used to enhance multivalency in biocompatible systems, appended with 1,2-mannobiosides which have been tested against Zika virus (ZIKV) and dengue virus (DENV) infections, and showed antiviral properties [98]. Additionally, fullerene lipidosome showed antiviral effects against influenza virus H1N1 in vitro by observing cytotoxic effects at different concentrations and comparing the activity [99]. Several in silico studies predicting the therapeutic efficiency of the carbon nanomaterials against microbial infections have also been reported in the last few years. Back in 2011, carbon nano fullerene was used to inhibit HIV-1 protease employing molecular docking and simulation approaches. The predicted models were similar to the results obtained experimentally, and ADMET properties were also promising, indicating fullerene as a novel HIV-1 protease inhibitor [100]. Docking studies were performed and it is clear that fullerene binds with PA subunit of endonuclease of the influenza virus and may probably inhibit the activity of the target. The models obtained were in agreement with the experimentally obtained results, suggesting fullerene was a promising candidate for the treatment of influenza viral infection [101]. HIV protease was inhibited by carbon nanotubes by using the Molecular Mechanics Generalized Born Surface Area (MM/ GBSA) approach. It showed good binding efficiency and it provided a keen insight required for designing SWCNT-based HIV-1 protease inhibitors [102]. In 2014, modeled armchair carbon nanotubes exhibited binding energies of 12.4 kcal/mol,  20 kcal/mol, and  11.7 kcal/mol against the HIV targets such as the HIV accessory protein (Vpr), Nef auxiliary protein, and Gag protein, respectively. Chiral CNTs exhibited 16.4 kcal/mol toward Nef, 10.9 kcal/mol toward Vpr, and 10.3 kcal/mol toward Gag proteins, and the zigzag CNTs showed the binding affinities of 11.1, 18.3, and  10.9 kcal/mol toward Vpr, Nef, and Gag proteins, respectively. These interacting energies suggested that CNTs were suitable for targeting HIV-mediated infections [103].

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In another recent study, SWCNTs were used to study the binding of these particles against the Ebola virus target (both wildtype and mutant) VP35 (viral protein 35) using MM/GBSA energy calculations. Binding energies obtained were 30.89 kcal/mol toward the wildtype, and 27.70, 25.29, and 28.28 kcal/mol toward mutants, which indicate the promising binding of SWCNTs [104]. Similarly, in this chapter, we employed molecular docking studies to predict the binding potential of carbon nano fullerene and carbon nanotubes toward the selected targets of SARS-CoV-2.

12. Binding potential of carbon nanotubes and nano fullerene toward SARS-CoV-2 targets The prioritized targets of SARS-CoV-2 that play a vital role in the pathogenesis of the virus are used for the current study, which includes the surface spike glycoprotein (S), RNA-directed RNA polymerase (RdRp), papain-like protease (PLpro), and the main protease (Mpro). Spike protein is responsible for the initiation of the infection as it mediates the entry into the host and contacts the receptor protein. The 3D structure of the postfusion core of S2 subunit (PDB ID: 6LXT) [105] retrieved was solved using ˚ resolution and it possessed six chains (A, B, C, D, E, F). X-ray diffraction of 2.90 A RNA-directed RNA polymerase is the central component of SARS-CoV-2, as it is involved in the viral replication cycle. Its 3D structure (PDB ID: 6M71) [9,10] was solved using electron microscopy with 2.90 A˚ resolution and is in complex with nsp7 and nsp8. PLpro (PDB ID: 6W9C) [106], which is nsp3, is involved in cleaving the N-terminus of the replicase protein of SARS-CoV-2, has a 3D structure solved by X-ray diffraction at 2.70 A˚ resolution, and has three chains: A, B, and C. Mpro is involved in cleaving the C-terminal of the replicase protein and its structure (PDB ID: 6Y2E) [85,86] is solved ˚ resolution. by X-ray diffraction at 1.75 A The 3D structures of all the four targets were retrieved in the PDB format from the RCSB PDB database. The chemical structure of carbon nano fullerene was retrieved from the PubChem database [94]. A carbon nanotube was modeled using a nanotube ˚ , diameter 7.474 A˚, and bond length 1.42 A ˚ , with 182 carbon modeler, of length 20.0 A atoms and 261 bonds. Molecular docking was performed using AutoDock Vina [75] by preparing the carbon nanotube and nano fullerene and the targets according to the standard protocols available using MGLtools [107]. Spike glycoprotein (PDB ID: 6LXT), when docked with carbon nanoparticles, showed good binding affinity, as depicted in Fig. 5. Carbon fullerene showed a binding affinity of 9.9 kcal/mol (Fig. 5A) interacting with the residues Gln957, Thr961, Ile1172, and Asn1173 (Fig. 5B). The interaction profile of fullerene and spike protein was visualized and analyzed by PyMol [108], and is shown in Fig. 5C. A carbon nanotube showed a binding affinity of 15.2 kcal/mol (Fig. 5D) interacting with the residues Lys921, Asn925, Asn928, Gly932, Leu1197, Asp1199, and Leu1200 (Fig. 5E); the

Molecular interaction modeling of carbon nanotubes and fullerene

Fig. 5 Interaction profiles of carbon nanotubes and nano fullerene with the spike glycoprotein visualized using PyMol and MGLtools.

interaction profile of a carbon nanotube and spike glycoprotein is shown in Fig. 5F. These residues are present at the binding pockets as predicted by CASTp [72] and DEPTH servers [71]. RNA-directed RNA polymerase (PDB ID: 6M71) also showed good binding affinity when docked with the nanoparticles (Fig. 6). Carbon nano fullerene showed a binding

Fig. 6 Interaction profiles of carbon nanotubes and nano fullerene with the RNA-directed RNA polymerase visualized using PyMol and MGLtools.

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Fig. 7 Interaction profiles of carbon nanotubes and nano fullerene with papain-like protease visualized using PyMol and MGLtools.

affinity of 12.0 kcal/mol (Fig. 6A). The residues interacting with fullerene are Pro323, Thr394, and Pro461 (Fig. 6B), which were analyzed using PyMol (Fig. 6C). A nanotube showed a binding affinity of 18.5 kcal/mol (Fig. 6D); interacting with the residues are Phe35, Ile37, Lys50, Asn79, Arg116, Thr206, Asn209, Asp218, Gly220, Asp221, and Asn713 (Fig. 6E). The interactions were analyzed using PyMol (Fig. 6F). These residues are also present at the predicted binding cavities of the target protein. Similarly, papain-like protease (PLpro) (PDB ID: 6W9C) exhibited good binding potential with carbon nanomaterials (Fig. 7). Carbon fullerene showed a binding affinity of 9.9 kcal/mol (Fig. 7A), interacting with the residues Leu199, Glu203, Tyr207, and Met208 (Fig. 7B), and was analyzed using PyMol (Fig. 7C). A carbon nanotube showed a binding affinity of 16.3 kcal/mol (Fig. 7D), interacting with the residues present at the binding sites such as His73, Thr74, Thr75, Asp76, Asn126, Asn156, Tyr171, Gln174, and His175 (Fig. 7E), and it is represented using PyMol (Fig. 7F). The main protease (Mpro) (PDB ID: 6Y2E) showed binding affinity of 10.7 kcal/mol toward fullerene (Fig. 8A), and it interacts with Thr199, Tyr237, Tyr239, Leu272, Leu286, and Leu287 (Fig. 8B); it was analyzed using PyMol (Fig. 8C). It is bound with carbon nanotubes (Fig. 8D) by the aids of binding energy of 17.8 kcal/mol and the interacting residues are Lys137, Thr169, Ala194, Gly195, Asp197, Tyr237, Asn238, and Leu272 of the main protease (Fig. 8E). PyMol representation of the same is shown in Fig. 8F. From molecular modeling studies, it is evident that nanoparticles showed promising binding affinity toward the selected targets of SARS-CoV-2. Both the carbon nanotube and nano fullerene showed the greatest binding energy of 18.5 kcal/mol and 12.0 kcal/mol, respectively, toward RNA-directed RNA polymerase. In addition, it is notable that the nanotube shows better binding affinity toward SARS-CoV-2 targets

Molecular interaction modeling of carbon nanotubes and fullerene

Fig. 8 Interaction profiles of carbon nanotubes and nano fullerene with main protease visualized using PyMol and MGLtools.

compared to that of the nano fullerene. Therefore, we propose that the carbon nanomaterials such as carbon nanotubes and carbon nano fullerene are suitable potential binders of the selected targets of SARS-CoV-2.

13. Limitations of functionalized carbon nanomaterials as therapeutic agents Despite all the tremendous advancements of carbon-based nanomaterials that have revolutionized the medical field, challenging tasks are yet to be accomplished. For instance, the insolubility of the CNMs may lead to the formation of metallic bundles in water or aqueous media, and therefore they cannot be used directly. However, many efforts have been made to modify the particles to make them soluble. Homogeneous nanotubes need to be produced in order to generate reproducible results and evaluate their biological activity. Studies have reported that multiwalled carbon nanotubes are harmful to animals and plants. Carbon nanoparticles could also lead to the presence of impurities, and irregular and nonuniform structures, due to their size. One of the most important challenges is that the size of CNMs could lead to possibilities of facilitating themselves into the body through the skin, inhalation, etc. as CNM are smaller in size. As they enter the body, their deposition could produce toxic effects on different organs and tissues of the body. Toxicity of the carbon nanomaterials is still a debatable question which requires extensive studies and analysis to be carried out.

14. Future perspectives As we have reported the molecular docking and interaction profiles of the carbon nano fullerene and carbon nanotube with the putative targets of SARS-CoV-2, future research

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should be focused on simulating the docked complexes using molecular dynamics to confirm the dynamics and stability of the interactions presented. Furthermore, experimental studies of the predicted models using in vitro assays are essential. The pharmacokinetic and toxicity features should be validated experimentally in further investigations.

15. Conclusion In conclusion, it is suggested that CNMs such as carbon nanotubes and carbon nano fullerene could be used as promising lead molecules against key targets such as spike glycoprotein, RNA-directed RNA polymerase, papain-like protease, and the main protease targets of SARS-CoV-2. The computational prediction of interactions of the receptor and carbon nanomaterials at a molecular level provides ample foundations for validation by molecular dynamic simulation studies and experimental investigation. Furthermore, this chapter not only provides information about the combination of CADD and nanotechnology to fight COVID-19, but also opens a new paradigm toward the identification of novel carbon-based nano-analogs and nano-derivatives against probable therapeutic targets for SARS-CoV-2.

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Molecular interaction modeling of carbon nanotubes and fullerene

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CHAPTER 9

Functionalization of carbon nanotubes: Fundamentals, strategies, and tuning of properties Baskaran Ganesh Kumara,b,∗ and K.S. Prakashc,∗ a

Department of Chemistry, P.S.R. Arts and College (Affiliated to Madurai Kamaraj University, Madurai), Sivakasi, Tamil Nadu, India b Department of Science and Humanities, P.S.R. Engineering College (Affiliated to Anna University, Chennai), Sivakasi, Tamil Nadu, India c Department of Chemistry, Bharathidasan Government College for Women (Autonomous) (Affiliated to Pondicherry University, Pondicherry), Muthialpet, Puducherry, India

1. Introduction Humanity has always benefited from modern technologies and used them to solve real-world problems [1–3]. Modern technologies often build on next-generation novel materials and their properties [4–7]. Carbon nanotubes (CNTs) are considered as next-generation materials for electronics, health care, and information technology [8–15]. CNTs contribute to both conventional and unconventional industries and have huge impacts on textiles, food, sensors, biogenetics, cosmetics, etc. Since CNTs were discovered, they have been a central part of chemistry, biology, physics, and materials science due to their versatile physical, chemical, electrical, optical, and mechanical properties. This versatility arises from organic carbon and nanoregime. The carbon creates a tunable chemical property and the nanoregime provides tunable optical, electrical, and mechanical properties [16,17]. CNTs have revolutionized existing technologies through speed, unprecedented efficiency, and ultra-portability. They not only make current technologies more efficient but also allow new sets of devices to emerge, such as flexible electronics and camouflage extra-dark paints. CNTs have wide possibilities and there are always more avenues to explore in both science and technology. Many reviews have explored carbon nanotubes in great detail [18–22]. Although the properties of carbon nanotubes are intriguing, they have additional properties such as flexibility, solution processability, and complete carbon chemistry through their functionality. Carbon nanotubes are surprisingly soluble in all common solvents and provide solution processability. Thus, solution-made CNTs can be made for making devices from ∗

Authors contributing equally.

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00014-5

Copyright © 2023 Elsevier Ltd. All rights reserved.

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spin coating, spray coating, dip coating, and printing. Hence, CNTs can be made as a variety of substrates including paper, plastic, glass, and silk [23,24]. Notably, they have carbon atoms as building blocks, which are a source of enormous chemical possibilities. CNTs have the advantage of every existing chemical opportunities and handle for tunable properties. Additionally, the nanoregime of CNTs provides size versus the tunable properties [25,26]. Hence the combination of carbon chemistry, solution processability, and nanoregime makes CNTs unique. Bearing in mind the volume of new CNT publications and emerging CNT technologies, research and development should be updated periodically. More over the hope and opportunities of CNTs should be pushed further by consolidated research and development. Therefore, detailed reviews on strategies on synthesis of CNTs and tunable methods are required. In this chapter, we attempt to consolidate various efforts to understand the world of carbon nanotubes. We start with the fundamentals of CNTs, including hybridization and possible reaction around the carbon atom of CNTs (Fig. 1). Then, we briefly explore high-yield synthesis of CNTs and discuss the effectiveness of the method. The effectiveness is assessed via various aspects based on simplicity, high yield, tunable properties, and key results. We next comprehensively analyze the functionalization of CNTs based on various chemical methods. All possible types of functionalization, including covalent and noncovalent functionalization, are discussed. Covalent functionalization involves direct attachment of a functional group with CNTs such as side wall functionalization and defect functionalization. Noncovalent functionalization has physical interaction of

Fig. 1 Formation of CNT from carbon sheet.

Functionalization of carbon nanotubes

groups with CNTs such as surface attachment, polymer wrapping, endohedral, and π-π stacking. We discuss all possible functional transformations in great detail, along with tunability in synthetic methods. We specifically discuss tuning of pure unfunctionalized CNT over functionalized CNT. Reports on functionalization of CNTs are highlighted and analyzed for immediate usability in industry. We conclude with the versatility of functionalization, potential of functionalization, new area of applications, and perspective on major hurdles.

2. Functionalization of CNTs Basically functionalization defines creating reactive sites by attaching the different groups such as alcohol, amide, carbonyl, carboxylic acid, polymers, etc. CNTs have unique properties used for many fields; however, functionalization is needed to exploit these properties as much as possible. Postfunctionalization, CNTs were found to have different or new optical, mechanical, magnetic, electronically and thermal properties, and also have a different soluble property. Moreover, functionalization is able to tune the bandgap and ensure efficient energy harvesting as well. Functionalization makes the material more flexible to use. Many problems in materials science are being solved by tuning their properties via functionalization of specific materials. For example, solubility issues in device manufacturing process are easy to overcome by improving a suitable functionalization. Specifically in CNTs, while attaching a functional group, the entire electronic and surface properties are changed and lead to a new useful CNT being created. Overall, complete different material is produced from the parent CNT, hence functionalization of CNTs is crucial in terms of producing novel CNTs. Surface properties are also heavily modified and essential properties can easily be achieved. These CNTs’ surfaces can be modified chemically through oxidation and reversibly absorbing amphiphilic structures or grafting [27–29]. The functionalization is classified into two main types, viz., covalent and noncovalent functionalization, and these are depicted in Fig. 2. The covalent bond attaches the functional groups on the side or end of the CNTs, and mainly changes the intrinsic electrical, mechanical, and thermal properties of the materials. Moreover, this covalent functionalization reinforces interfacial adhesion between CNTs and the composite matrix, increases the stability of the nano-template for the assembly of supramolecular targets, and tunes the electrical performance of the materials. Similarly, noncovalent functionalization on CNTs works based on supramolecular chemistry theory, which involves modifying the function through weak interactions without changing the CNT properties. Biopolymer-based noncovalent interactions have attracted significant attention from researchers due to their important roles in many scientific fields. In the following section, the functionalization of CNTs will be discussed in detail. Many techniques are being used to stabilize CNTs and prevent aggregates.

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Fig. 2 Various types of functionalization.

2.1 Covalent functionalization Covalent functionalization is a functional group attachment by the formation of new bond (equal sharing of electrons from two atoms) and the introduced chemical moiety. Covalent functionalization can further be classified into two subcategories: defect functionalization and side wall functionalization. Defect functionalization is mainly used for the purification of CNTs, producing holes, and shortening the length of CNTs. Side wall functionalization involves changing the hybridization of carbon networks from sp2 to sp3, and thus needs harsh reaction conditions; this also modifies the properties of CNTs significantly. Many side wall functionalizations have been reported such as fluorination, carbine addition, arylation, 1,3-dipolar cycloaddition, nitrene addition, radical addition, nucleophilic addition, hydrogenation, and polymerizations (Fig. 3) [30]. This type of functionalization may otherwise be called defect functionalization, because only defective carbon from CNTs is involved in the attachment of the new functional group. It may be either the side wall or the end of the CNT. Covalent functionalization is achieved by a

Functionalization of carbon nanotubes

Fig. 3 Covalent functionalization of CNTs.

suitable reaction—for example, a defective carbon atom can easily be oxidized using strong oxidizing agents. If oxidation is carried out, carbon becomes acid functionality and subsequently the acid group can easily be modified to other useful functional groups (amides, esters, etc.). As required, other functional groups can also be attached to the oxidized CNTs. Another main type of reaction in CNTs is addition reaction using reactive species like radicals, nitrenes, carbenes, and arenes. These reactive species covalently modify CNTs through free radical addition, CH insertion, or cycloadditions. Free radical addition reaction in CNTs can understand that electron transfer from CNT to aryl diazonium salt and peroxides. Nitrines are generated from organic azides via photochemical reactions. Another important reaction is 1,3-dipolar cycloaddition for the functionalization of CNTs without oxygen atoms. For example, the functionalization of CNTs (single-walled, double-walled, and multiwalled CNTs) with sodium naphthalide reduction followed by addition of diaryliodonium salts was reported in the literature [31]. Side wall covalent functionalization is the attachment of functional groups at the side of CNTs; for example, fluoro-nanotubes were alkylated successfully using alkyllithium

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reagents and the degree of functionalization was measured with the help of thermal gravimetric analysis combined with UV-Vis-Nir spectroscopy. It is important to note that dealkylation also occurs at 500°C under an Ar atmosphere [32]. In covalent functionalization, oxidative purification of CNTs is also an important process using liquid or gas phase oxidation. Oxidation of CNTs is performed in the presence of HNO3, H2SO4, and piranha solution (sulfuric acid with hydrogen peroxide). Other reagents are also being used with different reaction conditions. In many cases, metals are used as catalysts during the reaction. These metal catalysts are mixed with CNTs (inside the CNTs) and can be purified by oxidation via opening up of the ends of caps for closed CNTs. Other functionalization such as halogenations, amidation, esterification, cycloaddition, and nucleophilic and electrophilic addition can be done with suitable reagents. The solubility of CNT is highly modified with the help of polar functional groups such as -OH, -NH2, etc. This will also enhance the solubility with water because of polarity and through hydrogen bonding. When introducing functional groups, precise chemical composition of reagents should be used for the purpose of reproducibility and large-scale production.

2.2 Noncovalent functionalization Noncovalent functionalization is the interaction of CNTs with other functionalities without involving covalent bonds. Interactions between new group/molecules and CNTs can be hydrophobic interactions, π-π stacking, or electrostatic binding with CNTs. These are purely noncovalent or supramolecular interactions. When comparing the energy of noncovalent interactions and covalent bonds, noncovalent interaction is lower, but when combined over large surfaces, it has relative strength like covalent bonds. In noncovalent interactions, the hydrophobic nature of CNTs can enable interaction with the hydrocarbons of surfactants via hydrophobic interactions. At the same time, the hydrophilic part of a surfactant is available to interact with the environment and leads to the formation of new material with potential changes in its properties. Another important electrostatic interaction is formed from the charge sites from functionalized CNTs and other groups. Noncovalent functionalization may be classified into four types: (i) surface attachments of particles; (ii) polymer wrapping; (iii) endohedral functionalization; and (iv) π-π stacking [33]. The main advantage of noncovalent functionalization is that it will not alter the conjugated system of CNTs’ side walls, hence the final structural properties of CNTs are also not affected. This type of functionalization is an alternative way to tune the interfacial properties. The CNTs can be functionalized aromatic compounds, surfactants, and polymers. Their desired properties can be preserved while improving their solubility remarkably. Aromatic molecules can interact with the side walls of CNTs by means of π-π stacking; these

Functionalization of carbon nanotubes

kinds of functionalizations are highly used in the immobilization of biological systems with high degrees of control and specificity. The interaction between surfactants and CNTs is the physical adsorption on the CNT surface which lowers the surface tension of CNTs that also prevents aggregation. Moreover, surfactant-treated CNTs overcome the van der Waals attraction by steric/electrostatic repulsive forces (Fig. 4). These interactions depend on the properties of the surfactant, medium, and polymer matrix. Three types of surfactants are commonly used with CNTs: nonionic, anionic, and cationic. Three types of orientation of surfactant and CNT are possible, and these are shown in Fig. 4. Although surfactants enhance the solubility of CNTs, they are known to be permeable plasma membranes. Surfactantstabilized CNTs are limited to biomedical applications because of their toxic nature. Various biomaterials and biomacromolecules like proteins, enzymes, DNA, simple saccharides and polysaccharides, etc. can also be attached to CNTs in a noncovalent functionalization process. These simple saccharides and polysaccharides are inactive in the UV-Vis region, hence they are biocompatible and applicable in many medicinal applications. Normally, conjugated polymers are involved in wrapping methods. The aromatic groups in conjugated polymers interact with the surfaces of CNTs through π-π stacking and van der Waals interactions. Two important properties are required to make π-π interactions: the existence of π systems and the geometry of interacting species. Moreover, the formation of an electrostatic complex with DNA and RNA is highly important in biomedical applications. Recent updates of functionalization of CNTs are listed in Table 1 [34–54].

3. Conclusion and future perspective In this chapter we consolidated various efforts from fundamental understanding to advanced functionalization. Within the scope of the work, we discussed the possibility of carbon architecture and the synthetic possibilities. We considered a few key physical and chemical methods among the many that exist. Whenever possible, we framed the significance of the methods in terms of their simplicity, cost of production, and time and skill required for the synthesis. Although CNTs are better than any other materials, the functionalization of CNTs could make them even better. We discussed the nature of carbon atoms in CNTs and the possibility of converting these atoms to usable chemical functional groups. All possible forms of functionalization, including covalent and noncovalent, were considered. Covalent functionalization involves direct attachment of a functional group with CNTs such as side wall functionalization and defect functionalization. Noncovalent functionalization has physical interaction of groups with CNTs such as surface attachment, polymer wrapping, endohedral, and π-π stacking. Among covalent and noncovalent interactions, we observed that covalent methods are very reproducible and predictable. The properties of CNTs can be tuned to the required level and

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Fig. 4 Various types of interaction of surfactants and CNTs.

Functionalization of carbon nanotubes

Table 1 Recent reports on functionalization of CNTs and their importance. Sl. no.

1

2

3

4

5

6

7

Method used/type

Material

Key applications

Reference

Ball-milling of red phosphorus/ covalent Oxidation/ HNO3-H2SO4/ covalent WillgerodtKindler reaction/ covalent Oxidation, chlorination, and grafting Electrochemical cycling in acid medium Reduction chemistry/ covalent Ester and amide bonds

P-CNT

Advanced sodium ion battery anodes

[34]

Acid functionalized CNT

Biosensors, super capacitors, catalysts, etc.

[35]

Acid functionalized CNT

Biological systems

[36]

Polyurethane/ polyvinyl chloride/ multiwalled CNT CNT-protein

Effect on shape memory behavior

[37]

Highly active hydrogen evolution catalyst

[38]

Boron nitride CNTs

Strong potential for many fields

[39]

Polyimide (PI)/ titanium (Ti) wire composite Polymer nanocomposite-based CNT Al2O3 nanoparticles act as strong anchors at CNT-Al interfaces SWCNT

Improved interface performance

[40]

Optical applications

[41]

Enhanced mechanical property and superior electrical conductivity Hydrazine (HZ) sensing applications A specific areal capacitance of 34.55 mF/cm2 was achieved Gas sensor applications

[42]

Use in reinforced polymer composites

[46]

8

Polypropylene polymerization

9

CNT-Al2O3/Al powders

10

SWCNT

11

Strong acid

Carbonyl/quinone on MWCNT

12

Naphthalene1,4,5,tetracarbonic acid dianhydride 2,20 -(1,2Ethenediyldi-4,1phenylene) bisbenzoxazole

(F-MWCNTs/MO) nanocomposite

13

Inorganic halloysite nanotube

[43] [44]

[45]

Continued

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Table 1 Recent reports on functionalization of CNTs and their importance—cont’d Sl. no.

Method used/type

Material

Key applications

Reference

14

Noncovalent

CNT-nickel cyclam

[47]

15

Metal phthalocyanine/ noncovalent

Metal phthalocyanine-CNT

16

Noncovalent

17

Noncovalent

Design of other types of molecular systems

[50]

18

Noncovalent

Initial discharge capacity of 1569.8 mAh g1

[51]

19

Noncovalent

Noncovalent

Improved the physical property of nanocomposites Semiconductor

[52]

20

21

Noncovalent

Polyaniline/singlewalled CNT composite Fluorene and carbazole copolymers—CNT Polyoxometalate (POM)-pyrene hybrid (Py-SiW11) Polyamide 6 nanocompositesCNT Biethynyl-2,5-bis (dodecoxy)benzene/ CNT PMMA/CNT

Electrochemical reduction of CO2 Highly sensitive and selective sensing of acetone and hydrogen sulfide Raman analysis

Improved the filler dispersion and the fiber mechanical properties

[54]

[48]

[49]

[53]

performance of the desired application. CNTs have great potential and new avenues are yet to be explored in both science and technology. Since CNTs are versatile, their future has many opportunities and possibilities. Importantly fundamental also should be targeted in future to establish the best control on properties and applications. Based on our understanding, we suggest a few possibilities: (1) The electronic properties of the CNTs are not yet very well explored in terms of the mechanism of conduction. (2) The mechanical properties of the CNTs are not well established and often appear to be discovered or changed by accident. Hence, the most effective methods should be established to tune these properties. (3) 3. CNTs are central to physics, chemistry, biology, electronics, and materials science. Hence, the simplicity of synthetic methods should be established for nonexperts. (4) The costs of synthesis and characterization of CNTs are still very high. These should be reduced to make them more accessible to resource-limited settings.

Functionalization of carbon nanotubes

(5) 5. CNTs are versatile and often explored as single functional devices, but many biomaterials have multifunction. Therefore, the possibility of creating two or more applications using single CNT materials should be explored. (6) 6. Since the human body is made of carbon and CNTs have similar architecture and hence biocompatibility, the possibility of using CNT devices for internal medicine should be pursued further. With these future directions, we believe that opportunities of CNTs can be pushed further to real-world applications.

Acknowledgments BG is grateful to P.S.R. Arts and Science College, Tamil Nadu, India for their infrastructure and lab facilities. KSP is grateful to Bharathidasan Government College for Women (Autonomous), Puducherry UT, India for the infrastructure.

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Section C Functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy

CHAPTER 10

The advances in functionalized carbon nanomaterials for drug delivery Selin S. Sunera, Saliha B. Kurta, Sahin Demircia, and Nurettin Sahinera,b,c a

Department of Chemistry, Faculty of Sciences & Arts, and Nanoscience and Technology Research and Application Center (NANORAC), Canakkale Onsekiz Mart University, Canakkale, Turkey b Department of Chemical & Biomedical Engineering, and Materials Science and Engineering Program, University of South Florida, Tampa, FL, United States c Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

1. Introduction In recent years, attempts have been made to use functionalized carbon nanomaterials (FCNMs) in biomedical applications such as diagnosis, drug delivery, and stem cell therapy [1–4]. The diagnosis step for early diseases, which is first and most important step for intervention of diseases, was carried out with FCNMs in recent years [5–7]. FCNM-based diagnostic materials, in particular, stand out for use in well-accepted techniques for detecting bio-agents, which are ecologically damaging chemical agents [8–10]. Single-walled carbon nanotubes (SWCNTs), multiwalled carbon nanotubes (MWCNTs), graphene and fullerene, graphitic carbon nitrides (g-C3N4), and carbon dots (CDs) are most important members of carbon nanomaterials used for functionalization [11–14]. FCNMs are at the forefront of research about the creation of cutting-edge sensors for biomedical and environmental applications [15]. Due to their adaptability and many intrinsic features, as well as their performance on chemically resistant platforms, FCNMs have transformed the area of current analysis [15]. Aside from being disposable, their versatility and physicochemical features enable FCNMs to be portable and adaptable to multiplexed sensors. Indeed, a wide range of analytes, including heavy metal ions, explosives, smaller biomolecules and viruses, and volatile biomarkers, were effectively identified by employing FCNM-based sensors [16–18]. The superior performance of such biosensors has accelerated their development for use in high-performance diagnostic sensors [19–21]. The findings produced using FCNM-based materials for the early diagnosis of disease have piqued the interest of researchers in recent years. In addition, the potential of FCNMs for use as clinical drug delivery systems, due to their tunable surface properties depending on the functionalization molecules used, has come to the fore in recent years [22–25]. Especially, limitations of the clinical drug delivery applications including high toxicity, poor bioavailability of drugs, poor penetration and absorption from the biological system, and nontargeting effects cause various Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00011-X

Copyright © 2023 Elsevier Ltd. All rights reserved.

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problems during treatment of diseases and create significant systemic toxicity [23,25]. Novel FCNM-based carriers have recently attracted much attention as drug vehicles to overcome these disadvantages through excellent functionalities [15,26,27]. The unique properties of FCNMs allowed development of in vitro and in vivo triggered drug delivery systems for both hydrophilic and hydrophobic drugs [24,28,29]. In the last decade, FCNMs have developed very quickly and frequently, and due to this evolution the area of use for FCNMs is expanding [30]. FCNMs can be used as theragnostic nanoagents, which are nano-sized agents in therapeutic and diagnostic systems [31,32]. Furthermore, FCNMs were used as a template or carrier for stem cells [33]. Stem cells and FCNMs are two significant fields and incorporation of these will enhance the effect of existing studies by creating new environments [34]. FCNMs has the ability to attach to diverse molecules including the ligands of cells [2]. Therefore, FCNMs controlling both proliferation and differentiation of stem cells are perfect candidates for use in both therapeutic and diagnostic systems [35]. Several types of FCNMs such as carbon nanotubes (CNTs), carbon nanoparticles (CNPs), carbon dot particles (CDs), and graphene oxide (GO) sheets are usually utilized in stem cell therapy [30]. Here we focus on the potential applications of FCNMs in diagnosis, drug carrying and delivery, and stem cell therapy. The recent materials in design of functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy were listed in Table 1.

Table 1 Recent functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy. Functionalized carbon nanomaterials

Application areas

AS1411 aptamer added reducedGO/chitosan/gold nanoparticle

Diagnosis

Modified heptametin cyanine dye-fullerene C60 Screen-printed electrode modified with carbon black nanomaterial Amide couples functionalized CNTs Cysteamine-polyaminoamine grafted CNTs

Diagnosis Diagnosis Diagnosis Diagnosis

Purpose

Ref.

Design of aptasensor which reacted with membrane proteins of MCF-7 cancer cells with good selectivity, repeatability, and sensitivity Cell imaging and fluorescence detection by modified fullerene Smartphone-assisted tyrosine sensor device in serum Biosensor to detect the electron transfer of galactose oxidase enzyme Immobilization of urease enzyme onto functional CNT to use a biosensor for urea in the plasma

[36]

[37] [38] [39] [40]

Functionalized carbon nanomaterials for drug delivery

Table 1 Recent functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy—cont’d Functionalized carbon nanomaterials

Application areas

Modified CDs with polyamine containing organosilane

Diagnosis and drug delivery

Folic acid modified CDs

Diagnosis and drug delivery

Tocopherol polyethylene glycol succinate modified mesoporous carbon nanomaterials

Drug delivery

Functionalized CNTs with phosphotidylcholine and polyvinylpyrrolidone

Drug delivery

Folic acid conjugated chitosan functionalized GO

Drug delivery

Citric acid polymerized CNTs

Stem cell therapy

CNT-thermoplastic urethan nanocomposites

Stem cell therapy

Doxorubicin and mitoxantrone conjugated GO Cellulose conjugated graphene foam hybrid scaffold

Stem cell therapy Stem cell therapy

Purpose

Ref.

Provide simultaneously cell imaging by the fluorescence CDs and prolonged doxorubicin release as an anticancer drug inside the MCF-7 human breast cancer cells with negligible toxicity Use as a bioimaging tool depending on the fluorescence ability of CDs and cancer-targeting ability with folate groups on the CD surface, and provide targeting cellular uptake Improve the biocompatibility and dispersion ability with near-infrared (NIR) light and pH-sensitive responsive doxorubicin delivery Curcumin delivery from functionalized CNTs provide significantly inhibition efficacy on tumor growth with no toxicity and enhancing cell uptake in vivo in mice Multifunctional nanomaterial for near-infrared fluorescence/ photoacoustic imaging and tumor targeting photothermal therapy Citric acid polymerized CNTs can fix and form a stability to extracellular matrix and regulate the differentiation process Electrospun CNTs-Thermoplastic urethan nanocomposites can promote the attachment and growth of stem cells, and can enhance the proliferation and differentiation process of the stem cells Functionalized GO for cancer therapy

[41]

Cellulose-graphene scaffold regulates the stem cell proliferation and differentiation by forming a neural network

[49]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

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2. Functionalized carbon materials for diagnostic purposes Detecting biomarkers for a specific disease is the most promising strategy. In general, biomarkers of disease are biological molecules found in human tissues or fluids (urine, blood, saliva, and cerebrospinal fluids) that are related to diseases, such as nucleic acids, enzymes, proteins, and tiny molecules [50]. However, the biomarker expression level is frequently quite low in patients with early disease [51]. Furthermore, the biosystem is complicated, with several sorts of interference. As a result, early disease detection has increased obstacles in terms of sensitivity and selectivity for nanodiagnostics. Fortunately, recent breakthroughs in nanotechnology resulted in the appearance of novel nanomaterials, allowing the development of enhanced biosensing and bioimaging tools for disease detection. Nanodiagnostics, particularly nanomaterial-based biosensing and bioimaging, have piqued the interest of the scientific community in recent years, since they enable unprecedented breakthroughs in the detection of many diseases [52]. The most fundamental strategies for disease detection using functionalized carbon nanomaterials were documented as biosensing and bioimaging technologies [53]. Fig. 1 roughly depicts the recognition units and diagnostic approaches that may be utilized with functionalized carbon nanomaterials. Because of the practical role of carbon nanomaterial in electroanalysis and electrocatalysis, biosensing based on functionalized carbon nanomaterial has evolved into an adaptive diagnostic approach [54]. In addition to these benefits, it offers cost-effective, fast, on-site analysis of biological samples with excellent accuracy and sensitivity [55]. Biosensors are often classed as electrochemical biosensors, optical biosensors, thermal sensing biosensors, ion-sensitive, field effect transistors, and resonance biosensors based on the transducer unit [56]. Because of their simplicity, electrochemical biosensing and optical biosensing are most often utilized [53,57–60]. Bioimaging, on the other hand, permits the morphological characteristics of organs to be associated with disease symptoms, which is useful for discovering biomarkers and subsequently applying them to disease diagnosis [61]. Because of their unique optical properties, such as near-infrared photoluminescence, magnetic resonance, characteristic Raman bands, and tunable fluorescence, functionalized carbon nanomaterials are increasingly being used in bioimaging [62,63]. Furthermore, bioimaging based on functionalized carbon nanomaterials is a far superior alternative for detecting illness in vivo, as opposed to earlier biosensors, which were exclusively employed in vitro.

2.1 Graphene and graphene oxides (GOs) The physicochemical parameters of the starting material utilized in the fabrication of graphene (G)-based materials are connected to their efficacy in diagnostic applications [53,64–66]. The production of nanocomposites from the mixing of G with organic or inorganic molecules, on the other hand, represents significant progress for G-based diagnostic applications [67–70].

Functionalized carbon nanomaterials for drug delivery

Graphene oxide (GO), reduced graphene (r-G), and functionalized graphene (f-G) are all examples of G derivatives that are commonly employed in diagnostic applications. GO is produced via chemical oxidation of graphite followed by ultrasonic exfoliation of graphite oxide. Chemical functionalization of GO is made feasible by the functional groups on the GO surfaces [70–73]. The primary benefits of employing GO are its workability and water stability due to the ionizable groups on its surface [74]. Optical biosensing

Electrochemical 400

1.4

0

900 600 Z’ (Ω )

300

1200

30 20 10 0

500

1000

50

100

1 5 10

1.0

0

2

Absorbance (%)

1.8

1

100

3

0

200

2.2

0.5

Ratio of impedence change

300 Z’’ (Ω )

P-SWCNT RDX 2,6DNT DNP-G TNT 4-N-G-G

4

CEA concentration (ng/mL)

0 700

900

1100

1300

1500

Peptides

Genes Fullerene

G

-based nanomaterials

RNAs

Small bio-active Molecules (antigen, aptamer, antibody)

g-C3N4 OH

DNAs H O

CNT

OH Enzymes CD

BIOIMAGING Fluorescence Field

In vitro bioimaging r-CQDs

1900

BIOSENSING

Diagnostic units

Bare CQDs

1700

Diagnostic units In vivo bioimaging

r-CQDs-GS

Fig. 1 See legend on next page

Control

r-CQDs-GS (60 min)

201

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Surface-functionalized graphene-based materials were frequently used in the literature for the diagnosis of various cancer types [75–80]. As seen in Table 1, a graphenebased sensitive aptasensor for human breast cancer cell detection was reported by Shafiei et al.; the AS1411 aptamer was added to the synthesized r-GO/chitosan/gold nanoparticle composite and employed on the electrode surface. Membrane proteins of MCF-7 cancer cells reacted particularly with the three-dimensional structure of the aptamer, resulting in cell capture on the aptasensor. The constructed r-GO-based aptasensor demonstrated good selectivity, repeatability, and sensitivity [36]. In another study, an electronically readable prostate-specific antigen (PSA) sensor that detects PSA and is more sensitive and cheaper than low-cost point-of-care (PoC) diagnostic devices was created utilizing a dielectrophoresis (DEP)-based graphene oxide field-effect transistor (GOFET). The GOFET-based PoC device was described as the sole label-free analytical system that provides easy handling for the detection of PSA, with a detection limit of 1 pg/mL in serum and a large dynamic range up to 4 ng/mL with exceptional selectivity [81]. Moreover, a novel label-free electrochemical immunosensing technology for very sensitive detection of tumor markers was developed by Lan et al. based on rGO@Polystyrene (rGO@PS) nanoparticles functionalized with streptavidin protein. Streptavidin-functionalized rGO@PS nanoparticles with good electrochemical properties, good hydrophilicity, larger specific surface area, and high antibody loading capacity were reported to be a label-free, simple, rapid immunosensor with high sensitivity, good selectivity, and acceptable reproducibility for tumor markers [82]. A GO-based biosensor that can directly detect circulating TB7.7 in serum was also reported for simple, economical, and accurate diagnosis of tuberculosis (TB). Accordingly, GO was functionalized with the TB7.7-sensitive aptamer. With the prepared GO-based aptasensor, highly sensitive and specific detection was achieved for TB7.7 in buffer solution and serum, even at concentrations of 0.8779 nM and 0.7089 nM, respectively. Clinical application to serum samples from patients with active TB indicated the diagnostic performance of the Fig. 1, Diagnosis types using carbon-based nanomaterials. (Reprinted with permission from A.M. Anthony, R. Murugan, R. Subramanian, et al., Ultra-radiant photoluminescence of glutathione rigidified reduced carbon quantum dots (r-CQDs) derived from ice-biryani for in vitro and in vivo bioimaging applications, Colloids Surf. A Physicochem. Eng. Asp. 586 (2020), https://doi.org/10.1016/j.colsurfa.2019. 124266, J. Espina-Casado, T. Fontanil, A. Fernández-González, et al., Carbon dots as multifunctional platform for intracellular pH sensing and bioimaging. In vitro and in vivo studies, Sens. Actuators B 346 (2021), https://doi.org/10.1016/j.snb.2021.130555, T.A. Tabish, H. Hayat, A. Abbas, R.J. Narayan, Graphene quantum dot–based electrochemical biosensing for early cancer detection, Curr. Opin. Electrochem. 30 (2021) 100786, https://doi.org/10.1016/j.coelec.2021.100786, G.J. Mattos, J.T. Moraes, E.C.M. Barbosa, et al., Laccase stabilized on β-D-glucan films on the surface of carbon black/ gold nanoparticles: a new platform for electrochemical biosensing, Bioelectrochemistry 129 (2019) 116–123, https://doi.org/10.1016/j.bioelechem.2019.05.002, J. Wang, Near infrared optical biosensor based on peptide functionalized single-walled carbon nanotubes hybrids for 2,4,6-trinitrotoluene (TNT) explosive detection, Anal. Biochem. 550 (2018) 49–53, https://doi.org/10.1016/j.ab.2018.04.011.)

Functionalized carbon nanomaterials for drug delivery

aptasensor had 41.67% sensitivity, 92.86% specificity, and 78.87% accuracy based on receiver operator curve (ROC) analysis [83]. Similarly, the diagnosis of Alzheimer’s disease was also reported via functionalized GO-based materials by Park et al. Detection of major Alzheimer’s disease (AD) biomarkers (Aβ1–42 and t-Tau) in biofluids such as human plasma and artificial cerebrospinal fluid utilized an r-GO field-effect transistor (rGOFET) along a large logarithmic range of 10
1–105 pg/mL. It was also stated that it can be utilized for early detection of Alzheimer’s disease in clinical practice, as well as for accurate analysis based on analyte surface charge [84]. In addition, the successful diagnosis of Parkinson’s disease (PD) used the aggregates of alpha-synuclein (α-Syn), which is a potentially promising candidate biomarker for PD. A simple and sensitive electrochemical sensor to monitor α-Syn aggregation for early diagnosis of PD was reported by Jang et al. The sensor was prepared with methylene blue (MB)-labeled aptamer (Apt) adsorbed on r-GO via π-π stacking. Binding of the α-Syn oligomer to Apt induces desorption of Apt from the r-GO surface, resulting in electrochemical signal change. The resulting sensor allowed the highly sensitive and selective detection of the α-Syn oligomer according to voltametric change and is promising for early detection of PD [85]. Functionalized GO materials were also used for the diagnosis of virus-based diseases [86–89]. In a study, it was claimed that PCR aided by nanomaterials comprising rGO and gold nanoparticles (nano-PCR) developed for the detection of foot-and-mouth disease virus (FMDV) increased the detection limit 1000 times above real-time PCR. The sensitive and specific nano-PCR technique was found to be beneficial for diagnosing early FMDV infection and hence valuable for clinical and biological applications [87]. A dithiobis (succinimidyl undecanoate)/amine modified r-GO-polyamidoamine dendrimer thin film-based surface plasmon resonance (SPR) sensor was created for the effective and speedy detection of dengue virus (DENV), one of the most frequent deadly infections in tropical regions. The proposed sensor was claimed to have the potential to act as a quick clinical diagnostic tool for DENV infection due to its sensitive and selective response to DENV 2 E-proteins compared to DENV 1 E-proteins and ZIKV (Zika virus) E-proteins [88]. Moreover, in a study by Sharma et al., GO-based double junction capacitive (DIDC) biosensing platforms were reported to detect severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S1) proteins with enhanced selectivity and rapid response. The DIDC bioactive surface, consisting of an SiO2 substrate with Pt/ Ti properties, was modified with GO/EDC-NHS/anti-SARS-CoV-2 antibodies (Abs). It was reported that this electroactive immunodetection platform exhibits high sensitivity to the S1 protein of SARS-CoV-2 and can be used for point-of-care (POC) diagnostic applications due to its portability and scale-up capability [86]. In addition, functionalized graphene-based materials were used for the detection and determination of volatile compounds [90–92]. For example, it was established that four types of exhaled breath (EB) biomarkers, including acetone, isoprene, ammonia, and

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hydrothione, can be differentiated at sub ppm concentrations using the constructed GO-based biosensors. When clinical EB samples from lung cancer patients and healthy controls were analyzed, the artificial neural network provided 95.8% sensitivity, and 96.0% specificity for the diagnosis of E-nose-based lung cancer [91]. It was also reported that individuals with renal impairment may be recognized by comparing dynamic response curves on certain sensing components between patient and healthy samples. These findings suggest that the proposed GO-based E-nose sensor has high potential for noninvasive disease screening and diagnosis [91]. In another study, because of the synergistic effect of PPy and rGO, extraordinary detection was observed with 10.7% conductivity response in the structure of sodium alginate (SA) composite films (SA/rGO/ PPy) prepared by doping with reduced graphene oxide (r-GO) and polypyrrole (PPy), even in the presence of 2 ppm NH3 gas. It was claimed that the SA/rGO/PPy composite films generated in this manner may be employed for the diagnosis of renal disease, with an NH3 detection range of 2–15 ppm [90].

2.2 Carbon nanotubes (CNTs) Carbon nanotubes (CNTs) were extensively researched as potential sensor platforms due to the effective and practical tunability of their physical and chemical properties via functionalization/doping with appropriate chemical groups for new nanocarrier systems [93–95]. Because of the fast development of synthetic techniques, structural integration, surface area controlled heteroatom doping, and electrical conductivity, carbon nanotubes (CNTs) play a significant role in biomedical applications [27,96]. Without modification, CNTs are often harmful to specific human cells; with surface modification, they become biocompatible and nonimmunogenic [26,97]. CNTs were also used as contrast agents in imaging due to their important optical properties [98]. The CNT formulation reaches the target region after injection and may be investigated using techniques such as radiolabeling or gamma scintigraphy [99]. For example, in a study, an electrochemical immunosensor was designed based on a gelatin-modified transduction platform. Electro-active CNTs functionalized with dopamine (DA)/mucin-1 (MUC-1) were used as signal-generating probes in the construction of electrochemical immunosensors for early-stage diagnosis of breast cancer. The gelatinmodified electrode acts as a support to immobilize the antibody (anti-MUC-1), while the electrochemical response of functionalized electro-activated carbon nanoprobes was used for the quantitative measurement of MUC-1. The developed immunosensor was reported to be a promising material for early detection of breast cancer, allowing detection of MUC-1 in the linear range of 0.05–940 U/mL and with a limit of detection (LOD) of 0.01 U/mL [100]. In another study, multiwalled carbon nanotubes (MWCNT) were used as alpha-fetoprotein biosensors after being modified with vinyl ferrocene (VFc) and N-hydroxy succinimide acrylate and functionalization with

Functionalized carbon nanomaterials for drug delivery

antialpha-fetoprotein. From the obtained results, the presence of alpha-fetoprotein can be detected with high sensitivity in a wide linear range between 10 ng/mL and 50 μg/mL, which means the prepared biosensor can largely meet the real requirements for liver cancer diagnosis [101]. Wayu et al. designed an amide couple functionalized CNTs as a biosensor to detect the electron transfer of copper containing enzyme galactose oxidase [39]. Dervisevic et al. reported the cysteamine-polyaminoamine grafted MWCNT as a template for urease enzyme immobilization as a biosensor for urea in the plasma. The results indicated that the cysteamine-polyaminoamine grafted MWCNT-based electrode possessed excellent performance in urea analysis [40]. A novel electrochemical amperometric immunosensor was designed to detect midkine (MDK) indicators in early hepatocellular carcinoma (HCC). Carboxylated MWCNTs were conjugated with antimidkine antibodies, and differential pulse voltammetry was utilized to assess immunosensor effectiveness in detecting MDK antigen at concentrations ranging from 1 pg/mL to 100 ng/mL. With a detection limit of 0.8 pg/mL and a correlation value of 0.99, the MDK immunosensor demonstrated great sensitivity and linearity. In addition, the biosensor had excellent selectivity, stability, and repeatability [102]. In addition, in the study by Komane et al., it was reported that carbon nanotubes have the potential to be used in solving therapeutic challenges in neurological diseases such as ischemic stroke. In this study, carbon nanotubes were successfully synthesized for potential applications in the detection of neurological diseases such as ischemic stroke. Vertically aligned multiwalled carbon nanotubes (VA-MWCNTs) were purified with HCl and carboxylated with H2SO4:HNO3 (3:1) and acylated with SOCl2 for potential use in targeting studies and for applications in the diagnosis of neurological diseases, including possible ischemic stroke [103]. In a time of urgent need to use new powerful technologies not only for the accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also to combat the emergence of new viruses and pandemics, to overcome the current challenges Jeong et al. proposed a diagnostic protocol based on surface-enhanced Raman spectroscopy (SERS) coupled with vertically aligned Au/Ag-coated CNT-based biosensors. These CNT-based devices were reported to have the potential to capture viruses from various biological fluids/secretions including saliva, nasopharyngeal, tears, etc. [104].

2.3 Fullerenes The discovery of fullerene (C60) was revolutionary for the development of biosensors because of its unique properties such as broad UV-Vis light absorption, a combination of nucleophilic and electrophilic dual properties, structural angle tension, single oxygen generation, ability to be doped with multiple electrons and endohedral metal atoms, photo-thermal effect, and ability to move as electron acceptor [105]. Fullerenes were

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reported to have the benefit of delivering high sensitivity, increased sensitivity, high selectivity, real-time response, and quick signal transduction to many biological and biomedical analyses due to their unique features [106,107]. In the diagnostic field, fullerenes are utilized as an intermediate between the identification section of a biosensor and its electrode to accelerate the rate of electron transfer induced by the biocatalytic or the biochemical reaction of the analyte in contact with the biological element [105,108]. In the literature, in order to increase the oxidation of vitamin D and to determine its concentration in blood samples, a glassy carbon electrode modified with fullerene-C60, and copper-nickel bimetallic nanoparticle nanocomposites was prepared as an electrochemical sensor. The developed sensor showed satisfactory results when compared with fabricated sensors used for the detection of vitamin D3 in clinical and pharmaceutical samples [109]. In another study, a covalently bound double esterification click reaction was used to create two novel heptametin cyanine dye-fullerene C60 materials that absorb light in infrared and near-infrared spectrum regions. It was also reported that the obtained modified fullerene may be employed for cell imaging and fluorescence detection of different fullerene derivatives [37]. In a study by Suresh et al., the development of an effective immunosensor platform containing immobilized hydroquinone (HQ), fullereneC60 and copper nanoparticles (CuNPs) composite film (HQ@CuNPs-reduced fullerene-C60/GCE) on glassy carbon electrode was suggested for selective and rapid detection of PSA. The immunosensor’s signal response was evaluated using electrochemical impedance spectroscopy (EIS). The novel nanocomposite film demonstrated outstanding catalytic activity against hydrogen peroxide (H2O2) reduction due to the synergistic action of fullerene-C60 and CuNPs, resulting in considerably improved immunosensor signals. The clinical applicability of the suggested immunosensor was successfully evaluated in serum and urine samples, and the results indicated that the proposed immunosensor might set new boundaries in the detection of PSA in human blood samples [110]. In another study, an impedimetric sensor system was developed to detect cortisol in real saliva samples using molecularly cortisol-imprinted acrylamide polymers on a fullerene modified carbon electrode [111]. The aptamer loading capacity of the electrode modified with a fullerene@COF composite, which has several benefits such as large surface area, thin stability, and excellent electroactive and broad conjugate structure, was observed to be enhanced. Tobramycin was detected using an electrochemical impedimetric aptasensor with an exceedingly low detection limit (1.38 fg/mL). The prepared impedimetric aptasensor was shown to have great specificity, stability, repeatability, and regeneration [112]. Furthermore, fullerene-based materials were employed to diagnose idiopathic pulmonary fibrosis (IPF), an interstitial lung disease with unknown origin and notoriously difficult diagnosis. Zuo et al. investigated the detection of miR-3675-3p, which was described as a potential biomarker for the diagnosis of IPF in previous research. Based on several signal amplification techniques, a novel fullerene-based

Functionalized carbon nanomaterials for drug delivery

electrochemical miRNA biosensor for quick and sensitive detection of miR-3675-3p was presented in this work. After trial applications in human serum, this biosensor was shown to have lower LOD and a broader linear range than qRT-PCR, and it was found to be a promising material for the diagnosis of IPF [113].

2.4 Carbon black (CBs) Carbon black (CB), a kind of atmospheric particle, is made up mostly of carbon nuclei and has a porous surface. CB is a low-cost, amorphous carbon alloy with high conductivity thanks to sp2 carbon-carbon bonding [114]. Because of its great features like large surface area, strong electrical conductivity, and superior chemical stability, it has aided in the creation of electrochemical sensors and biosensors [115]. Several types of CBs were recently employed in electrochemical applications in the literature. Hydrogen peroxide [114], catechol [116], microRNA 125a [117], bisphenol a [118], and pesticide [119] were all detected using these biosensors. Because of its low toxicity and limited solubility, CB is frequently employed as a negative control in toxicological tests [120]. However, analysis revealed that CB can cause inflammation and histopathological damage in the lungs [121]. CB was considered to aggravate various respiratory disorders in humans, including lung inflammation and fibrosis [122–124]. As a result, CB-based biosensors have mostly been employed for in vitro research. When used to measure temperatures ranging from 18°C to 44°C, a flexible negative temperature coefficient (NTC) temperature sensor based on polyvinyl chloride/carbon black (PVC/CB) composites demonstrated high sensitivity (0.148% °C
1), excellent linearity (R2 ¼ 0.995), fast response time (0.7 s), and good repeatability. The tunnel effect was utilized to explain the NTC of the PVC/CB temperature sensor, and the sensor’s utility in monitoring human respiration rates and temperatures was proven [125]. In another work, a smartphone-assisted electrochemical device consisting of a screenprinted electrode modified with carbon black nanomaterial and a commercially available smartphone potentiate, named EmSmart3 Blue, was created for the sensitive detection of tyrosine [38]. Accordingly, the produced sensors have a tyrosine detection limit of 4.4 M and are less expensive than HPLC analyzers. Another study presented a mechanically flexible sensor application that analyzed the electrocardiogram (ECG) signals of the manufactured acetylene carbon black (AB)/polydimethylsiloxane (PDMS) electrodes and identified arrhythmia with high classification accuracy of 98.7%. The platform was developed to support a wide range of applications for various individualized physiological monitoring and diagnostics systems [126]. The amount of free bilirubin is a significant biomarker for the identification of jaundice-related disorders. Cerium nanocubes were produced as catalysts for a direct electrochemical sensor of free bilirubin in the investigation by Lu et al.; the sensor was made by simply replacing the screen-printed electrodes with ceria nanocubes and carbon black. This sensor detected free bilirubin with high

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sensitivity and selectivity in a quick response time due to the catalytic activity of Ceria nanocubes and the conductivity of carbon black [127]. In another study with CB-based materials, a sensor was prepared for the diagnosis of cardiovascular and respiratory diseases [128]. Long-term monitoring of respiratory and cardiovascular signals is required for the accurate diagnosis of cardiovascular and respiratory diseases. Similarly, assessing sleep quality and recovering from acute therapies necessitates the collection of long-term vital parameter data. To address these needs, Jayarathna et al. created “VitalCore,” a T-shirt-shaped continuous vital parameter monitoring device intended for continuous monitoring of respiration, pulse, and actigraphy. VitalCore’s key sensor for detecting respiration and pulse from chest expansion is a carbon black-based polymeric composite stretchy resistance band. These carbon black-based polymeric composite sensors were proven to detect respiratory peaks during sleep with 99.44% sensitivity, 96.23% accuracy, and 0.557% false negative rate. This T-shirt arrangement was also found to allow the user to sleep in all sleep postures with little data quality change and to function with 88.9%–100% accuracy for respiratory peak detection when walking [128]. Another study described the synthesis, manufacturing, and development of a selective polyetherimide (PEI)/carbon black (CB)-based sensor designed to detect aldehydes such as nonanal. Using a novel technique, spin coating of PEI/CB in 1-methyl-2-pyrrolidone (NMP) was followed by heat treatment at 200°C to reduce the composite, resulting in extremely sensitive and selective composite films with reduced hydrophilicity for nonanal detection. This detection film was demonstrated to be highly selective for aldehydes over ketones, hydrocarbons, and alcohols. More notably, the suggested sensor maintained its nonanal response throughout a 36-day period [129].

2.5 Graphitic carbon nitride (g-C3N4) Pathological alterations in diverse tissues and organs are frequently followed by changes in pH, temperature, ion concentration, redox status, biomolecules, and other biological microenvironmental factors [130,131]. As a result, the creation of signal monitoring probes based on g-C3N4 aids in the understanding of complicated biological processes and the development of sophisticated diagnostics [132,133]. Because of their semiconductor-like capabilities, g-C3N4 provides good optical markers for detecting signal variations in the environment [134,135]. Several sensors based on the adjustable photoluminescence and electrochemiluminescence (ECL) of g-C3N4 with different formulations have recently been developed. Bioimaging is the viewing and monitoring of molecular pathways and physical processes in living cells that have a significant influence on advances in biomedical science [136,137]. Due to its adjustable fluorescence emissions, high quantum yield, low toxicity, strong biocompatibility, and resistance to photobleaching, g-C3N4 has been used as an optical marker to replace traditional organic dyes in recent years [56,138].

Functionalized carbon nanomaterials for drug delivery

In general, the electrochemical and fluorescent characteristics of g-C3N4-based nanolayers were employed for glucose measurement [139,140]. As a glucose-sensing fluorescent material, highly biocompatible g-C3N4 (g-C3N4/PBA) nanolayers functionalized with phenylboronic acid were employed. The quantum yield (QY) of g-C3N4/PBA was reported to be 67%, the highest QY value for fluorescent g-C3N4s yet recorded. The g-C3N4/PBA biosensors had two large linear areas in the ranges of 25 nM–1 μM and 1 μM–1 mM, with a detection limit for glucose as low as 16 nM. Furthermore, the sensor demonstrated extremely low cellular toxicity, outstanding bioimaging characteristics, and selectivity in the presence of diverse interfering chemicals [141]. It was also reported that the unique physicochemical features of g-C3N4 nanolayers make them a viable instrument for two-photon fluorescence bioimaging. Liu et al. constructed an activatable two-photon fluorescent probe made of a nanocomposite of g-C3N4 nanosheets and hyaluronic acid (HA)-gold nanoparticles (HA-AuNPs) for the detection of hyaluronidase (HAase) and imaging of cancer cells for the first time. This nanocomposite was reported to provide a potential platform for extremely selective and sensitive imaging of HAase and cancer diagnostics [142]. Another work revealed the applicability of biosensors based on g-C3N4 nanolayers for easy, sensitive, and label-free detection of adenylate kinase (ADK) activity. The method is based on a catalytic reverse transphosphorylation process mediated by ADK (2ADP ¼ ATP + AMP). This technology effectively utilized biosensors produced based on g-C3N4 nanolayers for quantitative measurement of ADK activity in the concentration range of 0.1–100 U/L with a low detection limit of 0.06 U/L, as well as for detection of ADK in complicated biological environments. The new biosensing method was reported to provide a quick, cost-effective, highly sensitive, and label-free platform for ADK-based clinical diagnostics and biomedical research [143]. Another study carried out by Sakthivel et al. described a dual biodetection platform that uses electrochemical and fluorescent modes to detect the cancer biomarker CA15-3. Sulfur-doped g-C3N4 (S-g-C3N4) nanolayers were used to make the biosensor. While the heteroatom (S) in the structure increased the sensor’s optoelectronic characteristics, the surface functional group (-NH2) allowed antibody covalent attachment and improved selectivity during analysis. The suggested biodetection technology was able to identify the cancer biomarker CA15-3 (2.9 U/mL) in human serum samples, demonstrating its use for early disease diagnosis [144]. Despite advances in the use of peroxidase-like nanozymes for bioanalysis, most contemporary nanozyme biosensing devices are based on a single signal output. Environmental and human variables can have a significant impact on such sensing systems. Nanozyme detection systems with logical measurement signal outputs are expected to provide more reliable and robust detection performance. To build such ratiometric detection devices, three fluorescent g-C3N4-based nanozymes (g-C3N4Ru, g-C3N4Cu, and g-C3N4hemin) with good peroxidase-like activity were developed. The generated g-C3N4-based nanozymes were employed as sensors to detect

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o-phenylenediamine, and it was concluded that they may be used to develop biodetection systems based on fluorescence alterations [145]. Furthermore, septicemia, commonly known as sepsis, is a systemic inflammatory response syndrome that is the leading cause of mortality in severe conditions. One of the primary indicators of septicemia during diagnosis and detection of bacterial inflammation is procalcitonin (PCT), a peptide precursor of hormones. A sandwich-type carboxylic acid-functionalized g-C3N4-based electrochemical immunosensor for ultrasensitive PCT detection was developed. The immunosensor had a linearity range of 0.01–1.0 pg/mL and a limit of detection (LOD) of 2.0 fg/mL, according to the analytical data [146]. Sulfur-doped carbon nitride nanolayers (S-g-C3N4) were employed as a signal readout in human serum samples for sensitive and selective detection of L-cysteine (L-Cys). According to reports, the suggested technology is very sensitive and selective, making it ideal for quick and straightforward clinical detection of disorders such as Alzheimer’s and cardiovascular disease [146]. Acute myocardial infarction (AMI) is a significant public health issue because of its high fatality rate. The biomarker heart type fatty acid binding protein (h-FABP) is useful in the diagnosis of AMI. In the study conducted by Karaman et al., an electrochemical h-FABP immunosensor based on Cd0.5Zn0.5S/ d-Ti3C2Tx MXene (MXene: transition metal carbide or nitride) composite as signal amplifier and core-shell high-crystalline g-C3N4@CDs was developed. The electrochemical h-FABP immunosensor showed acceptable sensitivity with a limit of detection (LOD) of 3.30 fg/mL in the +0.1 to +0.5 V potential range and was described as a low-cost, environmentally friendly immunosensor with satisfactory stability for the diagnosis of AMI [147].

2.6 Carbon dots (CDs) Carbon dots (CDs) are the most recent members of the carbon-based nanomaterials family, which have piqued the interest of researchers due to their chemical and mechanical characteristics, dazzling fluorescence, excellent photostability, and strong biocompatibility [148]. CDs have garnered substantial interest in recent years in different research domains including bioimaging, sensing, and biomedicine due to their simple and lowcost production processes as well as the aforementioned features [149–152]. Because of the necessity of early disease diagnosis, bioimaging technologies such as optical imaging, positron emission tomography, magnetic resonance imaging (MRI), and ultrasound imaging were developed. Fluorescence imaging (FI) has emerged as a potent approach for clinical diagnosis among the numerous imaging modalities because of its noninvasiveness, ease, and low cost [153]. Numerous studies described the photophysical and biological characteristics of fluorescent probes such as organic dyes (e.g., rhodamine, porphyrin, and cyanine derivatives) and NPs (e.g., quantum dots, silicon NPs, and gold nanoclusters) throughout the last several decades [154–156]. They did, however, suffer from

Functionalized carbon nanomaterials for drug delivery

photoinstability, small Stokes shift, limited resolution, and toxicity [157–160], all of which led to the creation of fluorescent CDs. CDs are a next-generation probe for in vitro and in vivo bioimaging due to their high photostability, biocompatibility, water solubility, and multicolor emission [161]. Functionalized CD-based materials have frequently been employed in cancer detection as bioimaging and biosensing agents [162–168]. The expression of miRNA-21 is linked to the onset and progression of cancer, particularly gastrointestinal cancer. MiRNA-21 monitoring has practical applications in the detection and assessment of gastrointestinal cancer [169]. For miRNA-21 measurement, a turn-on ratio ratiometric fluorescence bioassay based on T7 exonuclease-mediated cyclic enzymatic amplification technique was devised, with CDs and FAM-labeled ssDNA as signal sources. This method included CDs with the triple functionalities of internal fluorescence, probe carrier, and quencher. The constructed CD-based biosensor had a strong linear relationship with miRNA-21 concentrations ranging from 0.05 to 10 nM, and the detection limit for miRNA-21 was determined to be 1 pM, with excellent selectivity and repeatability [169]. Furthermore, this sensor was utilized successfully to assess the amount of miRNA-21 expression in clinical blood samples from healthy people and gastrointestinal cancer patients [169]. A selective, rapid-acting, and environmentally friendly fluorescent immunoassay technique based on nitrogen-doped CDs (N-CDs) was proposed for the detection of Nuclear Matrix Protein 22 (NMP22, antigen) [170]. Othman et al. immobilized monoclonal antibodies (mAb, antibody) on N-CDs by the EDCe-NHS amidization technique and incubated the obtained N-CDs-mAb conjugates with a small amount of NMP22 to perform the immunoreaction between antigen and antibody. In conclusion, the fluorescent intensity of N-CDs-mAb conjugates was quenched after interacting with NMP22, and it was reported that they can be used for the diagnosis of urothelial cancer [170]. In another study with functionalized CDs, hafnium-doped CDs (HfCDs) with important advantages including robust stability, good biocompatibility, excellent water solubility, remarkable computed tomography (CT) contrast performance, and preferential tumor deposition capacity, were used for CT/fluorescence imaging of orthotopic liver cancer. In the study, HfCDs were able to localize to the tumor site and obtain rapid imaging within 1 min [171]. Furthermore, tumor necrosis factor (TNFα), a proinflammatory cytokine that plays important roles in cell death, differentiation, survival, proliferation, and migration as well as being an immune system modulator, is an excellent biomarker for the detection of many disorders, including cancer [172]. In this regard, a sensitive and low-cost electrochemical biosensor based on CDs was created for the first time. Poly methyl methacrylate (PMMA) was used as the matrix to contain the CDs in order to create the biosensing platform. TNF-α specific antibodies were successfully attached to this unique CD-PMMA nanocomposite with high biocompatibility, electrocatalytic conductivity, and surface area. A functional CD-based biosensor was created as an electrochemical immunosensor for the specific detection of TNF-α, with a

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dynamic range of 0.05–160 pg/mL, a lower detection limit of 0.05 pg/mL, and a sensitivity of 5.56 pg/(mL cm2) [172]. In another study, in vivo fluorescent images of Cy7CDs synthesized from cyanine dyes (Cy7) and polyethylene glycol using a hydrothermal reaction showed that Cy7-CDs can accumulate efficiently in tumors and can be used for bioimaging of tumors [173]. In addition, CD-based materials were employed to detect various key biological compounds for diagnostic reasons. For example, Ponnaiah and Prakash conducted a variety of investigations in response to the medical requirement of creating an accurate detection method for Crt concentrations in both blood and urine [174]. A novel nonenzymatic electrochemical probe built of tungstic anhydride (CDs/WO3@GO) doped with carbon dots placed on graphene oxide nanosheets was described in the study for the detection of Crt at the picomolar level in blood and urine [174]. In another study, Li et al. developed a sensor for the sensitive detection and quantification of Trp for the early diagnosis and prevention of tryptophan (Trp)-related disease. Trp is an important amino acid in protein and peptide metabolism in the human body. CDs treated with 3-aminoisonicotinic acid were employed as a highly sensitive and selective Trp sensor in this study. The pyridine ring on the surface of 3-aminoisonicotinic acid-modified CDs acted as an active site, forming a nonfluorescent composite with tryptophan in under 15 s, according to the findings. The produced biosensor might be employed in the practical application of Trp-related illness prevention and early clinical diagnosis [175]. Selective, sensitive, and precise detection and imaging of ascorbic acid (AA), a key biomolecule in the human body, is critical for clinical chemistry and diagnosis. When CDs were excited at 415 nm, they exhibited two emissions at 520 and 668 nm; however, the emission at 668 nm was damped when complexed with Fe3+ ions. However, in the presence of AA, recovery of fluorescence emission at 668 nm was identified. The produced CD-Fe3+ combination was found to be useful in determining AA and diagnosing AA-related diseases [176]. For rapid, convenient, sensitive, and simultaneous detection of different enzymes for the diagnosis, treatment, and prognosis of related diseases, a new strategy for simultaneous monitoring of g-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) activity was presented by Tong et al. based on dual-emission of CDs [177].

3. Functionalized carbon nanomaterials for drug delivery applications Carbon nanotubes (CNTs) [178], carbon nanoparticles (CNPs) [179], and carbon dots (CDs) [180] are common materials used as active agent carriers compared with the other carbon-based nanomaterials including GO nanosheets [181], fullerenes, and carbon black nanoparticles (CB NPs) [182]. Their intriguing abilities such as low toxicity, high bioavailability and stability, high surface area, low cost, perfect performances, and tunability make them promising nanomaterials for further clinical applications. However, the limited functional groups on bare carbon nanomaterials have reduced their drug loading

Functionalized carbon nanomaterials for drug delivery

capacities and targeting abilities. To overcome these disadvantages, carbon nanomaterials (CNMs) were functionalized and modified with various molecules such as proteins [183], cancer-targeting biomolecules like hyaluronic acid [184] and aptamers which are the short single-stranded DNA/RNA [185], multifunctional carbohydrates like chitosan [182], and hydrophilic/hydrophobic molecules [186], etc. The potential for use of functionalized carbon nanomaterials (FCNMs) was investigated by discussing drug-loading capacity, release kinetics, cell uptake, penetration and targeting abilities, toxicity, and clearance pathways of drug-carrier FCNMs, as listed in Table 2.

Table 2 List of functionalized of carbon-based nanocarriers and their efficacies. Carrier materials

Drug

Treatment

Efficacy

Ref.

PEG-grafted CNTs

Paclitaxel adsorption

Cancer

[28]

Ester and carboxylic acid functionalized CNTs

Hexamethylamine

Cancer

CDs derivated from chlorophyll

Metronidazole conjugation

Bacterial infection

Carboxyl-rich CDs

Doxorubicin conjugation

Cancer

Folic acid derivate CDs to functionalize stearic acid grafted polyethyleneimine nanomicelles

Doxorubicin

Cancer

Increased the drug loading and release capacities of hydrophobic drugs Enhanced encapsulation efficacy for poorly soluble drugs in aqueous solution Higher antimicrobial activity at lower dose than free drug with excellent intracellular penetration and long-term release No toxicity for healthy cells, with perfect inhibition effects for cancer cells. pH-sensitive delivery and use in targeted bioimaging Increased the cancer efficacy at lower carrier concentration than free drug, use as a bioimaging tool and targeting ability for cancer cells

[187]

[188]

[189]

[190]

Continued

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Table 2 List of functionalized of carbon-based nanocarriers and their efficacies—cont’d Carrier materials

Drug

Treatment

Efficacy

Ref.

Hyaluronic acid (HA) coated CNPs

Doxorubicin and verapamil dual drug loading Doxorubicin and paclitaxel

Cancer

[184]

Doxorubicin

Cancer

Doxorubicin

Glioma

pH- and enzymeresponsive targeting release pH-responsive delivery to cancerous cells improved the loading capacity and release profiles of the fullerene depending on chitosan modification and functionalization Near-infrared (NIR) induced on-off responsive chemophotothermal therapy Photothermal glioma therapy by NIR-triggered drug release

Chitosan modified and carboxylic functionalized fullerene

Bovine serum albumin (BSA) modified reducedGO nanosheets Oxidized CNPs

Cancer

[191]

[183]

[192]

3.1 Drug-loading capacity and sustainable release of FCNMs It is well known that the surface area of materials are dependent on the size and porosity of the materials. The morphological structures of carbon nanomaterials are convenient due to higher surface area, porous structure, and nanometer size range [193]. It is obvious that the drug-loading capacity of nano and porous materials like carbon nanomaterials are significantly higher than micron/macro size and nonporous carriers. Apart from the morphological structure of the carriers, loading processes could determine the loading capacity and release rate. Two basic techniques of physical interactions or covalent bonding of the carriers with drug molecules are chosen according to the functional groups and hydrophobicity of the drug molecules and carrier materials like FCNMs [194]. Hydrophobic interactions, π-stacking interactions, and capillarity-induced filling methods are the common types of physical processes for CNM-based vehicles [186]. The adsorption ability of doxorubicin as a hydrophilic cancer drug on CNT walls by π-stacking interactions was examined in an aqueous solution [29], but drug loading is limited using the same adsorption pathway for hydrophobic drug molecules like paclitaxel in aqueous conditions [28]. The loading capacity of nonsoluble drugs could be improved by functionalization of the carrier materials. Lay et al. reported that paclitaxel, a hydrophobic drug, dissolved in methanol solution and adsorbed to PEG-grafted CNTs by physical interactions [28]. Similarly, carboxylated carbon particles provide high loading capacity for poorly

Functionalized carbon nanomaterials for drug delivery

water-soluble carvedilol with perfect adsorption capacity and π-stacking forces [195]. Capillarity-induced filling is another physical loading technique applied by filling the tube-shaped carbon materials using capillary forces, which involves immersing the drug in a saturated drug solution. Ester and carboxylic acid on the FCNMs could enhance the encapsulation efficacy of hexamethylamine antitumor agent [187]. Conjugation, known as covalent linkage, is the most popular technique in the drug-loading process for CNMs related to its significant advantages compared with physical interactions. These chemical bonds between CNMs and drugs provide long-term release kinetics as well as controllable and high loading capacity. In drug conjugation, hydrophilic or hydrophobic drugs can be loaded into the CNM network in different conjugation reaction conditions and the high dissolution rate for poorly water-soluble drugs allows release in a controlled manner. Ardekani et al. prepared metronidazole conjugated CDs using chlorophyll as a carrier nanomaterial for the treatment of Porphyromonas gingivalis infection [188]. The nanometer size range of the CDs-antibiotic conjugates ensured that intracellular delivery and antibioticconjugated CDs had higher antimicrobial activity than free drug against cellular bacterial infection due to high intracellular penetration and long-term delivery effects of the CDs-antibiotic conjugates. In addition, metronidazole-loaded CDs were effective against the infection at sixfold lower dose than the free antibiotic. Therefore, lower doses of drug administration could reduce the toxicity and possible resistance to the antibiotic uses [188]. In a different study, Zeng et al. reported CDs synthesis rich in carboxyl groups from citric acid and urea molecules conjugated with the amine moiety of doxorubicin drug [189]. No toxicity was detected on normal cells for the CDsdoxorubicin conjugates, but significant anticancer ability affected tumorous areas for a long duration. These results indicated that drug conjugation to the carrier network could decrease the toxicity of drug as well as improve the anticancer activity. Furthermore, pH-sensitive delivery was seen only in cancer-targeting pH conditions, like pH 5, for diagnostic drug delivery with excellent green fluorescence intensity by a CD-based carrier system [189].

3.2 Cell uptake, penetration, and targeting of drug-loaded FCNMs The nanometer size range of carbon materials allows them to cross the cell wall as drug carriers and directly release the drug molecule into the cell. Thus, removal time of the applied drug from systemic circulation in the body could be prevented by using nanocarriers to improve the penetration ability of the drug to the specific site without drainage. Cellular uptake pathways of FCNMs occur by two different mechanisms via endocytosis or passive diffusion and penetration known as “pierce-through” linked to the size distribution and hydrophobicity of the carrier surface. In a review, it was suggested that phospholipid, polyethyleneimine, DNA, protein, and biotin functionalized

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CNTs could pass through cells by endocytosis, whereas passive diffusion and penetration occurred with polyethylene glycol, ammonium, acetamido, and stearyl alcohol functionalized CNTs [186]. In a study, it was reported that low hydrophilic content of modified CNTs with short polyethylene glycol (PEG) segment could enter the cells by the piercethrough method, whereas high hydrophilic segment modified CNTs with long PEG segments might pass into the cells by endocytosis [196,197]. The targeting ability of the carriers enables more efficient delivery to the specific tissues or cells, and significantly decreases side effects of toxic drugs by decreasing high dose administrations and drug leakage into body circulation. CNMs could be designed as targeting vehicles, generally by functionalization with various ligands and bio-agents such as hyaluronic acid [198], folic acid [42], aptamers, biotin [199], and peptides [200] for in vivo applications. Sarkar et al. prepared folic acid derivate CDs to functionalize stearic acid grafted polyethyleneimine nanomicelles as a drug carrier system for doxorubicin anticancer agent [190]. It was reported that the anticancer efficacy of this targeted carrier was significantly enhanced by about 10-fold compared with the free drug and this vehicle could be used as a bioimaging tool depending on the fluorescence ability of CDs. Folate groups on the CD surface provide receptor mediated endocytosis to the targeting cellular uptake [42]. Similarly, HA is a well-known targeting agent related to its highest affinity against CD44 receptors, which are generally overexpressed by cancerous cells. Wan et al. prepared hyaluronic acid (HA)-coated CNPs for targeting dual drug delivery in the treatment of tumors overexpressing CD44 receptors. The targeted cellular internalization of dual drugs was improved by using HA-coated CNPs and cytotoxicity of the loaded drugs was significantly decreased due to the targeting ability of CNPs by simple modification with HA [184].

3.3 Stimuli-responsive FCNMs as drug carriers The chemical structure of carrier systems could be affected by internal stimuli including enzymes, pH, redox agent, etc. and external stimuli such as light, heat, electrical and magnetic field, ultrasound, irradiation, etc. [201]. Stimuli-responsive carriers allow controllable release under these triggers, and on-off delivery kinetics could be tuned by external stimulation. Wan et al. reported doxorubicin- and verapamil-loaded CNPs modified with hyaluronic acid (HA), which is a well-known targeting biomolecule against cancer cells [184]. Dual drug release from this HA-modified carrier system could be applied in the presence of hyaluronidase enzyme stimulation and specific pH conditions at the targeted cancerous site. In another study, Li et al. prepared doxorubicin-loaded hyaluronic acid-modified carbon dots HA-CD@-CBA-DOX as a cancer targeting vehicle for the treatment of breast cancer [202]. As shown in Fig. 2A, HA-CDs were synthesized from citric acid and hyaluronic acid by hydrothermal treatment, then DOX cancer drug was loaded by an acid cleavable bond via the conjugation loading technique to create acid responsive linkage.

O O HO

OH O HO O

CH2OH O

OH

NH O CH3

(A)

n

p-CBA NHS ester

(B)

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Fig. 2 (A) Schematic representation of doxorubicin-loaded hyaluronic acid-modified carbon dots (HA-CD@-CBA-DOX) nanocarrier. (B) pH-responsive doxorubicin release profiles from HA-CD@-CBA-DOX in different pH conditions. (C) HA competition assay of HA-CD@pCBA-DOX at 5 μg/mL concentration in 4T1 cells with positive rate comparison and confocal laser scanning microscope images. (D) Tumor volume changes after intravenous injection with free doxorubicin and HA-CD@p-CBA-DOX in 4T1 tumor-bearing mice and tumor images and weights in each group. (Reprinted with permission from J. Li, M. Li, L. Tian, et al., Facile strategy by hyaluronic acid functional carbon dotdoxorubicin nanoparticles for CD44 targeted drug delivery and enhanced breast cancer therapy, Int. J. Pharm. 578 (2020) 119122, https://doi.org/ 10.1016/j.ijpharm.2020.119122.)

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Loaded DOX was sustainably released for 50 h in acidic intracellular conditions of a cancerous area related to acid cleavable chemical bonds, as demonstrated in Fig. 2B. This carrier system had perfect targeting ability for CD44-expressing 4T1 cancer cells and provided intracellular delivery. The cellular uptake by endocytosis of the HA-CD@CBA-DOX was investigated by the HA competitive inhibition test as shown in Fig. 2C. The 4T1 cancer cells could internalize a large number of carriers. In the in vivo studies, PBS and free DOX were injected in the control group, and HA-CD@-CBA-DOX carrier was injected to the tumor bearing mice. As indicated in Fig. 2D, tumor volume and weight in cancer mice treated with HA-CD@-CBA-DOX was significantly inhibited over time and was lower than the free DOX group. Another study designed a pH-sensitive fullerene carrier for anticancer doxorubicin and paclitaxel drugs by chitosan modification. In addition, the loading and release capacities of fullerene were improved by carboxylic acid group functionalization [191]. Drug release profiles of FCNMs could be controlled by external stimuli with various light sources including ultraviolet, visible, and near infrared (NIR). Especially NIR radiation shows high penetration ability compared with the others. Interestingly, important advantages of only FCNTs without drugs were reported as acting like a near-infrared (NIR) heater [203] or photoacoustic bomb agent [204] to inhibit tumorous cells, as well as vehicles for siRNA which silence cancer cells [205]. Doxorubicin cancer drug was loaded into bovine serum albumin-functionalized reduced GO nanosheets as a carrier for chemo-photothermal treatments. Protein-functionalized GO nanosheets had drug delivery triggered with NIR for brain tumor cells without any toxicity [183]. Oxidized CNPs exposed to near-infrared irradiation have photothermal effects related to graphite pore wall conversion into hot spots and provide NIR-triggered cancer drug release [192].

3.4 Toxicity of FCNMs as drug carriers Morphological properties including size, shape, and length, as well as surface functionalization, affect the toxicity of the CNMs. Spherical shape, size less than 50 nm, and 0.6 μm length of CNMs exhibit low toxicity on cells and biological systems As reported in a review, the toxicity of bare CNMs can be rates as fullerenes < CB < NPs < CNTs < graphene [182]. To improve the toxicity of these potential carrier systems in drug delivery applications, bioavailable biomolecules or synthetic polymers are generally used as functionalization agents. Khorsandi et al. reported that chitosan-modified CNMs, such as GO, CNTs, fullerene, and CDs, could be designed as potential drug carriers with excellent biocompatibilities [182]. Similarly, CNTs cause cellular activity malfunctions and death effects on mammalian cells by aggregation in the bloodstream with hydrophobic effects. The biocompatibility of hydrophobic CNTs could be improved by attaching hydrophilic materials such as poly(ethylene) glycol (PEG) and FCNTs are removed from the body via renal excretion [186]. In addition, some researchers reported that

Functionalized carbon nanomaterials for drug delivery

mesoporous CNPs and carboxylated mesoporous CNPs show no significant toxicity on cells and have perfect biocompatibility [206]. Han et al. indicated that carboxylated mesoporous CNPs had very low toxicity with 89% cell viability of caco-2 human epithelial cells even at high concentrations of 500 μg/mL [207]. In opposition to bare CNTs, mesoporous CNPs are hemocompatible with less than 1% hemolysis ratio [208]. In clinical processes, several drug administrations of free drug solutions were recommended for accomplishing treatment and these repeated doses caused nephrotic and systemic toxicity depending on the nature of the drug [209]. Using a carrier material improves the bioavailability of the drug by decreasing the administration dosage at the effective dose, because drug loading amount and cumulative release time from the drug vehicle can be tuned by loading processes and functionalization of the carrier networks [210]. Li et al. prepared doxorubicin-loaded blood plasma treated graphene nanomaterials which enabled sustainable drug delivery to the targeted site as well as perfect in vivo bioavailability with effective antitumor ability [211]. Especially in cancer therapy, there is growing interest in the utilization of functionalized carbon-based materials because of their intelligent advantages such as the abilities to reduce drug side effects, improve drug bioavailability, and increase the solubility and activity of drug, and tunable targeting [186].

3.5 Clearance pathways of drug carrier FCNMs Clearance pathways of drug carrier FCNMs should be known through in vivo applications to prevent the accumulation of highly stable CNMs after being internalized into the cells. Some research demonstrated that CNMs could be removed from cells through exocytosis and no cytotoxicity was determined during the administration [212]. Prencipe et al. reported that PEG-modified CNTs inhibit nonspecific clearance of the material by the reticuloendothelial system. Thus, long-term material circulation in the bloodstream and passive targeting effects on the cancerous cells could be ensured [213]. In addition, some chelating agents can be used for quick removal from the body. For example, radionuclides like indium were utilized to create hybrid materials with diethylenetriaminepentaacetic-grafted CNTs in the blood stream and these hybrids were cleared from the body within 3 h [214].

4. FCNMs for stem cells therapy Stem cells are undifferentiated cells with the capability to self-renew and differentiate into diverse phenotypes and cells multipotently and pluripotently [215,216]. The differentiation capacity of multipotent stem cells is limited to cell lineages within the tissue origin; however, pluripotent stem cells have no limitations [217,218]. Pluripotent stem cells can be differentiated into every cell type that make up a body [219]. Stem cell studies were mostly carried out in vitro different to in vivo which includes extracellular matrix

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(ECM), cell-cell interaction, and growth factors [220,221]. The advantages of nanomaterials are that they are able to create a new controllable environment for growth, proliferation and differentiation of stem cells [222]. Stem cells are usually utilized in theranostic applications like tissue engineering, disease modeling, drug testing, and regenerative medicine [223–225]. The advantages of employing stem cells are essential owing to self-renewability and differentiation [216,226]. These significant assets of stem cells enable their use especially in tissue engineering and moreover for remodeling, regeneration, and replacement of damaged/diseased tissue [227,228].

4.1 Carbon nanotubes (CNTs) for stem cell therapy CNTs are hollow nanosized materials, with diameters between 0.5 and 1.5 nm and lengths of up to 100 nm, which attracted great attention in specific areas such as energy storage, catalyst supports, conductive material fabrication, and biomedical applications due to their appealing mechanical, electrical, thermal, optical, and structural assets [229–231]. The physical properties of CNTs enable their use in theranostic applications such as regenerative medicine and tissue engineering where they are able to do the spadework for differentiation of stem cells and, at some point, stem cell banking [232–234]. Pluripotent stem cells convert into multipotent stem cells by differentiation and an example of a multipotent stem cell is mesenchymal stem cell (MSC) found in bone marrow and adipose tissue [235,236]. MSCs differentiate into osteogenic, myogenic, adipogenic, chondrogenic, and other lineages [237]. These stem cells are most commonly used in tissue engineering and regenerative medicine fields. Nowadays, MSCs are considered worthy candidates for healing of damaged tissues, building new tissue and transplantation of tissue for living organisms [35]. Thus, MSCs obtained from human bone marrow or other parts of the human body would be histocompatible for transplantation of tissue to the damaged part or formation of new tissue in the organism [238,239]. Due to this vital feature, immunological troubles can be prevented from causing transplant rejection. Moreover, this way of healing tissue is also considered to comply with ethical rules [240]. CNTs and CNT-based composites assist in the attachment and differentiation of stem cells [241]. CNTs play important roles in repairing bone, tissue, and organ structures [242]. CNTs are the most utilized materials for stem cell therapy due to structural properties like high mechanical strength, flexibility, and electrical conductivity [231]. The structure of CNTs is very similar to that of the ECM where cells grow, multiply, differentiate, and connect to each other [243]. The binding affinity of CNTs with fibronectin as an ECM protein allows control of cell behavior [244]. CNTs are often indicated to have cytotoxic effects; however, functionalization of these materials will allow them to be used safely in stem cell therapy [245]. One study showed that functionalization with histocompatible poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) promotes a decrease in the cytotoxic effect of the final product [242,246,247]. Moreover, this

Functionalized carbon nanomaterials for drug delivery

combination enhanced the hardness of the structure and elevated attachment of the cells [30,248]. CNTs are mostly employed in studies about bone and neural tissue regeneration. Rodrigues et al. presented a study of biocompatible polyvinyl alcohol combined with CNTs which carries the potential for MSCs to differentiate into the osteogenic lineage [249]. Another study showed that multiwalled CNTs (MWCNTs) improved the attachment, growth, and osteogenic differentiation of adipose stem cells; moreover, an evaluation of bone formation was carried out [250]. For the first time, poly citric acid-functionalized CNTs were utilized to repair the ECM and the outcomes of this experiment were very promising, as it enabled a connection between cells and tissues [46]. COOH-functionalized MWCNT inferred more cytocompatibility in proliferation and apoptosis tests. In addition to this qualification, COOH-MWCNTs are a perfect candidate for the differentiation process of osteogenic, chondrogenic, and neural stem cells [35]. A study of MWCNT-coated nanofibers asserted that there was enhancement of the electrical properties of the structure. Thus, this scaffold promoted neural cell growth of rat ganglia neurons and focal adhesion kinase expression in the PC-12 cell line, which is one of the most commonly used cell types for neural-based studies [251]. The combination of PLGA and COOH-MWCNTs with plasma treatment enhanced hydrophilicity of the surface and made that a perfect candidate for proliferation and differentiation of PC12 cells and played a role for maturity of Schwan cells [252]. Pouladzeh et al. reported the use of combination of thermoplastic urethane and MWCNTs, and the composite formed a nanofibrous scaffold used to determine the attachment and proliferation of rat MSCs, as illustrated in Fig. 3. The increase in the amounts of MWCNTs on TPU nanofibers elevated the electrical conductivity, and thus promoted cell adhesion, proliferation, and differentiation of rat MSCs [47]. Another study was carried out using CNTs scaffolds in cardiac tissue growth applications. The reaction of CNTs and photo-crosslinkable gelatin methacrylate provided compelling mechanical integrity and electrophysiological functions; however, it decreased the electrical impedance that impacted the cardiac structure [253]. A study reported a promising result about a polypyrrole array that controls the behavior of stem cells. Normally CNTs have adhesive hydrophobic properties and nanotips have adhesive hydrophilic features. Therefore, the combination can provide switching of the polypyrrole array between CNTs and nanotips for dynamic attachment and detachment stimuli on the cell surfaces with electrochemical oxidation and reduction. This dynamic situation plays an essential role in recognition of anchor points found on the cell surfaces for guiding MSCs to osteogenic differentiation [254]. Polyethylene glycol was also used to functionalize CNTs for differentiation of MSCs on the osteoblastic lineage route. Usually, differentiation of MSCs occurs via trophic agents like cytokines and growth factors by inducing cell proliferation and angiogenesis. Enticingly, this composite did not need trophic agents to differentiate from MSCs to osteoblastic lineages [255]. Therefore, this result shows that the functionalizing properties of CNTs enables them to be used for stem cell differentiation, proliferation, and growth.

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Fig. 3 Schematic presentation of (A) cycle for differentiation and proliferation of stem cells, and (B) effect of MWCNT amount on stem cell behavior with electrical conductivity. (Reprinted with permission from F. Pouladzadeh, A.A. Katbab, N. Haghighipour, E. Kashi, Carbon nanotube loaded electrospun scaffolds based on thermoplastic urethane (TPU) with enhanced proliferation and neural differentiation of rat mesenchymal stem cells: the role of state of electrical conductivity, Eur. Polym. J. 105 (2018) 286–296, https://doi.org/10.1016/j.eurpolymj.2018.05.011.)

4.2 Graphene oxide (GO) for stem cell therapy Graphene oxide (GO), or a two-dimensional single layer of hexagonal carbon called graphene oxide nanosheets (GONs), is an oxidized form of graphene and possesses many hydroxyl groups on the surface [30,256]. Similar to other carbon-based nanomaterials, GONs have high quality mechanical strength, electrical conductivity, and opacity [257,258]. This nanomaterial has tunable amphiphilicity, flexibility, low toxicity, and drug-loading capacity. GO is one of the most favored nanomaterials for stem cell therapy [256,259–261]. GO functionalized with bioactive molecules is essential for use in biomedical applications and stem cell regenerating medicine [262]. Furthermore, GO can modulate the differentiation of stem cells and form a three-dimensional scaffold for bone marrow modeling [263]. GO is used for differentiation of MSCs to osteogenic lineage due to high absorption capacity for surface factors like proteins and small molecules such as dexamethasone, beta glycerol phosphate and ascorbic acid associated with the differentiation process of adipogenic and osteogenic lineages. GO provided more capacity compared to graphene itself owing to electrostatic interactions between hydroxyl groups and the surface factors and small molecules [264]. Conjugation of GO and collagen sponge was clinically approved and created an appropriate environment for bone regeneration. This combination

Functionalized carbon nanomaterials for drug delivery

elevated the stiffness of the scaffold without causing any cytotoxic effect. Moreover, the GO-collagen combination offers a novel platform promoting osteogenic differentiation in bone regeneration [265]. Another study reported that GO is more effective than CNTs and graphene due to differentiation of dopaminergic neurons from embryonic stem cells (ESCs) [266]. An interesting study combined GO with oxygen-plasma treated polycaprolactone (PCL), which was used to build a scaffold containing laminin as an ECM protein. The functionalized GO-PCL scaffold provided an enhancement of oligodendrogenesis from neural stem cells (NSCs) and endorsed early and mature oligodendrocyte markers. Oligodendrocytes are known for playing an important role in regeneration of damaged neuronal networks due to this study and might be very beneficial for future therapy of the central nervous system [267]. Suryaprakash et al. reported a study about doxorubicin and mitoxantrone as chemo drugs loaded into GO, and this GO combined with MSCs to reduce or destroy the tumor cell line (LN18). The schematic representation of this procedure is shown in Fig. 4. The GO-drug-MSC combination had dose-independent effects. GO-MSC was used to migrate as a vehicle through tumor cells in human body. Moreover, the process of killing tumor cells can be imaged due to fluorescence features of the GO-Drug-MSC combination [48]. Guo et al. synthesized a combination of bacterial cellulose and graphene foam to enhance the biocompatibility, differentiation, and proliferation of NSCs. The authors suggested that the bacterial cellulose-graphene foam combination could be used in regenerative medicine [49]. Another study fabricated poloxamer-reduced GO (pRGO), and this combination improved the effect of tumor targeting and photothermal therapy by laser irradiation synergistically. The efficiency of tumor targeting therapy was found to be 2.5 times higher than the conventional therapy [268]. The effect of GO on

Fig. 4 Schematic representation of the combination of graphene oxide, chemo drugs, and mesenchymal stem cells to reduce or kill the tumor cells by drug release. (Reprinted with permission from S. Suryaprakash, M. Li, Y.-H. Lao, et al., Graphene oxide cellular patches for mesenchymal stem cell-based cancer therapy, Carbon 129 (2018) 863–868, https://doi.org/10.1016/j.carbon.2017.12.031.)

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differentiation of stem cells displays differences depending on the stem cell type [269]. A reported study showed that GO enhanced the differentiation of MSCs; however, another study indicated otherwise, as GO inhibited the differentiation of cancer stem cells [270,271]. Jiang et al. generated a scaffold of GO incorporated with chitosan for cardiac stem cell differentiation. The GO-chitosan scaffold was used as a background for cardiac stem cells (H9C2), and this scaffold presented excellent quality for cell viability and enhanced the cell attachment. This study proved that the GO-chitosan scaffold can modulate cardiac differentiation directly without using any external electrochemical stimulation [272].

4.3 Carbon nanoparticles (CNPs) for stem cell therapy Carbon nanoparticles (CNPs) are nanosized and spherical-shaped materials based on the element carbon [273]. Carbon nanoparticles synthesized by bottom-up and topdown methods are categorized as carbon dots (CDs) or carbon quantum dots (CDs), graphene quantum dots (GQDs) fullerene, carbon black (CB), etc. [274–276]. CNPs possess attractive characteristics like mechanical strength, electrical conductivity, thermal conductivity, and optical properties; moreover, these CNPs have low toxicity [273,277,278]. CDs have fluorescence and GQDs have luminescence properties and they are zero dimensional materials, unlike other types of CNPs [279,280]. CNPs are mostly used for diagnosis, cell tracking, regenerative medicine, and drug delivery systems in stem cell therapy [278]. CDs are fluorescent nanoparticles that possess low toxicity and biocompatibility and they are safe to use in biological applications like stem cell therapy [281]. In a study, CDs were synthesized by citric acid and ethylenediamine and employed for tracking and promoting the long-term MSC differentiation to osteogenic tissue. More importantly, this was the first publication about CDs having long-term capacity for tracking and promoting cell differentiation [281]. Another study of CDs formed from adenosine and aspirin showed that CDs can track bone marrow stem cells toward endocytosis. Even higher doses like 0.1 mg/mL concentration of CDs did not affect the cell viability of the stem cells. Moreover, CDs directly affected the differentiation of bone marrow stem cells contrary to other CDs through osteogenic tissue without adding any type of external osteoinductive factor. These CDs are promising nanomaterials for use in stem cell therapy and bone regeneration [282]. Chen et al. synthesized gadolinium (Gd3+)functionalized CDs with citric acid and ethylenediamine as biocompatible agent and Gd3+ brought a new property of magnetism in addition to fluorescence. The proliferation of MSCs was imaged by Gd-CDs with fluorescence and magnetic resonance as dual modality [283]. Graphene quantum dots (GQDs) are hexagonal-shaped and nanosized material containing - conjugation [284]. GQDs possess many excellent features such as aqueous

Functionalized carbon nanomaterials for drug delivery

solubility, intrinsic fluorescence, and superior biocompatibility; moreover, the functionality of GQDs surface enables their use as therapeutic agents [285,286]. A study developed GQDs with self-renewal effects for detecting by fluorescence labeling. Furthermore, GQDs promoted adipogenic differentiation of MSCs [287]. GQDs are great candidates as bioimaging agents for stem cells and have very little cytotoxicity. Bioimaging by GQDs occurs with excitation ranging from green to yellow light [288]. The other important point about GQDs is their use in the field of biosensing. Xu et al. reported ethylenediamine functionalized GQDs for ultasensing sensing of Ni2+ ions with high antijamming capability [289]. An interesting study by Fasbender et al. reported the synthesis of 3 nm-sized GQDs and observed the effects on rare hematopoietic stem cells with marginal impacts on the transcriptome; at the same time, GQDs showed low toxic effects. The study suggested that the low toxicity of GQDs was related to encapsulation of the GQDs inside the cell, which protected it from the toxic effects of GQDs [290]. Fullerene is a carbon-based cage-like material containing allotropic forms and consisting of C60 and C70 [291]. The physical properties are the same as CNTs including high mechanical strength, electrical conductivity, and versatility [275]. Hao et al. showed that fullerene-C60 enhanced the differentiation and proliferation of brown adiposederived stem cells. This study showed that fullerene-C60 can transfect the cell and regulate some gene expression like ERK and p38 of MAPK signaling that is associated with stem cell survival, proliferation, and differentiation. Furthermore, improvement of cellcell communication by fullerene-C60 was reported [292]. Kostyuk et al. reported that pentaphosphonic acid potassium salt-functionalized fullerene-C60 modulated the differentiation of MSCs to myogenic lineages, while functionalization increased the fluorescence activity of fullerene-C60. The transcript factors related to myogenic differentiation were elevated during the interaction with fullerene-C60; however, the gene expression associated with osteogenic and adipogenic differentiation remained stable or decreased. This study suggested that the effect of functionalized fullerene-C60 on myogenic differentiation might be related to autophagy or intracellular oxidative stress in cells [293]. A study indicated the combination of immunofluorescence staining with fullerene-C60 ensured tracking of DNA damage in human bone tissue [294].

5. Conclusion It is concluded that FCNMs are promising materials for the diagnosis of disease, usage as drug delivery systems, and in stem cell therapy with superior properties such as tunable optical, electrical, and surface features depending on functionalization molecules. Functionalization of CNMs helps their evolution into materials that offer many significance parameters such as low toxicity, even biocompatibility, targeting, selectivity, and sensitivity, which are properties sought in materials used for biomedical applications. In

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summary, FCNMs as drug carriers have improved the limitations of therapeutic agents in existing clinical applications. High drug-loading capacity and sustainable delivery kinetics, cell uptake, penetration, and targeting abilities, stimuli-responsive release, and low toxicity could be designed by functionalization of CNM-based vehicles. FCNMs have compelling properties, and it is essential to mimic the natural environment of stem cells of extracellular matrix, allowing modulation of the growth, proliferation, and differentiation of stem cells. The most important websites regarding working on functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy are as follows: https://haydale.com/about-haydale https://www.mpbio.com/eu https://www.nanoamor.com https://www.nanomagic.com/ani https://nano-c.com https://www.acsmaterial.com/blog-detail/carbon-nanomaterials.html https://www.internano.org/node/1393 https://sabinano.co.za http://tda.com https://www.srlchem.com/products/product_tree/entryId/3618

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CHAPTER 11

Functionalized carbon nanomaterials for diagnosis, drug delivery, and stem cell therapy Vraj Shah, Chirantan Shah, Shishir Raut, and Manan Shah Department of Chemical Engineering, School of Technology, Pandit Deendayal Energy University, Gandhinagar, Gujarat, India

Abbreviations CD CNH CNM CNT DOX EPR MWCNT NIR PAI PDT PTT siRNA SWCNT

carbon quantum dot carbon nanohorn carbon nanomaterial carbon nanotube doxorubicin enhanced permeability and retention multiwalled carbon nanotube near-infrared region photoacoustic imaging photodynamic therapy photothermal therapy small interfering RNA single-walled carbon nanotube

1. Introduction Carbon nanomaterials (CNMs) fall under the inorganic class of nanomaterials which are being used extensively for drug delivery and gene-carrier systems with major usage in theranostics (i.e., a combined approach of therapeutics and diagnostics) of cancer and stem cell therapy. Existing therapies for cancer and stem cells are often found to be inefficient due to drug delivery, lack of precision, and unwanted side effects [1], and CNMs have recently emerged as solutions to these problems. They are able to: (i) absorb infrared (IR) light that can be used in photothermal therapy; (ii) produce fluorescence by absorbing IR rays; and (iii) produce acoustic signals that scatter less than photons, making them excellent tools for biomedical imaging due to their thermal and optical properties [2,3]. Carbon nanomaterials include various types such as carbon nanotubes (CNTs), nanohorns, graphene nanosheets, fullerenes, quantum dots, carbon nanoparticles, and carbon Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00002-9

Copyright © 2023 Elsevier Ltd. All rights reserved.

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nanodiamonds; CNTs and graphene are the most explored CNMs in the biomedical field. CNTs have some limitations in biomedicine due to their lower water solubility, nonbiocompatibility, and high toxicity, which have been resolved in recent years through surface functionalization [4]. They can be modified by the addition of covalent and noncovalent groups to obtain optimized fCNTs with stability and structural integrity, resulting in better biocompatibility and hemocompatibility as well as reduced cytotoxicity. They are able to pass through a number of organic barriers and enter plasma membrane without consuming energy to position themselves near the nucleus while carrying drugs, DNA, RNA, biosensors, and proteins, due to their dynamic surface modification properties, making gene therapy and drug delivery possible [5]. fCNTs essentially behave as nanocarriers by bio-conjugating with various therapeutic agents for the localization of selective cells, diagnosis of those cells, and drug transport for the in vivo or ex vivo treatment of those cells [6]. fCNTs have shown exceptional results in cancer theranostic such as cervical, breast, and prostate cancer due to their ability to accumulate in the angiogenic blood vessels of tumor cells along with fluorescent probes assisting in their localization and detection through imaging [7]. fCNTs provide superior treatment options compared to potentially lethal conventional chemotherapy, due to their efficacy and slow drug release system in the targeted tumor cells [8]. Further studies are being carried out to obtain fCNT systems where combined loading of drug and gene is possible, meaning that dynamic responses according to cell environment can be achieved, resulting in higher flexibility in the usage and control of fCNTs. In the field of regenerative medicine, fCNTs are being translocated inside stem cells via phagocytosis for biomedical labeling and imaging due to their enhanced retention and insignificant decay of photoluminescent intensity [9]. fCNTs are being primarily used as a cytocompatible method for stem cell labeling and in vivo tracking to differentiate and localize specific cells associated with some shortcomings: (i) internalization of fCNT by surrounding cells resulting in false labeling; and (ii) lesser retention time. These issues are being studied and improved with new studies.

2. CNTs for drug delivery Drug delivery refers to a process of inducing drugs in a controlled environment to achieve maximum possible therapeutic effect. Four objectives to be considered while developing new drug delivery systems are: (i) increasing bioavailability; (ii) minimizing toxicity and other harmful effects; (iii) reducing the effect of drug on nontarget cells; and (iv) keeping drug degradation and loss to a negligible amount [10].

Functionalized carbon nanomaterials

Table 1 Properties and their applications in drug delivery [11]. Properties

Application

Can penetrate cells High surface area

Targeted drug delivery Enables attachment of multiple molecules thus improving the versatility of nanodrugs Different functional groups can be attached on both the surfaces of the CNTs Enzymes, antibodies, or any other biomolecules can be attached to the nanotube surfaces Can act as drug carrier Can help in in vivo monitoring of drug delivery

Surface amenable to functionalizing Biofunctionalized nanotubes Hollow lumen of CNTs Spectroscopic properties

With nano-biotechnology gaining more interest, significant research is being carried out in nanotechnology-based drug delivery. For this purpose, various research projects have discussed the potential of carbon nanotubes (CNTs), which are carbon-based, one-dimensional, rolled-up sheets of graphene having an sp2 hybridized structure [11,12]. Some favorable properties that have provided impetus to research are particularly high surface area, high mechanical strength, good thermal and electrical conductivity, and light weight. Additionally, CNTs were found to be nonimmunogenic (not affecting immunity) when functionalized and tailored to be highly soluble in water. Furthermore, they can be eliminated in vivo via renal and/or fecal excretion [13]. CNTs can be classified into two types: (1) single-walled carbon nanotubes (SWCNTs) consisting of a single-layer graphene film with a dimension of 0.5–1.5 nm; and (2) multiwalled carbon nanotubes (MWCNTs) comprising of multiple layers of graphite sheets of varying diameters stacked together. These properties and their application are summarized in Table 1.

2.1 Need for functionalizing CNTs CNTs, when considered individually, have some inherent limitations. In a study conducted by Sukwong et al. [14], a group of mice was exposed to CNTs in doses of 50 and 500 μg. The results showed that CNTs were toxic and were found to evoke protein secretion along with an excretion-enhancing inflammatory response. Additionally, due to the size, structure, and bundling effect (which hinders the uptake and collection of molecules within a biological environment), CNTs have been found to be hydrophobic with limited solubility in aqueous and organic solvents [10]. Functionalizing CNTs helps to reduce this bundling effect as well as in vivo and in vitro toxicity, thereby improving the biocompatibility of CNTs. Antimicrobial agents like amphotericin B can be transported within mammalian cells with the help of fCNTs, which can act as carriers, thus

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reducing toxicity as compared to the toxicity of a free drug [15]. Functionalization can be achieved in two ways: covalent and noncovalent functionalization [16]. In the noncovalent or physical modification method, the surface of CNTs is functionalized without disturbing the graphene sheets. Drug molecules can be attached on the surface of CNTs through adsorption. This method is typically used to load polymers, proteins, and peptides onto CNTs. Conversely, covalent functionalization is achieved by disturbing the graphene system by exposing CNTs to concentrated acids (mainly H2SO4 or HNO3) [17]. This is a particularly tricky method, as CNTs are subjected to high temperature and chemical treatments.

2.2 Functionalized CNTs (fCNTs) for drug delivery In a study by Kakran and Li [18], MWCNTs covalently functionalized with graphene oxide (GO) were loaded with anticancer drugs having limited solubility in water, such as camptothecin and ellagic acid. The results showed that loading these drugs on both the nanocarriers improved their cytotoxic activity with negligible toxicity affecting nontarget cells. MWNCTs were functionalized with a carboxylate (-COOH) group which is found to increase the dispersibility of CNTs without affecting the mechanical properties [19]. Another known way of increasing dispersibility of CNTs in aqueous solutions is by PEGylation. Polyethylene glycol (PEG), a nonbiodegradable polymer, is widely used for in vivo applications to functionalize CNTs. Not only does it enhance the bioavailability of CNTs [20], but also makes the drug delivery system less susceptible to an attack by phagocytic cells [21]. As for toxicity, an investigation comparing carboxylated multiwalled carbon nanotubes (CMWCNTs) and PEGylated multiwalled carbon nanotubes (PEG-MWCNTs) resulted in PEG-MWCNTs showing significantly less toxicity than CMWCNT [22]. In the same study, PEG-MWCNTs were then loaded with a chemotherapy drug thereby exhibiting a better performance than presumed. Thus, functionalizing CNTs with PEG is a sound and proven method to improve drug delivery systems. Saikia [10] investigated the performance of SWCNT-mediated pyrazinamide (PZA) against tuberculosis (TB) enzyme. PZA, widely used in TB therapy, can deteriorate human health when induced in high dosages. Experiments proved that covalent functionalization in conjunction with narrow-diameter nanotubes was thermodynamically favorable. Functionalized nanotubes facilitated the delivery of PZA to active TB sites without interfering with target cells. Thus, with more research and in vivo assessments, functionalized nanotubes can be used for drug delivery in lieu of direct ingestion. In a comprehensive review, Beg et al. reported that functionalizing CNTs with inert silica and pH-sensitive polymers produced nanospheres which could be used for targeted delivery of drugs such as fluorescein. It should be noted that fCNTs have not always shown positive results. For example, Nunes et al. [23] administered amino-functionalized MWCNTs to the cortex of the

Functionalized carbon nanomaterials

brain, causing structural deformation along with degradation of the nanotubes. Transdermal drug delivery with the help of CNTs can also prove to be a challenge due to unwanted side effects, and thus needs to be studied in depth. Thus, numerous studies, some of which we have considered here, elicit the versatility of CNTs in drug delivery and offer an excellent alternative in lieu of established delivery systems such as polymeric nanomaterials and matrices. In addition to CNTs, functionalized fullerenes have also emerged as potential carriers for drug and gene delivery due to their hydrophobicity and optimal sizes [24]. Fullerenes (C60) are an allotrope of carbon that have demonstrated desirable drug release profiles for antitumor drugs like doxorubicin. A large number of studies to investigate application of nanomaterials in drug delivery are in clinical trial stages. While they have proved to be a breakthrough in medical sciences, proper assessments and in-depth analyses should be carried out to investigate their impacts on human health and the environment. Although there has been explosive development of novel nanomaterials, much of this field is uncharted and the extant literature to date demonstrates this. Therapy models are being developed by oncologists to further understand drug delivery systems and improve their efficacy. Only after meticulously weighing both the advantages and disadvantages can functionalized carbon nanomaterials become feasible for clinical applications.

3. FCNMs for cancer treatment Cancer is one of the major causes of death worldwide, with millions of deaths each year, and this is visibly a rising trend. If diagnosed early, it can be treated effectively through tumor removal/reduction, ensuring a higher survival rate. The treatment involves chemotherapy and radiation exposure, which is harmful to the health of the individual. Over the past decade, carbon nanomaterials have been used in theranostics, which deals with a combined approach of diagnostics (using a primary radioactive drug to identify/diagnose tumor location) and therapeutics (using a secondary radioactive drug for treating the tumor); however, their toxicity, safety, and efficacy remain major concerns. After appropriate functionalization, these nanomaterials gain improved biocompatibility and can be loaded with anticancer drugs, bioactives, genes, and siRNAs through hydrophobic interactions or π-π stacking for enhanced selective accumulation in a tumor environment with better permeability and retention. CNMs help in labeling and detection of tumor cells in their early stage of growth with the help of fluorescent probes. CNMs used for biomedical applications are modified by covalent addition of hydrophilic functional groups (electrophiles, radicals, sidewall halogens, etc.) and noncovalent modification with amphiphilic molecules (polymer composites and biomolecules). Covalent modifications are generally stable but result in reduced intrinsic properties, whereas noncovalent modifications are comparatively mild with lower stability. This is a major concern during the functionalization process; therefore, optimization for striking a proper balance between stability and structural integrity of CNMs is essential (Fig. 1).

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Fig. 1 Chemical functionalization of CNMs for biomedical applications [25].

3.1 CNMs used for cancer treatment 3.1.1 Carbon nanotubes (CNTs) Acting as promising carriers, CNTs have a distinct hollow and cylindrical structure with single, double, triple, or multiple walls that have been surface-engineered through functionalization to carry anticancer drugs like topoisomerase inhibitors and antimicrotubule drugs due to their increased targeting potential to cancer cells. Singh et al. [26] were able to utilize functionalized multiwalled CNTs for effective treatment of lung cancer, achieving maximum efficiency in the sub-G1 phase associated with minimum pulmonary toxicity. CNTs can also act as gene carriers for loading plasmid DNA, siRNA, and micro-RNA; they can also be used similarly for thermal therapy and photodynamic therapy (PDT) [27]. SWCNTs have been employed for in vivo cancer detection through fluorescence imaging as a result of their emission in the near-infrared region (NIR) (1100–1400 nm) [28]. Apart from tumor visualization, CNTs are also used as ultrasound contrast agents or photoacoustic imaging (PAI) agents. They have a higher contrast and resolution compared to fluorescence imaging due to the reduced scattering nature of ultrasound [29]. Raman scattering is also used as it offers higher durability for monitoring

Functionalized carbon nanomaterials

of CNTs, along with other imaging techniques like PET scans and multimodality imaging [30,31]. 3.1.2 Carbon nanohorns (CNHs) Composed of a single GR tube with a conically closed tip, CNHs are either small (30–50 nm) or large (about 100 nm) which can be functionalized to obtain a novel carrier system for adsorbing/loading smaller molecules. Compared to CNTs, CNHs have a uniform structure, easy production, and are noncontaminable by metals with low acute toxicities [32]. CNHs have been used in magnetic resonance imaging (MRI) along with gadolinium and PAI-guided photothermal therapy (PTT) [33]. It has been confirmed that the drug delivery of cisplatin using CNHs is more effective than delivery in free form using single-walled CNHs, as shown by a higher degree of tumor suppression in the former, and a higher loading rate [34]. CNHs can also act as effective gene carriers with decreased toxicity and as regulators of gene expression [35]. CNHs have been used to treat prostate cancer cells through the delivery of siRNA. Polyamidoamine dendrimer was used by Guerra et al. [36] to modify CNHs to provide better interactions with DNA/RNA that can be used in prostate cancer therapy. 3.1.3 Graphene nanosheets (GR) Composed of graphene, graphene oxide (GO) or reduced GO (structured in a honeycomb-shaped lattice) are used in tumor hypothermia due to their high adsorption in the infrared region as well as to load a variety of anticancer drugs. Iron-oxide-nanoparticle-modified graphene oxide has been used in treating metastasized pancreatic cancer, which is generally hard to locate and presents various surgical difficulties [37]. They have a high loading capacity and act as carriers for drugs and genes into cancerous cells, utilizing PEI and chitosan to improve the binding with DNA/RNA. They can also be used for hybrid PDT and PTT therapies as well as hybrid loading of drug and gene. 3.1.4 Fullerenes (C60) These are icosahedron cages of carbon shaped like soccer balls, with sizes of 0.7–50 nm, which can be used as multifunctional vectors to attach drugs through covalent or noncovalent encapsulation. Fullerene complexes with metals act as good MRI contrast agents and their derivatives can be used in fluorescence imaging of cancer but are rarely used for the sole purpose of diagnostics [38]. Functionalized fullerenes act as antioxidants, which provide safety against the oxidative pressure induced in doxorubicin (DOX) by inhibiting the formation of superoxide dismutase and glutathione peroxidase [39]. Thus, it is now possible to use a combination of DOX and fullerene for localization and treatment of cancer through intracellular delivery of DOX. Fullerenes can be used as gene carriers forming stable DNA complexes, resulting in insignificant toxicity and efficient selectivity of organs [40].

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Further reading D. Chen, C.A. Dougherty, K. Zhu, H. Hong, Theranostic applications of carbon nanomaterials in cancer: focus on imaging and cargo delivery, J. Control. Release 210 (2015) 230–245, https://doi.org/10.1016/ j.jconrel.2015.04.021. G.M. Olyveira, G.A.X. Acasigua, L.M.M. Costa, C.R. Scher, L.X. Filho, P.H.L. Pranke, P. Basmaji, Human dental pulp stem cell behavior using natural nanotolith/bacterial cellulose scaffolds for regenerative medicine, J. Biomed. Nanotechnol. 9 (2013) 1370.

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Carbon-based nanomaterials: Potential therapeutic applications Kamla Pathaka, Manish Kumarb, Shashi Kiran Misrac, Beena Kumarid, and Nikita Kaushalb a Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Ambala, India c School of Pharmaceutical Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur, Uttar Pradesh, India d Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, Haryana, India b

1. Introduction Due to their ability to manufacture a range of allotropes such as nanotubes, amorphous carbon, fullerenes, diamond, and, more recently, graphene, carbon nanomaterials have become increasingly attractive. Nanostructures or carbon nanomaterials provide amazing flexibility in altering various properties for unique applications due to their chemical inertness. They have acidic or basic media resistance, structural stability at high temperatures without air, and the customizable chemical nature of hydrophobicity, to name a few characteristics. Nanoscale carbon materials can take many forms, including thin films, graphene foams or sponges, carbon nanotube forests, carbon fibers, carbon nanowalls, and porous carbon materials. Carbon nanomaterials’ functionality can be altered by adding or doping metal elements such as gold, platinum, or silver, as well as chemical and physical changes. Carbon nanoparticles are used in a wide range of fields, including energy, the environment, water, biology, and many others [1,2].

2. Types of carbon-based nanomaterials Carbon is one of the few chemical elements (together with silicone) that can polymerize at the atomic level, resulting in extremely long carbon chains. Carbon atoms have a valence of four due to the four electrons in the outer electron layer (Fig. 1A and B) and can form single, double, or triple covalent bonds with other elements. Carbon atoms have these characteristics due to their unique electron structure and smaller size compared to other group IV elements. Nanomaterials are particles with at least one dimension between 1 and 100 nm in size [3,4]. All nanoparticles made of carbon atoms are referred to as carbon-based or carbon nanomaterials. The geometrical structure of carbon-based nanomaterials is the most used way for classifying them. Carbon nanostructures come in a variety of shapes, including Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00003-0

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a

b

c

Promotion

2p2

1

C

2s

2s2

1s2

1s2

d

2p3

e

g

OH zig-zag

armchair

chiral

O

f OH O

Fig. 1 Representation of carbon atom and carbon-based nanoparticles: (A) electron configuration of a carbon atom before and after 1 s-electronic promotion; (B) schematic representation of a carbon atom structure with two-electron orbitals around the nucleus and six electrons distributed on them; (C) structure of a fullerene C60; (D) structure of a single-walled nanotube; (E) different types of single-walled nanotubes: armchair, zig-zag, and chiral; and (F) structure of an oxidized singlewalled nanotube [3].

tube-shaped, horn-shaped, spherical, and ellipsoidal. Fullerenes are spheres or ellipsoids; carbon nanotubes are tube-shaped particles; nanohorns are horn-shaped particles; and carbon nanotubes are tube-shaped particles. Carbon nanoparticles are presently employed in a wide range of technical applications, including micro- and nanoelectronics, gas storage, conductive polymers, composites, displays, antifouling paints, textiles, long-lasting batteries, gas biosensors, etc. [4–6]. In recognitions of advancements in nanofabrication techniques and nanomaterials over the last two decades, graphite is now being actively used as a starting material to engineer various types of carbon-based nanomaterials (CBNs), including single- or multiwalled nanotubes, fullerenes, nanodiamonds, and grapheme. Many studies have concentrated on using these beneficial characteristics for a range of applications, including electronics and high-strength composite materials [7–9].

2.1 Carbon nanotubes Carbon nanotubes (CNTs) have become the most extensively used CBNs since they were discovered [10,11]. Graphite discharge, or chemical vapor deposition, is a

Carbon-based nanomaterials: Potential therapeutic applications

commonly used method for creating carbon nanotubes. Because of their variable physical features (e.g., diameter, length, single-walled vs multiwalled, surface functionalization, and chirality), as well as their extended sp2-carbon [11], they have a vast range of optical and electrical properties. CNTs have been researched for usage in a variety of industrial applications due to their wide range of beneficial features [12]. CNTs, for instance, are well known for their high mechanical strength: they exceed a range of high-strength materials that are commercially available (e.g., high tensile steel, Kevlar, and carbon fibers) in terms of measured stiffness and flexibility. As a result, they have been used to reinforce composite materials including plastics and metal alloys, resulting in a wide range of commercially available products [13]. However, inadequate interaction with the matrices that surround them results in an inefficient transfer of load between matrices and CNTs, The promise of incorporated composites of CNT as load-bearing ultra-highstrength materials has yet to be established [13]. Rather than focusing exclusively on composite mechanical strength, many recent research efforts have concentrated on embedding carbon nanotubes into other materials to make use of their multifunctional properties (i.e., electrical and thermal conductivity, as well as optical characteristics). CNTs’ amazing electrical properties, combined with their nanoscale size, are especially important in the field of electronics to create nanoscale electronic circuitry [14,15]. CNTs also have a low electric field threshold for emission of fields in comparison to some other common field emitters [16,17]. As a result, CNTs are being studied in electron emission devices that are highly efficient such as electron microscopes, gas-discharge tubes, and flat display screens. Due to field emission, CNTs exhibit a strong brightness that could be used in lighting [17]. Generally, carbon nanotubes are hydrophobic and exhibit poor solubility in physiological solution, thus they require functionalization. Both physical (plasma treatment, ultrasound, and radiation) and chemical methods (inorganic salts, mineral acids, organic acids/salts, and polymers) are utilized to facilitate dispersion of CNTs in aqueous and nonaqueous media [18]. Structural modifications are carried out either by exohedral or endohedral functionalization. Exohedral functionalization involves covalent (present of COOH at side wall and cavity) and noncovalent interaction (π-π stacking and van der Waal) between molecules, whereas the endohedral functionalization constitutes entrapment or filling of the voids of CNTs with polar substances [19]. Functionalized carbon nanotubes significantly penetrate cell membrane, can translocate, allow targeted drug delivery, and hence are used as fascinating theranostic agents in the management of a myriad of cancers. Several electronic sensors developed with functionalized CNTs are easy to operate and give quick responses. Sheikhpour et al. (2020) developed single-walled carbon nanotubes (SWCNTs) coated with organic substances that were highly efficient in identifying the changes in the volatile organic component (cancer biomarkers) and find potential in lung cancer treatment [20].

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In another research a cluster of superparamagnetic Gd3+ ions (1  5 nm) were decorated on SWCNTs (20–80 nm) and the gadonanotubes were explored as magnetic resonance imaging contrast agents. The developed gad nanotubes were smart, stable in physiological systems, and were ultrasensitive pH probes with high potential for detecting early-stage cancer [21]. Golubewa et al. (2020) demonstrated applications of functionalized agglomerated SWCNTs against the treatment and diagnosis of glioma cells. The system exhibited promising photothermal and photoacoustic theranostic agent for the destruction of cancerous cells due to interaction of light pulses (laser radiation) with aggregate SWCNTs within cytoplasm [22]. A heterostructural conjugate with magnetic iron oxide and oligonucleotide (DNA) encapsulated in SWCNTs was designed and applied as a multimodel bioimaging agent. The resulting conjugate exhibited distinct Raman scattering and near-infrared/visible range absorbance properties. The iron oxide nanoparticles could easily be introduced in the biological system that could be observed as two-dimensional nanostructure through MRI in the murine macrophage cells [23]. Tissue toxicity, biodistribution, and biodegradability have always remained critical issues with carbon nanotubes that are reliant on the size, length, and concentration of nanotubes. Literature describes that SWCNTs exhibit different pharmacokinetic pattern than multiwalled carbon nanotubes by the virtue of electrical, thermal, optical, and kinetic properties.

2.2 Graphene The most recent nanomaterial to make a splash is graphene. Geim and Novoselov’s seminal work [24,25] identified a simple method for exfoliating graphite to create graphene and examined its unique electrical characteristics. Although graphene and carbon nanotubes have similar thermal, optical, and electrical properties, the atomic sheet structure of graphene is two-dimensional. Massless Dirac fermions and the quantum Hall effect explain optical transparency in the visible and infrared spectrum, as well as charge excitation of low-energy systems at room temperature. Graphene is also structurally strong while remaining extremely flexible, which makes it perfect for thin, flexible materials [26,27]. Chen et al. designed nanoparticle-based photosensitizer containing gadolinium entrapped graphene nanoparticles (Gd@GCN). The developed nondimensional system (5 nm) has intense fluorescence at high proton relaxivity, hydrophilicity, and more tumor cells selectivity compared to bare graphene nanoparticles. Gd@GCNs have enhanced permeation and retention in solid tumor cells with little toxicity due to the safe encapsulation of gadolinium ion in a graphene shell [28].

2.3 Fullerenes Carbon molecules or molecular forms of carbon are allotropic modifications of carbon that are generally referred to as carbon molecules. Fullerenes were discovered in 1985

Carbon-based nanomaterials: Potential therapeutic applications

by R.F. Curl, R.E. Smalley, and H.W. Kroto [29], who were awarded the Nobel Prize in Chemistry in 1996. The fullerene family is constituted of several atomic clusters (n > 20) made up of carbon atoms on a spherical surface. Carbon atoms are frequently located near the vertices of pentagons and hexagons on the sphere’s surface. Carbon atoms in fullerenes are linked by covalent bonds and are often in the sp2-hybrid form. The most common and well-studied fullerene is fullerene C60. The spherical molecule has 60 carbon atoms at the vertices of 20 hexagons and 12 pentagons, making it exceedingly symmetric. Fullerene C60 has a diameter of 0.7 nm [30]. Fullerenes have highly been explored in pharmaceuticals (delivery of therapeutics), the health sector (bioimaging), and materials science (engineering tools as conductive devices) due to their exclusive physicochemical, thermal, mechanical, and optical characteristics. These carbon-derived substances are widely accepted cargo for the efficient delivery of bioactive agent at targeted site and for diagnostic or bioimaging purposes. Fullerenes (C60) are sp2 hybridized carbon allotropes that consist of 60 carbon atoms arranged in a single bond C5-C5 (12 pentagon) and double bond C5]C6 (20 hexagon) manner. The empty core of fullerene can entrap various atoms (metals and radioactive) and lipid molecules for efficient theranostic drug delivery. The lipoidal metallic fullerene is known as endohedral metallofullerene and has better efficacy to penetrate the cell membrane. This carbon nanomaterial is functionalized by various chemical approaches. Fullerenes are frequently conjugated with poly ethylene glycol and pullulan, which exhibit strong potential for suppression of tumor cells (photodynamic tumor therapy) and positive MRI signals [31]. Carboxylated and polyhydroxylated fullerenes (C60) are preferred for bioimaging and clinical diagnosis. This new class of bioengineered CNM (carbon nanomaterial) is employed for the management of cancer utilizing principles of photodynamic therapy, photoacoustic imaging, radiotherapy, and photothermal therapy. Liu et al. (2011) designed cytospecific pullulan functionalized fullerenes as photosensitizer while treating hepatoma cells via photodynamic therapy. Functionalized fullerenes efficiently produce reactive oxygen species when they come in contact with visible light, and thus serve as therapeutic and bioimaging agents by providing anatomical structures of highly vasculature cancer tissues [32]. Hydrophilic polysaccharide pullulan has high affinity for asialoglycoprotein receptors, thus its conjugation with fullerene (C60) exhibits significant suppression of HepG2 cancerous cells along with a photodynamic effect. Polyhydroxy fullerenes or PHF are wellreported theranostics due to their high-water solubility, biodegradability, biocompatibility, and antioxidant properties. These systems drastically suppress tumor size (72% in 24 h) via photothermal therapy and provide photoacoustic tomography on treatment with nearinfrared laser [33]. Iron oxide decorated C60 was functionalized by PEG 2000 to form a stable nanocomposite in physiological solution. The system was further linked with tumor targeting molecule folic acid (FA) to obtain an efficient antitumor theranostic against breast cancer (MCF-7 cells). The designed hybrid nanoplatform (C60-IONP-PEG-FA) had minimal toxicity and was explored for multifunctional tasks including tumor diagnosis,

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photosensitization, and photothermal and radiofrequency thermal therapy. Selective and localized anticancer effects against malignant cells were also observed [34]. Furthermore, a doxorubicin (DOX)-loaded tumor-specific PEG functionalized hybrid C60@Au aggregate was designed that had potential for photodynamic and radiofrequency thermal therapy. The developed theranostic containing doxorubicin exhibited higher and selective antitumor efficiency (8.6-fold) compared to the parent fullerene. Moreover, it exhibited potential application in photosensitization, X-ray analysis, and radiation therapy that facilitated chemotherapy through imaging of tumor cells [35]. The empty interior core of these fullerenes (C60) welcomes entrapment of metal atom and forms metallofullerenes that are highly advantageous over bare fullerenes. Encaged metal offers electrons over the fullerene surface and generates reactive oxygen species, and hence is suggested for magnetic imaging resonance (MRI). Gadolinium (Gd3+), a paramagnetic ion, has been projected as a magnetic resonance contrast agent due to its stability and lower toxicity. The limitation with Gd3+ chelates is leakage (in vivo) of metal ions due to a metabolic process which may cause systemic toxicity. Gd3+ containing metallofullerenes (GD@C60) preserves the physicochemical properties of Gd3+ in the fullerene cage and thus prevents in vivo leakage and dissociation [36]. Several water-soluble pH responsive chemotherapeutic gadofullerene derivatives, i.e., Gd@C60(OH)x and Gd@C60[C(COOH)2]10 have been designed and projected as MRI contrast agent in chemotherapy. These functionalized gadofullerens are dependent on the pH of the biological system, the concentration of the fullerene derivative, and the temperature of target site. The theranostics are active and stable in the microenvironment of cancer (acidic and high temperature) and form irregular clusters or aggregation at alkaline pH. Gadofullerenes offer a new model to fabricate contrast agent probes having a high performance of approximately 100 times higher than normal contrast agents that would be executed as magnetic label and pH-sensitive probes as well [37]. Shu and coworkers (2008) developed a tumor-targeted imaging agent, gadofulleride antibody conjugate. The system showed greater proton relaxivity (12 Mm 1 s 1) than the parent gadofulleride aggregates (8.1 Mm 1 s 1). A water-soluble gadofulleride-antibody (green fluorescence protein) was endohedral metallofullerene and acted as a tumor-targeted highly efficient imaging or MRI contrast agent [38]. Functionalized metallofullerenes are also involved in radioimmunotherapy or nuclear medicine to deliver radionucleotides. Metallic radionucleotides are entrapped in the cage of fullerenes that eliminate any undesirable effect or toxicity caused by catabolism or leakage of administered system. 212Pb (half-life 10.6 h) causes myelotoxicity on accumulation in bone marrow and has limited usage in radiotherapy despite its good decay characteristic. Fullerene-derived 212Pb@C60 melonic ester was developed, which captured Pb inside the core of fullerene and did not allow it to accumulate in the bone marrow. Water-soluble radio-fullerenes of 212Pb were uniformly biodistributed and played a vital role in radioimmunotherapy [39].

Carbon-based nanomaterials: Potential therapeutic applications

Shi and coworkers (2014) developed stable metallofullerene by decorating iron oxide over C60 (C60-IONP) and thereafter functionalized it with PEG 2000 for targeting MCF-7 tumor and biosensing. A prepared hybrid nanoplatform (C60-IONP-PEG) was multifunctional and has features to diagnose and alleviate hyperpermeable vasculature cells of tumors. Moreover, the system was explored for magnetic targeting, thermal therapy, photodynamic therapy, and radiotherapy [34]. One of the major applications of fullerenes is explored in direct photochemical and photodynamic therapy (PDT) due to generation of active singlet oxygen. PDT involves combined principles of visible light and photosensitization. Functionalized water-soluble fullerenes can mediate light and destroy microorganisms (Gram-negative bacteria), cancerous cells (metastatic), and other infectious bodies [40]. Functionalized polyhydroxy fullerenes (PHFs) and carboxy fullerenes (CFs) are actively engaged in “acoustic explosion,” a type of continuous laser irradiation technique to kill targeted cancerous cells in the presence or absence of oxygen. Radioactive tracers based on lanthanum endohedral metallofullerenes were designed for diagnostic and therapeutic purposes. A conjugate of lanthanum endohedral metallofullerenes “La2@Ih-C80” and π-extended tetrathiafulvalene was synthesized which had exclusive chemical, electronic, and magnetic features. The conjugate was stable and exhibited a paramagnetic property due to high electron potential and redox active characters [41,42].

2.4 Nanomaterials made of carbon and other carbon-based materials Buckminsterfullerene (C60) is a 60-sp2 carbon spherical closed cage structure that is commonly referred to as the buckyball (truncated icosahedron). For its discovery in 1985 by Curl, Kroto, and Smalley and further research, which led to the discovery of electrical characteristics and possible uses deriving from its highly symmetrical structure. They won the Nobel Prize in 1996 for the discovery of it [43,44]. The discovery of C60 may be considered the beginning of the scientific search for CBNs and their possible applications. Since more practical and scalable CBNs like graphene and CNTs have appeared in recent years, C60’s popularity has declined. Several scientists have produced C60 variations for medicinal uses because of its consistent size and structure, as well as the ease with which it may be chemically changed. C60’s antihuman immunodeficiency virus (HIV) activity is the compound’s most intriguing and promising feature. Due to C60’s hydrophobic nature and peculiar chemical structure, Schinazi et al. found a series of C60 derivatives that are water-soluble and capable of reducing the protease activity of HIV by attaching to its active site [45]. Since then, more C60 compounds have been found to target other important HIV enzymes, including reverse transcriptase, due to their anti-HIV activity. C60 p derivatives could represent a viable class of AIDS medicines in the future, according to these studies [46,47].

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Nanodiamonds are smaller than 10 nm and are made by subjecting graphite to a highenergy treatment, usually detonation. They exhibit photoluminescence and fluorescence as well as biocompatibility similar to that of a bulk diamond. NDs are often composed of tetrahedral clusters with sp3 carbon, unlike other CBNs. Nanodiamonds’ surfaces are functionalized with various functional groups or sp2-carbon for colloidal stability, allowing chemical modification for the targeted drug and tissue labeling as well as gene delivery. For example, Lin et al. employed magnetic NDs and fluorescent to distinguish cells recently. NDs coupled with polyethyleneimine (PEI) were similarly effective gene carriers, with none of the cytotoxicity seen with PEI alone, according to Zhang et al. [48].

3. Carbon nanomaterials as drug carriers Breakthroughs in nanotechnology have greatly aided the utilization of a range of nanomaterials (e.g., liposomes, polymersomes, microspheres, and polymer conjugates) as vehicles for delivering therapeutic medicines [49,50]. Carbon nanotubes, which have been shown to interact physically with a variety of biomacromolecules, have also been intensively researched for potential drug delivery systems (e.g., proteins and DNA). To covalently link pharmaceutical chemicals or specific moieties to CNTs, several chemical modification techniques have been devised [51].

3.1 Carbon nanotubes for drug delivery A fascinating study on the interactions of carbon nanotubes with DNA molecules was published by Zheng et al. In the presence of single-stranded DNA (ssDNA), carbon nanotubes were distributed successfully in an aqueous medium. Strong interactions between CNTs and DNA molecules were discovered in microscopic and spectroscopic tests, which resulted in the individual dispersion. According to the model of molecular dynamics, the base of ssDNA interacted with the surface of CNT via stacking, which resulted in a helical wrapping around the CNT by the ssDNA chains. This paper emphasized the utilization of carbon nanotubes for gene delivery DNA-specific separation techniques as well as gene delivery for molecular electronics [52]. Because of their numerous characteristics, carbon nanotubes are commonly used in biomedical applications. This is the most tempting option to carry chemotherapeutic drugs, proteins, and DNA [53–56]. Due to their high NIR light absorption properties, CNTs are also efficient photothermal agents. MWCNTs with iRGD-polyethyleneimine (PEI) functionalization and candesartan conjugation were produced by Su et al. (CD). The functionalized right-PEI-MWCNT-CD was constructed using plasmid AT (2) [pAT (2)]. V3-integrin and AT1R of tumor endothelium and lung cancer cells, respectively, were targeted with iRGD and CD. CD showed synergistic VEGF downregulation as a chemotherapeutic, and effectively inhibited angiogenesis when administered in combination with pAT [57]. An advanced nanocomposite was developed through a

Carbon-based nanomaterials: Potential therapeutic applications

DOX-loaded MWCNT-magneto luminescence carbon quantum dot (CQD) nanocomposite for photothermal therapy and chemotherapy. The negative surface charge of GdN@CQDs-MWCNTs made it easier for binding with positively charged DOX molecules. Near-infrared light absorption was strong in this substance. In vivo photothermal therapy with GdN@CQDs-MWCNTs/DOX-EGFR elevated the temperature of the tumor site of mice treated with GdN@CQDs-MWCNTs/DOX-EGFR to 51.8°C after 5 min of laser irradiation at a power density of 2 W/cm2. When the mice’s tumor location was cured, the temperature of the control group did not change much. The reduction in tumor volume revealed that this heating action promoted the photothermal therapy and release of DOX. To combine photothermal and chemotherapy, Dong et al. used a TAT-chitosan functionalized MWCNT nanosystem loaded with DOX. The Dong-woo team used a PEGcoated CNT-ABT737 nanodrug to target mitochondria in cancer cells in order to increase apoptosis [58]. By tearing the mitochondrial membrane, the nanodrug’s cytosol release caused lung cancer cells to apoptosis. Finally, the chemical was found to have therapeutic properties in vivo. A “gold nanoparticle-coated carbon nanotube ring,” also known as CNTR, has been developed with improved Raman and optical signal quality. It has been claimed that it improves the photothermal conversion behavior @Au and CNTR’s photoacoustic (PA) signal [59]. Image-guided cancer therapy was greatly influenced by the chemical. The photothermal cancer-killing efficacy of SWNT-Au-PEG-FA nanomaterials was enhanced by surface plasmon resonance (SPR) absorption of gold.

3.2 Quantum dots and graphene quantum dots (GQDs) for drug delivery These carbon-based nanomaterials are interesting candidates for theranostic drug delivery systems due to their selective cellular uptake and fluorescent property in the cells. Nanoscaled carbon dots have inherited optical properties due to their quantum confinement. These nanodots can be easily aqueous dispersible, highly biocompatible and quickly functionalized for development of suitable theranostic. The presence of a carboxylic functional group on the surface of carbon dots offers interaction with amino group and metals to form photoluminescence nanodots that are successfully utilized in photodynamic treatment as photosensitizers. Wu et al. (2016) synthesized photoluminescent nanodots of polyethyleneimine; glycerol conjugated reducible carbon dots (size 143 nm) that consisted disulfide linkage for eletrostatic interaction with negative charged molecules. The theranostic nanodots were capable of making an electrostatic complex with single-stranded RNA (negatively charged) and a gene silencing process was started through induction of apoptosis. When uptaken by target cells, the nanodots treated genetic defects in tumors and generated blue fluorescence. For chemotherapy, folate as a targeting ligand was conjugated with the nanodots to target oversuppressive folate receptors in lung cancer [60].

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A functionalized protein-quantum dot conjugate offers remarked theranostic applications. It is highly stable in physiological fluids and serves as a bioimaging agent. Graphene-quantum dots (GN-QDs) have been surface functionalized with gemcitabine entrapped serum albumin nanoparticles to target pancreatic cancer and bioimaging. Intense green fluorescence was depicted inside the cancerous pancreatic cells, suggesting efficient uptake of the nanohybrid conjugate inside the cells. Entrapped gemcitabine mediated sustained release, with improved bioavailability at the cells [61]. Polymers are utilized for surface functionalization of quantum dots to modify the safety, stability, and biocompatibility of the system. One of the attractive approaches is encapsulation of QDs into an amphiphilic di and triblock copolymers such as synthesis of self-assembled α,β-poly(N-hydroxyethyl)-D,L-aspartamide, lipoic acid with PEG. Thereafter, bioactive micelles of folic acid in aqueous solvent were developed. The formed amphiphilic copolymeric system was used to create a hybrid of gold silica quantum dots (Au-SiO2/QDs). The anticancer drug doxorubicin was entrapped in the hydrophobic core of the synthesized hybrid, which enabled high internalization of the drug in breast cancer cells (MCF-7). On laser beam irradiation at 810 nm, micelles containing Au-SiO2/QDs exhibited a powerful cytotoxic effect via photothermal therapy [62]. Al-Jamal et al. (2009) designed nanostructural lipid carrier functionalized QDs loaded with paclitaxel. The hydrophobic QDs were successfully entrapped within the bilayers of lipoidal carriers, with higher biocompatibility in aqueous media. Glyceryl monostearate, oleic acid, and soya phosphatidylcholine were utilized for the development of fluorescent parenteral dosage form with enhanced efficacy and reduced toxicity of paclitaxel. Intense near-infrared fluorescence was traced in mice with liver cancer. Outcomes received from histopathology studies suggested significantly high accumulation of drug in lung cancer cells [63]. Another, indium phosphate core-zinc sulfide shell-QDs-based antiepidermal growth factor (EGRF) encapsulated micelles were developed. Aminoflavone, an antitumor drug, was conjugated on the nanoengineered hybrid for the preparation of a novel theranostic. The system displayed higher cellular uptake and cytotoxicity against EGRF overexpressing breast cancer cells (TNBC cells). The near-infrared fluorescence from hybrid micelles suggested in vivo biodistribution and efficient tumor regression property in orthotopic triple negative EGRF overexpressive cancerous cells [64]. The unique features of graphene quantum dots, such as an oxygen-rich surface and a single atomic layer with a small lateral size, make them excellent for loading therapeutic compounds and enhancing their stability in physiological media. Furthermore, the fluorescent property of GQD makes it a suitable platform for tracking medicine administration into cancer cells [65–67]. As a result, over the last 10 years, GQDs have become commonly used for medication administration in a variety of illnesses. The Zhu group used a GQD-embedded zeolite imidazolate framework (ZIF-8) as a drug carrier, and ZIF-8 proved to be an effective drug carrier. The drug release behavior of DOX-loaded ZIF-8/GQD nanoparticles was revealed to be acidic pH-responsive [68]. GQD-capped

Carbon-based nanomaterials: Potential therapeutic applications

fluorescent mesoporous silica nanoparticles/DOX-loaded aptamer could be used for intracellular drug delivery and real-time drug release monitoring. The ATP aptamer induced GQDs to be released from nanocarriers in tumor cells’ ATP-rich cytoplasm, resulting in the release of DOX [69]. Based on GQDs’ important physical and chemical properties, Wei’s group created a DOX-loaded GQD that was then dyed with Cy5.5 using a cathepsin D-responsive (P) peptide. In vitro and in vivo, the drug-loaded nano-conjugate demonstrated increased cellular absorption and tissue penetration, allowing for improved therapeutic performance [70].

3.3 Graphene quantum dots (GQDs) for cancer therapy Several types of nano medicines, ranging from chemotherapeutics to radioisotopes, were conceivable for loading and application in cancer therapy because of their outstanding physicochemical properties, low toxicity, good hydrophilicity, stable intrinsic fluorescence property, and surface functional groups [71]. Curcumin-loaded GQDs were produced by Lee’s group as a hydrophobic anticancer agent for synergistic chemotherapy [72]. In vivo, GQD demonstrated excellent singlet oxygen generation and photodynamic treatment (PDT). Using scanning transmission electron microscopy, the diameter of GQD was discovered to be between 2 and 6 nm (STEM). According to ESR peaks, GQD was able to produce singlet oxygen (1O2) when irradiated in the presence of 2,2,6,6-tetramethylpiperidine. The absence of an ESR signal in the presence of 5-test-butoxy carbonyl-5-methyl-1-pyrroline N-oxide, on the other hand, suggested that no more ROS were produced during irradiation. Additionally, there was no discernible GQD dispersion at the injection site. A tumor in female BALB/c mice treated with GQD started shrinking after 9 and 17 days of in vivo PDT. When exposed to an alternating magnetic field (AMF) and/or NIR irradiation, Yao et al. (2017) evaluated whether GQD-capped magnetic mesoporous silica nanoparticles could produce heat. In an in vitro investigation, the material was demonstrated to be effective for chemophotothermal therapy and magnetic hyperthermia [73]. For targeted photothermal therapy, Fan’s group employed IR780 loaded on folic acid functionalized GQD. After 5 min of laser irradiation, the temperature at the tumor site of the IR780/GQD-FA treated mice increased rapidly to 58.9°C, and an in vivo anticancer study demonstrated a marked suppressive effect on tumor growth, with the tumor almost vanishing by the 15th day [74].

3.4 Graphene oxide for drug delivery Because of its large surface area and availability of electrons, graphene is an excellent drug carrier. Wang et al. [75] observed that when a substantial amount of doxorubicin (DOX) was placed onto phospholipid monolayer coated graphene, DOX was released more consistently at an acidic pH than at a basic pH. DOX might be physisorption-deposited

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onto a graphene sheet and then surface-modified with PEG-NH to improve stability and compatibility in a biological medium. There has been successful loading of both hydrophobic drug (indomethacin) and hydrophilic drug (DOX) on poly-N-isopropyl acrylamide (PNIPAM) grafted GO (GPNM) via—interaction, H-bonding, and hydrophobic interactions on PNIPAM. Wang et al. covalently bonded PNIPAM with GO using the free radical polymerization approach (FRPP). At an acidic pH, the regulated release of DOX was favorable due to greater hydrophilicity, higher solubility of DOX, and a reduction in the hydrogen bonding interaction between the GPNM surface and DOX [76]. Extensive research has been performed on biomedical applications of functionalized graphene oxide such as drug delivery, tissue engineering, gene delivery, and bioimaging. Theranostic applications of functionalized graphene include optical imaging, magnetic resonance imaging, Raman imaging, and photoacoustic imaging apart from the therapeutic effect. A single sheet of two-dimensional graphene and its oxide exhibits sp2 hybridization and possesses an extraordinary surface to volume ratio. Adorned carboxylic and hydroxide functional groups offer covalent functionalization with countless hydrophilic polymeric compounds including poly ethylene glycol, poly (methyl methacrylate), polyvinyl pyrrolidine, poly vinyl alcohol, and chitosan. Noncovalent functionalization or supramolecular interaction is more preferred as it does not make changes in the inherent chemical properties of graphene and its oxides. This kind of functionalization occurs through π-π interaction, van der Waal forces and electron donor-acceptor complexes that enhance water dispersibility, chemical reactivity, binding ability, and sensing properties of the conjugated substances [77]. Like graphene, graphene oxide also possesses two-dimensional sheets with enormous surface area. Abundant uncharged epoxide and hydroxide functional groups are present in basal plane of graphene oxide that offers attractive sites for functionalization with other molecules. Usman et al. (2018) developed a graphene oxide-based theranostic drug delivery system. Natural protocatechuic acid was conjugated with graphene oxide via π-π stacking and hydrogen bonding followed by surface adsorption of gold nanoparticles and gadolinium (III) nitrate hexahydrate as diagnostic agents. Enhanced cytotoxicity against HepG2 cells was observed with higher T1 contrast agents [78]. Biocompatible graphene oxide functionalized with poly ethylene glycol depicts high solubility and stability to the nanohybrid system. It offers conjugation of enormous therapeutics for the alleviation of myriad ailments with supreme activity. In this series, a theranostic delivery system was developed that contained doxorubicin embedded on a PEG functionalized multifunctional graphene oxide-iron oxide nanohybrid (GO-IONP). The system behaved as cancer theranostics and active optical absorber of the visible to near-infrared region, and thus showed potential for magnetic field-induced tumor cells

Carbon-based nanomaterials: Potential therapeutic applications

destruction [79]. Another, multifunctional nanoprobe including reduced graphene oxide-iron oxide was noncovalently conjugated with PEG and exhibited stability in the physiological system and high optical absorbance of the near-infrared region with a superparamagnetic property. The developed theranostic nanoprobe (RGO-IONPPEG) was suitable for MRI, photoacoustic, and triple model fluorescence systems. Furthermore, passive tumor targeting via photothermal therapy was proposed [80]. In this series, a nanodimensional theranostic system was developed by Luo et al. (2018) using ultra-small SPIONs (superparamagnetic iron oxide particles) and nanoengineered graphene oxide. The designed theranostic exhibited a pH-sensitive chemotherapeutic agent and MRI contrast agent [81]. Bahreyni et al. (2017) developed two conjugations of graphene oxide with aptamers, i.e., MUC1-NSA-24 and MUC1-Cytochrome C, for efficient programmed death of breast cancer cells (MCF-7 and MDA-MB-231). Both the aptamer conjugates exhibited promising molecular recognition probes and specific chemotherapeutic agents without damaging the normal cells [82]. GO has lately been regarded as an appealing nanomaterial for cancer therapy due to its inherent size- and shape-dependent optical features, unusual physicochemical behavior, exceptionally large surface to volume ratio, and changing surface properties [83]. Yu et al. developed a GO (GO (HPPH)-PEG-HK) that was functionalized with a v6-targeting peptide (HK-peptide) and coated with a photosensitizer (HPPH). According to in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging, the GO (HPPH)-PEG-HK activated dendritic cells and drastically reduced tumor development and lung metastasis by enhancing the infiltration of cytotoxic CD8+ T lymphocytes within tumors [84]. Kang’s group developed a DOX-loaded RGO-gold nanorods vehicle for photothermal therapy and chemotherapy in combination. A significant release of DOX was found due to the NIR photothermal heating influence and the acidic nature of the tumor microenvironment. Due to the tight packing, the absorption peak of Au NPS on GO was raised from 528 to 600 nm. When subjected to laser light (808 nm, 1.0 W/cm2), Au (30 nm)-GO (20 nm) showed a maximum temperature increase of 23.2°C [85]. According to Cheon et al., a DOX-loaded BSA functionalized graphene sheet could be an effective tool for combining chemo- and photothermal therapy for brain cancers [86]. Su et al. [87] developed a new material that combines a sponge-like carbon material loaded with chemotherapeutics on graphene nanosheets (graphene nanosponge) and lipid bilayers (lipo-GNS) customized with tumor-targeting protein. The ultra-small lipo-GNS (40 nm) demonstrated a significant accumulation in the tumor site, showing that the xenograft tumors were successfully inhibited in 16 days [88]. Development of polydopamine with a mesoporous silica (MS) layer to functionalize RGO before adding hyaluronic acid (HA) and DOX was carried out. Because of its pH-dependent and near-infrared-triggered DOX release, the RGO@MS

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(DOX)-HA was an excellent chemo-photothermal agent. A TiO2-MnOx conjugated graphene composite was recently developed by Dai et al. [89] as a smart material for tumor elimination. Our team developed 131I-labeled PEG-functionalized nanoRGOs for combined radio and photothermal treatment. Effective tumor accumulation was seen after intravenous injection of 131I-RGO-PEG, as confirmed by gamma imaging. When exposed to near-infrared (NIR) light, RGO has a high NIR absorption and may promote photothermal heating of the tumor. By releasing beta rays, I131 was able to kill cancer cells [90].

3.5 Carbon nanohorns for drug delivery These carbon-based nanomaterials are very similar to carbon nanotubes in their morphological structure. Single-walled nanohorns (SWNHs) are popularly involved in designing theranostic agent due to their easy and large-scale production, higher biocompatibility, lack of metallic contamination, and lower toxicity. Uniform structure of these materials facilitates their wide use in photodynamic therapy [91]. Carbon nanohorns are attractive cancer theranostics possessing a large surface area, unique physicochemical properties, and minimum toxicity. A multifunctionalized zinc phthalocyanine-loaded SWNH theranostic was reported for photothermal and photodynamic therapy in the treatment of cancer. Protein bovine serum albumin was conjugated on the carboxyl site of SWNHs to make a stable and biocompatible bioimaging agent. On subcutaneous administration, double phototherapy was irradiated that killed almost all tumor cells [92]. Recently, Daochang et al. (2021) developed a nanodevice consisting of an aqueous dispersible polyglycerol-gold functionalized carbon nanohorn. Thereafter, doxorubicin was entrapped that conferred additional biomedical applications of the device, both chemotherapeutic and diagnostic. The developed nanodevice (DOX@CNH-PG-Au) exhibited good water dispersibility and stability. Furthermore, it could be easily uptaken by 4T1 breast cancerous cells in mild acidic conditions and was capable of inducing apoptosis. On intravenous administration, the system exhibited synergistic efficacy by drug and gold nanoparticles, i.e., DNA intercalation and radio-sensitization, respectively. Photoacoustic imaging and radio-chemotherapy were executed by this newly designed carbon nanohorn-based theranostic [93].

4. Toxicological assessment Carbon nanomaterials are a new class of materials with a variety of biomedical uses, including drug delivery, biomedical imaging, biosensors, tissue engineering, and cancer therapy. However, the toxicity of these substances continues to impair biological systems. To date, some investigations on CNT toxicity have been carried out [94]. Metal contamination in carbon nanotubes could have a significant effect on toxicity [95].

Carbon-based nanomaterials: Potential therapeutic applications

Contaminants such as metal ions were incorporated into CNTs during the production process, producing cell toxicity. The length of CNTs has a substantial impact due to their failure to be internalized by cells [96]. CNTs of various sizes were manufactured, and their toxicity on cells and DNA was studied by several researchers [97]. According to Donaldson’s group, long-term retention of long CNTs results in severe inflammation and fibrosis. CNTs with a greater diameter and an equivalent average length are also more poisonous. Due to variations in size, shape, and chemical surface states, SWCNTs and MWCNTs had different cytotoxic effects on cells. In the presence of natural dispersants, individual CNTs tend to bundle together, causing toxicity. Surprisingly, cell toxicity was observed after surface functionalization of CNTs. Jo’s group found that –COOH functionalized SWCNTs were more hazardous than nonfunctionalized SWCNTs in HUVEC cell lines. Li et al. [97] discovered that strongly cationic functionalized MWCNTs have higher potential for lysosomal damage than carboxyl group functionalized or moderately amine group functionalized MWCNTs, as evidenced by confocal imaging, because of their high cellular uptake and NLRP3 inflammasome activation. Graphene, like carbon nanotubes, is limited in biomedical uses due to its toxicity. Ou et al. [98] examined the toxicity of graphene in a variety of organs in a recent review article. Graphene’s toxicity in animals and cells has been well investigated. In biological systems, certain factors such as concentration, lateral dimension, surface property, and functional groups are thought to have a substantial impact on its toxicity [99]. Incubation of GLC-82 cells for 24 h with GO at a concentration of 100 mg/L resulted in the formation of reactive oxygen species (ROS) and toxicity. Many research organizations have created GO with a variety of biological components to reduce the adverse effects of GO in a variety of medical applications. Wang’s group used blood protein to cover a graphene sheet to reduce its toxicity. As previously noted, GQDs, like other carbonbased materials, have several unique properties that have led to their widespread use in biological applications. Because the toxicity of GQDs differs from that of graphene and GO, it is a severe and pressing issue that needs to be addressed. According to multiple studies, various factors appear to influence the toxicity of GQDs. Because of their reduced size, GQDs appear to have a toxicity advantage over GO and CNT. Wang et al. [75] also showed a cell viability mapping curve for many cells under the same conditions, indicating that GQDs smaller than 10 nm exhibit exceptionally high cell viability. Nanomaterial concentrations, without a doubt, have a significant impact on toxicity. When it comes to GQDs, the concentration tolerance of cells is variable. GQD cytotoxicity is related to size and concentration, according to Shen’s group [100]. In a 100 ns scale simulation, they discovered that GQDs of a small size may infiltrate the POPC membrane. GQD penetration may have an impact on the thickness of the POPC lipid membrane. At the start, all angles between GQDs and lipid membranes were 0°. During the simulation, smaller GQDs punctured the POPC membrane, forming a 45° to 70° angle. Larger GQDs were absorbed exclusively on the lipid membrane surface, resulting

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in a 0° to 10° angle. Additionally, the surface functional groups of nanomaterials have been revealed to have a major impact on their toxicity [101]. Several studies have identified several factors that contribute to CNT toxicity. Contamination of carbon nanotubes with metals could have a significant impact on toxicity [102]. During the manufacturing process, contaminants like as metal ions were introduced into the CNTs, causing cell toxicity. Due to their failure to be internalized by cells, the length of CNTs has a significant impact on their toxicity. Several researchers researched the toxicity of CNTs of various diameters on cells and DNA. Long-term retention of long CNT, according to Donaldson’s group, causes severe inflammation and fibrosis [103]. CNTs with a larger diameter and a longer average length are also more toxic. SWCNTs and MWCNTs demonstrated varied cytotoxic effects on cells due to differences in size, shape, and chemical surface states. Furthermore, solubilizing agents had a considerable impact on CNT toxicity. Individual CNTs tend to bundle together in the presence of natural dispersants, creating toxicity. Surprisingly, after surface functionalization of CNT, cell toxicity was reported. In HUVEC cell lines, Jo’s group discovered that –COOH functionalized SWCNTs were more dangerous than nonfunctionalized SWCNTs. Because of their high cellular uptake and NLRP3 inflammasome activation, Li et al. [103] discovered that strongly cationic functionalized MWCNTs have higher potential for lysosomal damage than carboxyl group functionalized or moderately amine group functionalized MWCNTs, as evidenced by confocal imaging. Because of its toxicity, graphene, like carbon nanotubes, is limited in biomedical applications. In a recent review publication, Ou et al. [98] looked into the toxicity of graphene in a range of organs. Graphene’s toxicity in cell and animals has been thoroughly studied. Concentration, surface property, lateral dimension, and functional groups are regarded to have a significant impact on the toxicity of biological systems. According to Li et al. [103], incubation of GLC-82 cells with GO at a concentration of 100 mg/L for 24 h resulted in the generation of reactive oxygen species (ROS) and toxicity. To lessen the negative effects of GO in some medicinal applications, many research organizations have produced GO with a variety of biological components. To minimize the toxicity of graphene, Zhou’s group covered it with blood protein. GQDs, like other carbon-based materials, offer various unique features that have led to their broad use in biological applications, as previously stated. Because GQD toxicity differs from that of graphene and GO, it is a serious and urgent problem that must be addressed. Various factors appear to influence the toxicity of GQDs, according to multiple studies. GQDs appear to have a toxicity advantage over GO and CNT due to their smaller size. Wang et al. [51] also demonstrated a cell viability mapping curve for a large number of cells under the same conditions, suggesting that GQDs smaller than 10 nm had extraordinarily high cell viability. Nanomaterial concentrations have a major impact on toxicity, without a doubt. The concentration tolerance of cells varies when it comes to

Carbon-based nanomaterials: Potential therapeutic applications

GQDs. According to Shen’s group, GQD cytotoxicity is proportional to its size and concentration. Shen et al. discovered that GQDs of a tiny size can enter the POPC membrane in a 100 ns scale simulation. The thickness of the POPC lipid membrane may be affected by GQD penetration. All angles between GQDs and lipid membranes were 0° at the start. Smaller GQDs penetrated the POPC membrane at a 45° to 70° angle during the simulation. The lipid membrane surface was the only place where larger GQDs were absorbed, resulting in a 0° to 10° angle. Furthermore, it has been discovered that the surface functional groups of nanomaterials have a significant impact on their toxicity [104]. CNTs of varying sizes were created by several researchers, who tested their toxicity on cells and DNA [105]. According to reports, long-term retention of CNT was found to promote considerable inflammation and fibrosis. Furthermore, CNTs with a bigger diameter and an equal average length have a higher toxicity. Because of their differences in chemical surface states, structure, and size, MWCNTs and SWCNTs have different cytotoxic effects on cells. In addition, the solubilizing chemicals had a considerable impact on the toxicity of CNTs. In the presence of some natural dispersants, individual CNTs tended to bundle, causing toxic effects. Surprisingly, surface functionalization of carbon nanotubes resulted in cell toxicity. In HUVEC cell lines, Jo’s group discovered that –COOH functionalized SWCNTs were more damaging than nonfunctionalized SWCNTs [106]. Due to their considerable cellular absorption and NLRP3 inflammasome activation described by Li et al. [107], it was shown that strongly cationic functionalized MWCNTs possess higher potential for lysosomal damage than moderately amine group functionalized MWCNTs or carboxyl group functionalized MWCNTs, as evidenced by confocal imaging. Graphene, like CNTs, is not appropriate for biomedical usage because to its toxicity. In a recent review of research, Ou et al. [98] explored the toxicity of graphene in many organs in detail. Graphene’s toxicity in animals and cells has been studied extensively [98]. Several parameters were discovered to have a significant impact on its toxicity in biological systems, including lateral dimension, concentration, functional groups, and surface quality. According to Li et al. [107], incubating GLC-82 cells with GO for 24 h at a concentration of 100 mg/L resulted in the formation of reactive oxygen species (ROS) and toxicity. Various research groups have combined GO with a variety of biological substances to mitigate GO’s negative effects in biomedical applications [108]. Chong’s group coated graphene sheets with blood protein to reduce their adverse effects [109]. GQDs, like other carbon-based materials, exhibit several fascinating properties that have led to their widespread use in biological applications, as previously described [110].

5. Future prospective and conclusion Carbon nanotubes have been the subject of substantial research as one of the most commonly used types of nanomaterials over the last two decades. Carbon-based

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nanomaterials (CBNs) have been utilized in a wide range of fields due to their intrinsic mechanical, electrochemical, electrical, and optical properties. Because of their changing surface features, size, and form, CBNs have received a lot of attention in biomedical engineering over the last decade. CBNs are becoming promising materials due to their inorganic semiconducting capabilities and organic-stacking properties. As a result, they are able both to respond to light and to interact with biomolecules. CBNs might be exploited in the future by merging these properties into a single organism to be suitable for biomedical applications. Several chemical modification techniques have been established and successfully used in bio-applications such as drug delivery, biomolecule detection, tissue engineering, and cancer therapy because of their harmful influence on the biological system. This chapter discussed the advancements in the usage of CBNs in biomedical applications. It also reviewed some recently discovered key attributes of CBNs and how they might be used in improved bio-applications. Because carbon nanotubes produce toxic effects, more research into their toxicity and pharmacokinetics is needed.

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Carbon-based nanomaterials: Potential therapeutic applications

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Carbon nanomaterial-based nanocrystals for dental applications Deepa Thomasa, R. Reshmya,f, Eapen Philipa, M.S. Lathab, Aravind Madhavanc, Raveendran Sindhud, Parameswaran Binodd, and Ashok Pandeye a

Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara, Kerala, India Department of Chemistry, Sree Narayana College, Chathannur, Kollam, Kerala, India c Rajiv Gandhi Center for Biotechnology, Jagathy, Thiruvananthapuram, Kerala, India d Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIRNIIST), Trivandrum, Kerala, India e Centre for Innovation and Translational Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India f Department of Science and Humanities, Providence College of Engineering, Chengannur, Kerala, India b

1. Introduction Nanotechnology research and technologies are continuously changing and resulting in the introduction of new products to the market. The rapid growth of nanotechnology science, particularly in the dental and medical fields, has attracted attention due to its promising benefits and applications compared to traditional materials. Nano product application in dentistry is increasing fast and has made progress in various biomedical applications, such as regeneration of tissues. It reshaped the dental and medical fields by enhancing materials physicochemical characteristics, helping to develop new methods of diagnosis. The inclusion of nanomaterials into dental treatments has been directly linked with potential benefits. The global demand for dental materials is projected to expand rapidly due to many factors such as patients’ better consciousness about biomaterials, increased population and life expectancy, and people’s desire to lead a healthier lifestyle. The emergence of nanotechnology has enhanced the effectiveness of the dental biomaterials. This technology produces materials that have many good characteristics or improve the characteristics of existing materials. Nanodentistry is characterized as the science that uses nanostructured material to diagnose, treat, and prevent oral and dental diseases, relieve pain, and maintain and enhance dental health. It aims to guarantee patients’ systematic oral health care and highlights the prevention efforts of oral diseases. With the use of modern and reliable diagnostic methods, it is possible to avoid or treat a variety of oral diseases at an early stage. Variants of innovative oral care products that focus on nanoscale properties, ranging from implants to oral hygiene, are available. There are numerous applications of nanomaterials in various dental subdisciplines. Nanomaterials may display restorative and antimicrobial properties in preventive healthcare areas, while nanofillers may improve the bioactive Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00018-2

Copyright © 2023 Elsevier Ltd. All rights reserved.

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and physical properties of materials in restorative dentistry. The introduction of nanodimension particles enables interaction at molecular level, thereby enhancing the total effectiveness and affinity compared to macro- and micro-dimension particles. The high volume of the surface, which is a particular characteristic of nanoparticles, implies that more atoms are available on the surface of nanoparticles than deep inside. This is especially beneficial as surface atoms have more bondable exteriors compared to core atoms, with the opportunity to generate strong new bonds; therefore, nanoparticles are much reactive compared to macro particles [1–3].

2. Materials for nanodentistry Nanodentistry is an interdisciplinary research area which encompasses the use of new nanomaterials and appliances in all fields of human functionality. The advancement of nanodentistry through the use of nanomaterials and biotechnologies has the potential to enable almost perfect oral health. Nanomaterials are supposed to possess novel physical, chemical, and biological properties and be substantially better. The characteristics of nanomaterials may vary according to numerous factors, including the category and morphological framework of the materials. Common materials used in nanodentistry include nanofibers, nanopores, nanowires, and nanocrystals (Fig. 1) [4]. The applications of these materials in dentistry can be classified as diagnostic treatment applications, preventive treatment applications, restorative treatment applications, and regenerative treatment applications.

Nanofibre

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Nanowire

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Nanocluster

Fig. 1 Materials for nanodentistry applications.

Nanocrystal

Nanoring

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Nanosphere

Carbon nanomaterial-based nanocrystals for dental applications

2.1 Nanofibers Nanotechnology has enhanced the dynamic properties of fibers used in dentistry and their durability has made them suitable for better dental regeneration. There are several specific elements for nanofibrous structures, such as high surface area and adaptability for modification and porosity in the range from submicron to nanoscale, which closely mimics an extracellular matrix. A vast variety of nanofibers, with excellent efficacy, is popular in the dental sector. Numerous experiments have proved the effectiveness of nanofiber-polymer materials as tissue engineering scaffolds. As carbon nanofibers possess a high degree of surface roughness, they are considered to be ideal for dental implant applications. Numerous nanofibrous electrospun scaffolds such as poly-L-lactic acid/carbon nanotubes/hydroxyapatite (HA) and poly-L-lactic acid/gelatine/nano HA have been shown to enhance dentin adhesion and proliferation [3,5–7].

2.2 Nanopores Nanopores in a very thin membrane can be represented as miniscule holes with diameters of up to 100 nm. The nanometer-sized pore allows an effective passage of DNA sequencing. Researchers may mainly use this technology in nanodentistry for diagnostic applications. Nanoporous anodic alumina, porous silicon, and titania nanotubes are used to produce drug-releasing implants. It is possible to design them electrochemically to adjust the length, shape, and diameter of the pore to form implants that can release drugs [8,9].

2.3 Nanocrystals These are all the materials that consist of nanocrystallites in at least one dimension. They are made of metals or oxides or minerals that are of special interest because of their electrical, magnetic, optical, mechanical, chemical, and other properties. Biomimetic HA nanocrystals demonstrate remarkable characteristics and are ideal for bone tissue engineering and orthopedic applications [10].

2.4 Nanowires Nanowire is an extremely thin oblong structure and has a diameter of 20–80 nm [11]. Nanowires hold potential applications in dental treatment. HA nanowires have been documented to be precipitated from solution at high temperature and thus imitate the natural enamel HA when inserted into scaffolds, display an ability to repair enamel, and remineralize carious lesion [12,13]. Furthermore, they are able to offer good mechanical properties when reinforced with composite polymer [13].

2.5 Nanorod They are nanoscale structures having dimensions of 1–100 nm. Nanorods have been used frequently in restorative dentistry. HA nanorods have been found to have a unique effect

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on enhancing properties of the dental adhesives. Nanorods of silver and zinc oxide have been used in dental implants.

2.6 Nanoring A nanoring is a nanoscale-thick cyclic nanostructure. They have a distinctive texture pattern and exhibit unusual properties induced by the existence of cavities. These cavities may greatly enhance nanomaterial functionality. Due to prominent interface bonding supported by high nanoring surface area, the HA nanoring composite showed better mechanical performance [14].

2.7 Nanobelt Nanobelts are nanostructures that consist of rectangular sectional cross-bands. They are millimeters long and have many advantages, including longevity, usability, and low cost. A nanobelt contains a single crystal with a width ranging from 30 to 300 nm and a thickness of 10–15 nm. These are the oxides of elements such as zinc, gallium, silicon, etc., and have excellent potential in biomimetic dentistry [15].

2.8 Nanoclusters Nanoclusters belong to a group of nanoparticles which have at least one nanoscale dimension and size distribution. These may be composed in stoichiometric ratios of an element’s single atom or combinations of various atoms. It was shown that nanoclusters, although larger than individual nanoparticles, enable materials to be achieved with better surface characteristics such as better shine, polishing, and wear resistance. They are used in restorative dentistry. The nanoclusters porous structure promotes a higher connectivity to the polymer matrix, which improves the dispersion of mechanical stresses applied to the dental composite [16].

2.9 Nanoshells Nanoshells are spherical nanoparticles made of dielectric core covered with a thin metallic coating. The core is usually made of silica, and the metallic outer layer is made of gold. They have a variety of dental applications including teeth photo-degradation inhibition, fluorescent diagnostic applications, and bioconjugate preparation. They have also found application as a tool for controlled site-specific drug delivery to infected cells in periodontal therapy [17].

2.10 Nanospheres Nanospheres consist of nanometer-sized spherical matrixes, and are used for restorative dentistry. Peptide nanospheres found application in dental adhesives and restoratives, and

Carbon nanomaterial-based nanocrystals for dental applications

Fig. 2 Nanotechnology approaches.

provide significant strengthening and improvement of their mechanical properties. In addition, it has been shown that nanospheres possess therapeutic efficacy in tissue engineering applications [16,18].

3. Nanotechnology approaches The common approaches for nanomaterial synthesis are shown in Fig. 2.

3.1 Top-down approach In the destructive or top-down approach, smaller pieces are created from bulk materials. This fabrication technique involves the size reduction of large pieces of materials into the precise nanoscale dimension using nano-lithography, mechanical milling, laser ablation, sputtering, and thermal decomposition. This process uses greater quantities of materials, and if excess material is thrown away it may lead to waste. Materials reduced to the nanoscale can show very diverse properties and allow for specific applications.

3.2 Bottom-up approach In a constructive or bottom-up approach, products are synthesized by chemical reactions from atomic or molecular level, resulting in size growth of the precursor particles, which

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can take time. The process of material production from atoms to clusters to nano-materials includes pyrolysis, chemical vapor deposition, spinning, sol-gel, and biosynthesis. It starts by modeling and formulating custom molecules that have the capacity to self-organize or self-assemble into higher-order architectures.

3.3 Biomimetic approach Biomimetics, also referred to as bionics, is the application of principles and ideas of nature in order to construct new materials, tools, and systems. This method mimics a biological system for the creation of nanoscale devices [19].

3.4 Functional approach In the functional approach, components of a specified functionality are created regardless of how they might be constructed. This approach simply ignores the nanoparticles production method and the goal is to create a nanoparticle with a specific functionality [20].

4. Applications The various applications of nanomaterials in the dental field are described in Fig. 3.

4.1 Endodontics The dental discipline concerned with studying and treating dental pulp is endodontics. Under the surface of a tooth’s hard tissue is an unmineralized soft tissue layer known as

Dentifrices

Prosthodontics

Nano dentistry Applications

Periodontics

Orthodontics

Endodontics Fig. 3 Applications of nanomaterials in dentistry.

Carbon nanomaterial-based nanocrystals for dental applications

the dental pulp. The pulp is made up of odontoblasts, immune cells, connective tissue, blood vessels, and nerve fibers. This particular architecture allows the pulp to create and maintain dentin, which supply calcium, immunity, sensation, and tooth vitality [21]. However, the pulp is vulnerable to caries and infections, leading to pulpitis—pulp inflammation, which is usually painful. This eventually causes necrosis of the pulp, which ends the functionality and vitality of the tooth. A key obstacle hampering the effectiveness of recovering pulp tissue involves problems in tissue revascularization induced by the remarkable and miniscule source of blood flow at the tooth root apex. Due to the advent of modern tactics and technological advances, the field of endodontics is changing rapidly. Innovations in endodontic functional materials make significant contribution to the rapid growth of endodontics. Developing fluid-resistant filler is essential for successful treatment. Studies supported the effective usage of polymer nanomaterials for the generation of pulp and soft tissue revascularization. Rejuvenation or angiogenesis stimulation is necessary for the production of healthy and vital pulp. The primary objective of endodontic care is to eradicate the root canal system’s bacterial infection, prohibiting microorganisms from inhibiting periapical healing or even leading to apical lesion growth. The obturating agent is the filling used for root canal therapy to substitute the tissue of the pulp inside the infected tooth cementum. Tests have shown that the nanomaterials can enhance root canal therapy efficiently by modifying the filling material. Root canal filling substances are divided into two major groups: the core and the sealant. The most widely using obturating agent is gutta-percha, which is a good choice due to its bioinert properties. Although it is the most commonly used material for root canal therapy, it has many practical and mechanical disadvantages such as its flexible, nonadhesive, and limited antimicrobial properties, and it can be easily displaced by pressure. This latter problem can be solved by using nanomaterials like silver nanoparticles, zinc oxide nanoparticles, and chitosan nanoparticles as sealant along with gutta-percha. Bioglass, glass ceramics, and zirconia are also used as endodontic sealers. The benefits of nanoparticles that have gained interest in endodontics include greater penetration into the dental tubules, strong antimicrobial activities, and reduced micro-leakage. Due to these useful properties, the use of nanoparticles in endodontic sealant development has become attractive for many researchers. The sealer purpose is to bind the core materials into the canal and to fill the gaps between the canal wall and core materials. Sealers also function as a lubricant to improve the placing of the core filling materials. Root filling substances with antimicrobial properties contribute to the removal of residual microorganisms that are unaffected by both chemical and intracanal preparations. Numerous polymeric nanomaterials have nanofibers and structural compositions that imitate those of a human extracellular matrix and can therefore be used as a skeleton for regeneration of tissue. The feasibility of polymeric nanomaterials demonstrates their ability to solve many of the challenges faced today in the dental field. For clinical therapies, resin nanoparticle-based bondable endodontic sealants have been used

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to cover the interfaces to prevent reinfection of the root canals. The use of nanoparticlebased sealants has been found to have advantages, including variation of the adhesive to nano-irregularities, fast setting time compared to traditional sealers, insolubility in tissue fluid, chemical bonding to tooth tissue, dimensional stability, and conductivity [21–25]. Studies demonstrated that the inclusion of nano HA crystals in epoxy resin increases osteoblast adhesion, proliferation, and mineralization, and is a better alternative for commercially available endodontic sealer [25,26]. The final step in root canal treatment is obturating the root canal system. Hence, from the apical foramen to root canal orifice, a permanent three-dimensional seal is formed. Imperfect sealing and the appearance of gaps between the root canal wall and the obturating material will cause failure. The characterization of an efficient sealer requires physical properties, ease of handling, biocompatibility, and sealing ability. The capacity of sealers to seal is a prerequisite for their choice. Laboratory assessment of the sealing capacity of new endodontic sealer products is required before clinical use. Zinc oxide nanocrystals alone or in combination with eugenol, glycerol, linoleic acid, isostearic acid, propylene glycol, and barium sulfate are widely used in endodontic applications. Cements based on zinc oxide-eugenol have been found to possess favorable biocompatibility characteristics. They also possess antibacterial characteristics. Studies have shown that ZnO nanocrystals are biocompatible and new bone formation and bone remodeling have been enabled [27]. Composites made of nanocrystalline biocellulose fibers and mineral trioxide aggregates are used for endodontic applications. A study found that the incorporation of biocompatible biocellulose speeds up the hardening processes of mineral trioxide cement aggregates. Morphological analysis revealed that the inclusion of biocellulose favors the formation of hydrosilicate and provides better mechanical strength [28]. Silver nanocrystals and their functionalized derivatives have outstanding application for endodontics. The capacity to generate silver as a nanocrystalline material has improved its biological and antimicrobial properties significantly. Studies have indicated that silicon-based sealers that combine gutta-percha powder and silver nanocrystals have good biocompatibility and longevity with sufficient sealing capabilities and are resistant to bacterial penetration [29,30]. Amorphous TiO2 embedded with nanocrystals of Ag2O demonstrates sufficient antibacterial activity with no cytotoxicity [31]. Tetracalcium nanocrystals found endodontic applications. Studies have shown that the antibacterial property of mechanically activated tetracalcium phosphate nanocrystals and their antimicrobial activity make them promising tools for application as endodontic sealers [32]. It has been reported that HA nanocrystals can resist micro leakage when applied to orthodontic cement banding [33]. In the production of endodontic instruments, nickel titanium alloy has been used to enhance their material characteristics. Compared to stainless steel alloys, these alloys offer higher strength and low elasticity modulus. These alloys, applied for endodontic

Carbon nanomaterial-based nanocrystals for dental applications

purposes, can be subdivided into instruments containing nano austenite crystal configuration (BCC crystal structure) and nano martensite crystal configuration (monoclinic distorted crystal structure). Endodontic devices constructed from austenitic alloys have super elastic characteristics, while the martensitic instruments can be easily deformed and exhibit a shape memory effect upon heating. Martensitic alloy usage allows for more robust devices with greater resistance to cyclic fatigue compared to austenitic alloys. Such properties are of interest in endodontology, as they enable the creation of root canal devices that use these desirable qualities to get a benefit in the preparation of curved canals [34,35]. Nanostructured zirconia-based ceramics can be employed in endodontics applications [36].

4.2 Orthodontics Orthodontics is a dentistry specialty devoted to the diagnosis, prevention, and rectification of malpositioned jaws and teeth. It may also concentrate on altering facial growth, known as orthopedic dentofacials. Orthodontic care can involve the use of fixed or removable devices. Most orthodontic treatment is performed using fixed appliances. These appliances may provide a sufficient mechanical influence of the teeth, and offer a better treatment result. Due to their enhanced material characteristics, nano-based materials are considered to be suitable candidates in orthodontics applications. Nanotechnology may be used to improve orthodontics therapy performance. Enhanced features in the mechanical and medical specifications can be achieved by using nanotechnology. For example, the frictional force between components can be reduced and its motion can be facilitated by using nano coating in arch wires. Yamagata et al. developed orthodontics adhesives based on ZnO nanocrystals and Eu3+, which are visible under near-ultraviolet radiation. Enan et al. performed a thorough study into the in vivo impact of nano HA glass-ionomer cement banding under orthodontic bands. The findings showed that the inclusion of nano HA leads to micro leakage reduction across orthodontic bands [37]. Nano HA is also used in materials for the remineralization of the enamel. Calcium nanophosphate can be used as a remineralizing agent in orthodontic brackets. Calcium nanophosphate crystals lead to greater product bioactivity resulting from the enhanced surface area [38]. In orthodontic patients, enamel demineralization near to fixed orthodontic appliances arises from the frictional force between bands and brackets and creates complications. Reducing the frictional force between the orthodontic wire and the brackets tends to be able to increase the flexibility of the target tooth and therefore leads to a reduction in treatment time. Nanoparticles have acted as a component of dry lubricants in recent years. Dry lubricants are solid-state components which are capable of minimizing the friction between two sliding surfaces without needing a liquid. It is believed that the decoration of nanomaterials such as zinc oxide particles on wires used for orthodontics will

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minimize the friction force between brackets and wires, and thus facilitate the process of treatment compared to traditional materials [39]. In a study, it was suggested that wires covered with nickel-phosphorous electrolytes film fused with tungsten disulfide nanoparticles which has an inorganic fullerene-like structure could provide an unique ability to actively reduce friction during tooth movement. SEM analysis showed that the multicrystalline Ni3P film bonded to the substrate surface very well [40]. It is possible to use nano-filled polymer composites to connect orthodontic brackets to teeth. Compared with total-etch glues, they have strong marginal seal to enamel and dentine. The benefits of these materials include outstanding optical features, ease of handling, and superior polishability. Nanofillers can also lessen the wear rate of orthodontic adhesives, which is one of the most significant bacterial adhesion factors. Nanoionomer with fluoro alumina silicate crystals can enhance the mechanical properties and the release of fluoride [41]. Nanosilver-coated orthodontic brackets have similar properties to normal orthodontic brackets as regards the tissue reaction. They can be used in human teeth to reduce the area of decay and demineralization of the tooth during orthodontic treatment with the advantages of the antibacterial properties of nanosilver and thus to create a new form of orthodontics brackets. Adhesive composites which contain silver nanoparticles and nanofillers can help to prevent the demineralization of enamel around the brackets without major impacts on physical properties [42,43]. Nanoparticles made of alumina have been incorporated in polysulfone for orthodontic brackets. The material’s rigidity adds strength to the brackets. This material eliminates bracket frictional and mechanical resistance to orthodontic wires, while preserving bracket transparency. The revolutionary material has resistance properties and biocompatibility [44]. Research suggested the inclusion of antimicrobial nanoparticles to orthodontic adhesives cements can avoid plaque buildup and bacterial adhesion by the agents and resin-modified glass ionomers. Nano-fillers with Ag/HA have excellent antibacterial characteristics and possess shear bond strength [45].

4.3 Periodontics Periodontal disease or gum disease is a state of inflammation of the teeth tissues and weakening of periodontal ligament attachment with bony support, which damages the teeth tissues. The disease begins by the incursion of the anaerobic Gram-negative bacteria around area between the teeth and gums (gingivae). The epithelium of the gingivae then moves toward the tooth exterior, creating periodontal pockets. If it is left unattended, it may result to the settle down of tartar or calculus by the microbes and thus lead to the destruction of the auxiliary framework around the tooth and subsequently tooth loss. Periodontal defects are seen as a severe issue by clinicians.

Carbon nanomaterial-based nanocrystals for dental applications

The basic tenet of effective periodontal treatment begins with the establishment of good oral hygiene. Different methods for the management of periodontal disease have been used. There are two key targets for periodontal treatment. The first is to remove contaminated tissues by bacterial plaque, and the second is the regeneration of damaged periodontal tissues. Open flap debridement (OFD), scaling and root planning (SRP), and guided tissue regeneration (GTR) are the major strategies adopted for periodontitis treatment. They involve the simplistic reattachment to bone grafts and controlled tissue regeneration. The latest advances in nanotechnology progressively offer an effective approach for the cure of numerous dental diseases like periodontal disease. Because of a larger surface area to volume ratio and electrical and chemical synergistic effects, biomimetic nanostructured materials can give better performance for periodontal tissues regeneration. Researchers designed a nano-toothbrush, integrating colloidal particles of nanogold or nanosilver between the bristles of the toothbrush. Periodontal dressing materials made from bacterial cellulose nanocrystals are found to improve epithelialization and decrease inflammatory reactions [46]. Nano HA-based composites help to reduce the inflammation and prevent phagocytosis by their attachment with the tooth tissues. Nanocrystalline HA has gained significant attention because it can closely imitate the physicochemical properties of biological apatite compounds as well as enhanced osseointegrative capabilities and they can act a potential class of bone graft materials. Nanocrystalline HA are able to attach to the bone and facilitate bone healing by fostering osteoblast action and enhancing local growth [47]. Local drug deliveries have been gaining recognition and prominence in periodontology. For periodontal therapy, various polymers such as chitosan, collagen, dextran, polyethylene glycol, alginate, and polyglycolic acid can be used. Besides being used as scaffolds, they can also be utilized as drug delivery systems to enhance periodontal restoration. Polymeric materials in different formulations and shapes can serve as intra-pocket drug delivery tools for periodontitis treatment. Access to the site of tooth furcation and periodontal pocket regions under the gum line is easier for nanoparticle carriers, while it may be unreachable for other delivery systems. Reduction of the frequency of administration in the periodontal pockets by the application of nanoparticles will increase therapeutic effects and minimize side effects. Nanostructures have greater biological fluid stability and a high dispersibility in an aqueous medium. They can be used for GTR in the manufacture of biodegradable periodontal membranes. The periodontal membrane serves as a mechanical shield that prevents the clot and enables a selective repopulation of the root surface during the healing process. It is widely believed that the use of biomaterials maximizes the beneficial effects of cell therapies and regulating the delivery of cell or growth factor for periodontal therapies and regeneration. Triclosan-incorporated nanoparticles made with poly(D,L-lactide), poly(D,L-lactidecoglycolide), and cellulose acetate phthalate have been found to be efficient in reducing

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periodontal inflammation. The in vivo analysis demonstrated the penetration efficacy of the developed nanostructures through the junction epithelium [48]. In addition to polymers being employed as matrix materials, they are also utilized for the development of polymers with antimicrobial activity. Several antibacterial polymers such as chitosan are used against pathogenic microorganisms [49]. Infection is a significant cause of GTR failure. Recently, multifunctional GTR membranes are known not only to have regenerative barriers and tissue functions, but also to show antibacterial effects against periodontal pathogens. It is possible that the nanoparticles of metal and metallic oxides with antibacterial properties are integrated in the GTR membranes. Adding zinc oxide to poly caprolactone is found to result in the formation of GTR membranes with antibacterial, durable, and osteoconductive properties. The introduction of ZnO nanoparticles produced antibacterial effects against the periodontal pathogen P. gingivalis, thus promoting the viability and osteodifferentiation of the seeded periodontal ligament stem cells, without adversely affecting their biocompatibility [50]. The inclusion of Ag nanocrystals into the dental resin composite has been found to improve the mechanical properties. This leads to the formation of a long-term antibacterial dental resin composite without sacrificing the mechanical properties of the resin and which is beneficial for the prevention of secondary caries [51]. A gradual loss of teeth supporting structures is one of the main consequences of periodontal disease; a dental restorative operative should be undertaken to restore the appearance, performance, and efficiency of the damaged structures. Scaffolds made up of polymer nanoarchitectures can imitate the physicochemical properties of the extracellular matrix, and are effectively used to restore and regenerate periodontal tissues. HA nanocrystal-embedded poly(L-lactide) is utilized for scaffold regeneration applications. It has been found that the inclusion of HA nanocrystals enhances the surface characteristics and mechanical properties of poly(L-lactides), and make them suitable for periodontology applications [52]. Various studies demonstrated the efficacy of chitosan- and titanium-reinforced nanocrystalline HA for bone regeneration. Calcium sulfate nanocrystals have shown better treatment results in terms of bone restoration and reluctance to degradation than the traditional ones. In another study, nanoceramic composite made of zinc oxide nanoparticles, nanocalcium phosphate, carbon nanotubes, and alginate showed remarkable outcomes for periodontics therapy [53–55].

4.4 Prosthodontics Prosthodontics is a specialty of dentistry that focuses on making artificial substitutions for missing mouth and jaw portions. It is a unique combination of technology, art, and creativity that seeks to rehabilitate people with missing teeth and facial structures. It requires different care methods, including the use of fixed dental prosthetics, bridges, implants, and dentures. This field of dentistry is of great importance, as there seemed to be a thin

Carbon nanomaterial-based nanocrystals for dental applications

balance of patient satisfaction and dissatisfaction due to the required specificity with the prostheses. Nonetheless, it is recognized that one or more of the following categories contributes to the chief complaints of the patients: convenience, functionality, and appearance. In general, loss of comfort is a major component of concern when a dental prosthesis is needed. It is also clear that the permanent reconstruction of the tooth by artificial implantation often helps to reduce irritation for the patient. Prosthodontics treatment allows people who lose a tooth to live a comfortable life. Properly designed dental implants are a proven means for patients to regain self-confidence in their social activities. Proper dental prosthetics in terms of color, design, and appearance provide confidence for patients who feel esthetically burdened by a lack of complete dentition. Various forms of nanomaterials are used to enhance the properties of resin, ceramics, maxillofacial materials, luting cements, and polyvinyl siloxane impression material that are commonly used for prosthodontics applications. Acrylic resins make up approximately 95% of the denture base materials used in the prosthodontics market. Because of their advantages such as longevity, dimensional stability, and ease of handling and processing, these resins are considered the best base materials for dentures. Studies have shown that the integration of TiO2 nanoparticles into a poly methyl methacrylate denture base enhances its mechanical and antibacterial characteristics [56]. The crystalline phase TiO2 nanoparticles have free electrons which can be correlated with surface reactions. Oxygen was absorbed on the surface of TiO2 nanoparticles that diffused in the nanocomposite samples. The amount of oxygen diffused in the poly methyl methacrylate matrix was therefore lower than in pure poly methyl methacrylate, which resulted in a slower thermo oxidant polymethyl methacrylate loss [57–60]. It was shown in another study that the incorporation of cellulose nanofibers may greatly increase the elastic strength of a poly methylmethacrylate denture base material [61]. Effective antibacterial denture base resin composites are formed by the inclusion of cellulose nanocrystal/zinc oxide nanohybrids. Modest doses of nanohybrids can considerably hinder the growth and attachment of bacteria to the exterior of composites of dental resins and do not impair their mechanical properties [62]. In another study, composite resin with improved mechanical characteristics, significant biocompatibility, and remarkable antibacterial activity was achieved by combining nanocrystalline cellulose and silver composites with the poly methyl methacrylate matrix [63]. Due to its important metallic properties and toughening transformation, zirconia is considered a good prosthetic material. This transformation of the tetragonal into monoclinical phases can be utilized to improve the mechanical characteristics of zirconia, in particular its tenacity. Yttria is one of the most well-known dopants for inducing toughening transformation. The inclusion in yttria to zirconia polycrystal reduces the driving force and temperature for tetragonal to monoclinic transformation. This means that yttria-stabilized tetragonal zirconia polycrystal nano-ZrO2 exhibits superior biocompatibility, which is ideal for use in prosthodontics [64]. Nano-crystalline ZrO2 offers further

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possibilities in various application solutions. The excellent qualities of nano-ZrO2 such as natural color, high resilience and strength, stable chemical characteristics, and strong corrosion resistance indicate its broad potential for application. Researchers have found that in removable prosthodontics, the inclusion of nanomodified zirconium oxide particles enhances the properties of matrices of resins [36,65,66]. Compared to traditional luting cements, nano-particle mixed luting cements have shown improved bond strength for enamel and dentin. Because the nanoparticles can penetrate deeply into the dentinal tubules, they can bind well with dentin, thus increasing the elastic module and decreasing polymerization shrinkage [67]. Studies have shown that the addition of nano ZnO and MgO increases zinc poly carboxylate dental cement’s tensile strength and have indicated that nano-modified zinc poly carboxylate exhibits remarkable physical and mechanical performance relative to traditional zinc poly carboxylate cements [68]. Similarly, the inclusion of nanocrystalline HA and fluoroapatite particles to glass ionomer cements improved flexural resilience, long-term dentin bonding, and continued fluoride release capability. The study showed that the glass ionomer cement added with hydroxyapatite has great promise as a consistent restorative material and is ideal for prosthodontics use [68–70]. Poly methyl methacrylate integrated with silver nanoparticles may be developed as an antimicrobial, antifungal, and biocompatible denture base resin. Coating silicone products with silver nanoparticles may be of great benefit in patients who are using maxillofacial prostheses to avoid infection with fungi [71]. Titanium is a suitable biomaterial for dental implants because of its robustness and hydrophilic nature. In addition, it is similar to natural human bones, and has strong biological safety, high resistance to corrosion, and an elastic frame. One of the most critical aspects of dental implant long-term effectiveness is the proper biological alignment of the implant surfaces with the encircling host tissues. The shift of titanium implant surfaces into nanostructures has already been introduced to benefit their biological integration with the neighboring soft tissues [72]. It has also been found that by the use of coating strategies, inherent performance characteristics of titanium implants may be enriched. Nanocrystalline HA is potentially a perfect candidate to be used as a coating for Ti, Ti alloys, and stainless steel implants, and it is analogous to the inorganic material of bone. HA coatings turn implants into a biocompatible substrate to which cells tend to bind, rather than uncoated implant metal surfaces. In vivo trials indicated that Ti implant surfaces modified with HA nanoparticles showed improved bone binding and facilitated the development of new bones [73,74]. In addition, nanocrystals of other materials such as silver, diamond, etc. are used for coating purposes. Studies have shown that nanocrystalline silver coating on the titanium implant surface helps to prevent biofilms on dental implants [75]. In another investigation it was shown that the nanocrystalline diamond coating improved the strength, inertness, and thermal conductivity of titanium-based dental implants. The corrosion resistance and biocompatibility of the nanocoated implants ensure a selective protective shield and prevent the release of metals into the

Carbon nanomaterial-based nanocrystals for dental applications

body [76]. The nanocrystalline titanium-coated titanium implant has a greater wear tolerance than traditional titanium implants. The nanocrystal coating also helps to lower its coefficient of friction. In vitro and in vivo biological examination of the nanomodified alloy has demonstrated its excellent bio-tolerant character [77]. Cui et al. demonstrated that nanocrystalline titanium zirconium nitride coatings can further improve the corrosion resistance of titanium implants [78]. Zinc oxide nanocrystals synthesized by the microwave-assisted solvothermal technique exhibit excellent biocompatibility and antibacterial behavior, and are ideal for bone tissue engineering and dental implant coating applications [79].

4.5 Dentifrices Dentifrices are formulations designed to clean the teeth and other areas of the oral cavity. These come in the form of tooth powder, gels, toothpastes, dental creams, and dental foam. These are recommended for preserving oral health, and cleaning and polishing natural teeth, and also help to prevent weakening of the teeth. Toothpaste is a dentifrice used to help preserve oral hygiene along with a toothbrush. Major components are an abrasive, binder, surfactant, and humectant. Paste helps to remove debris and plaque, freshens breath, and whitens teeth. Tooth powder represents a substitute for toothpaste. It is expected to improve the teeth’s personal appearance by keeping teeth cleaner, reducing bad odor by removing food particles from the area between teeth, and also keep the gums healthy. From the Roman era itself, a number of items such as certain animals bones, egg-shells, and oyster and murex shells were used for teeth cleaning. After burning, these are reduced to a fine powder, and often mixed with honey. Mouthwashes are another important category of dentifrices and come in a number of formulations, often claiming to destroy plaque-forming bacteria or to freshen breath. Typically they are recommended for use in their basic form after brushing, but some companies suggest prebrush rinsing. Dental analysis found that mouthwash is used as a brushing aid instead of a substitute, as the plaque’s sticky resilient nature prohibits it from being effectively removed by chemicals alone and involves physical removal of the adhesive proteins. Nanomaterials could be used in dental care products for a variety of purposes, such as controlling the microbial population and plaques as dental biofilm sections, assisting the process of enamel or dentine mineralization, and supplying nanoscale nutrients to regulate ideal pH. HA nanocrystals or their zinc-, fluoride-, or carbonate-modified derivatives are widely used in dentifrices. To recover the depleted mineral of dental tissue, the use of artificial nanosized calcium phosphate-based biomaterials such as nanocrystals of HA in dentifrices is seen as a smart approach. It is highly demanding for high-quality toothpaste to enhance the efficacy of oral hygiene. Nano-toothpastes appear

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to be an effective alternative. The assemblage of the bacterial molecules in the hydroxyapatite crystals’ porosities is caused by the porosity of the enamel prisms. Nano-toothpaste is successful in closing these porosities and helping to enhance the color of the tooth [80]. Nano HA in toothpastes has a good bonding capacity with proteins as well as plaque and bacterial fragments. Several studies have shown that the introduction of nano HA in toothpaste improved the structural strength of the enamel and increased remineralization. It also reduced bacterial migration to the tooth surface. Nano HA may be used individually or in conjunction with other chemicals, such as sodium fluoride and strontium, as it fixes small holes and enamel depressions. It has also been shown that synthetic carbonate HA biomimetic nanocrystals achieve in vitro remineralization of distorted enamel surfaces and are successful in closure of dentinal tubules, thereby demonstrating a possible application in desensitizing dentifrices. A dentifrice containing zinc-carbonate HA nanocrystals has been shown to reduce dentinal hypersensitivity significantly [81]. Crystalline cellulose nanoparticles are used as multifunctional agents for dentifrices. These particles have proven to be less abrasive than silica dioxide, and are used in dentifrice formulations to avoid damage to tooth enamel [82]. Similarly, nano tooth-whitening agents help to improve their performance in whitening and minimize adverse side effects. Calcium peroxide nanoparticles are able to pierce deeper into the tooth structure by means of micro and nano cracks, resulting in better surface contact and hence improved efficacy of the whitening agent [2]. Many nanomaterials have been identified in several experimental studies, including bioactive nanoparticulate glass, nanosized carbonated apatite, either alone or in conjunction with silica, nanostructured calcium fluoride, and amorphous calcium phosphate nanoprecursors, to help enamel and dentine remineralization; these can be used in toothpastes and other dentifrice components in the near future [83,84]. Silver nanocrystals or synthetic nanostructured glass structures have been identified for possible use in dentifrices. Studies have shown the capability of zinc-carbonate hydroxyapatite nanocrystals containing mouth-rinsing solution for decreasing bacterial adherence and reducing the initial formation of biofilms. In another study, it was found that nano calcium fluoride powder comprising crystallite particle clusters has anticaries characteristics and can be used successfully in dentifrices [85,86]. Nanocrystalline titanium dioxide is widely used in toothpastes [87].

5. Future trends There has undoubtedly been a sudden spike in the requirement for dental biomaterials, and there are no dental materials available that have the perfect properties for any dental application. As a result of productive research to develop new nano products, the number of products available for different dental applications is expected to increase dramatically in the near future. It is very likely that this technology will be able to be exploited in

Carbon nanomaterial-based nanocrystals for dental applications

pursuit of the betterment of society. Nanotechnology will drastically alter dentistry, health care, and human life generally. Future nanomaterials will also perform a vital role in the context of dental regeneration through insights obtained in tissue engineering, developmental biology, and molecular biology and cellular science. Dental tissues have limited regenerative ability. Nonetheless, the combination of stem cells and nanomaterials can promote the regeneration of these tissues. The development of nanoparticles with specific surface morphology and physiochemical characteristics and incorporation into composites provides a promising solution to dental tissues restoration. Nanotechnology is changing dental practice profoundly. Oral health care facilities will become less daunting to dental surgeons in the near future, and more appropriate to patients, and the results will become substantially more favorable. However, at the same time, the issues related to ethics and human protection will have to be resolved before molecular nanotechnology can join the current medical and dental treatments.

6. Conclusion Emerging nanotechnology research has sparked attention in probable uses and profits compared to traditional materials, especially in the dental and medical fields. Furthermore, developments in nanotechnology will make room for the development of materials and technologies to help clinicians to detect, diagnose, treat, and control oral disorders at the earliest possible stage. The eventual outcome behind using nanobiomaterials depends heavily on the accurate and consistent choice of preclinical models appropriate for testing the safety and efficacy of developing therapies in humans. A greater knowledge of nanomaterials is needed for the future of dentistry. Major challenges for nanobiomaterials in dentistry lie in recognizing the relationship between nanomaterials and oral and maxillofacial tissues.

Acknowledgment Reshmy R. and Raveendran Sindhu acknowledge the Department of Science and Technology for sanctioning projects under the DST WOS-B Scheme.

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CHAPTER 14

Application of carbon and metal-based nanomaterials in modern health care systems R. Reshmya,f, Eapen Philipa, P.H. Vaisakha, Rekha Unnib, Aravind Madhavanc, Raveendran Sindhud, Parameswaran Binodd, and Ashok Pandeye a

Post Graduate and Research Department of Chemistry, Bishop Moore College, Mavelikara, Kerala, India Department of Chemistry, Christian College, Chengannur, Kerala, India c Rajiv Gandhi Center for Biotechnology, Jagathy, Thiruvananthapuram, Kerala, India d Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIRNIIST), Trivandrum, Kerala, India e Centre for Innovation and Translational Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India f Department of Science and Humanities, Providence College of Engineering, Chengannur, Kerala, India b

1. Introduction Metallic nanocrystals (MNCs), due to their uniform size and marked body distribution in nanometers, have received a lot of attention in various fields including healthcare systems. MNCs can be effectively utilized for developing new healthcare devices because of their diverse characteristics [1]. The specialty of metallic nanoparticles is their compatibility to attach with ligands, antibodies, and drugs. Due to reduced volumes, complex morphologies, and controllable exposed crystal facets, MNCs show superior properties to their bulk equivalent. Consequently, the manufacturing of metal nanocrystals as well as the modification of its properties for various applications have drawn significant interest. One common explanation is the manufacture of sealed nanocrystals. High-index aspects and widespread catalytic behavior have been easy to accomplish in the case of metals like Pt, Ag, Pd, and Au. However, it remains difficult to manufacture MNCs including Co, Ni, and Cu with diverse architectures, shapes, and sizes. The production of base MNCs is very far from adequate compared with the high performance of metals. Certain specifications should be satisfied for efficient usage of magnetic nanoparticles in genetic biology, respiratory disease, cancer screening, and imaging, including: (i) strong and consistent superparamagnetic moment; (ii) high stability of colloids under physiological conditions; (iii) ability to enter the reticulo-endothelial network;

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00019-4

Copyright © 2023 Elsevier Ltd. All rights reserved.

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(iv) biocompatibility and nontoxicity; and (v) ability to be biologically linked to nucleic acid, fats, medical goods, etc. [2,3]. In this fairly recent and large area of biomedical nanotechnology, diverse nanoparticles have shown applications in different fields.

1.1 Synthesis of metal nanocrystals Metals in nanoparticulate shape have provided fresh ways to use such various novel products, including their usage as bulk products in a traditional known way. Our focus in this chapter is primarily on the healthcare uses of MNCs. The methods of synthesis of MNCs can effectively be grouped into three categories: physical synthesis, chemical synthesis, and biosynthesis. In addition, every category has its merits and demerits; for example, it is easier to obtain more clean nanoparticles by the physical method with the possibility of conveniently avoiding the presence of unwanted surface adsorbed molecules. Similarly, biosynthesis methods focused on synthesis utilizing biological processes like microorganisms, plants, or some biologically inspired materials give a greener substitute than other procedures in contrast. However, compounds based on wet chemical synthesis are commonly used because they have been well formulated in contrast and provide the possibility of manipulating a large variety of criteria from which to produce nanoparticles with suitable functionality, size, shape, and surface finish. Some common physical methodologies for synthesis of MNCs are the evaporation/ condensation process, generation of spark discharge, laser ablation, radiolysis, spray pyrolysis, mechanical milling, etc. Biosynthesis and synthesis based on biological/natural materials, metal nanoparticles of gold, silver, and its alloy have already been demonstrated utilizing microbes, plants, and chemicals. Many bacteria and fungi have been used as bio-factories for the production of metal nanoparticles. In all instances, intracellular and extracellular production of nanoparticles was shown based on the form of microorganism used. The nanocrystals synthesized by this path are not usually particularly monodisperse. The extremophilic actinomycete and Thermomonospora species are reported to achieve reasonable size and shape diversity using an environmentally friendly microbial synthesis. Shaker et al. also demonstrated the production of gold nanotriangles with size control in high percentage using gold nanoplates and lemon grass extracts to fine-tune their optical properties in the near-infrared zone. Stable colloidal gold was first chemically synthesized by Michael Faraday, who reduced chloroaurate ions using dispersed phosphorous and CS2 [2]. The main principle for metal synthesis is that nanoparticles shall use as a metal precursor and reduce it in an appropriate solvent in the presence of an appropriate reducing, stabilizing, and forming agent. Mostly metal nanoparticles are synthesized in the organic phase. Brust and Schiffrin showed a two-phase process of synthesizing stable

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thiol-capped gold nanoparticles. The size regulation and the monodispersity that this method ensured had an important influence on fine metal nanoparticles production. Subsequently, many new approaches for appropriate surface modification of nanomaterials using thiols were established. Several surface modification strategies have now been developed as an indispensable tool for multiple conjugation strategies to interface nanoparticles with biological, organic, and inorganic matrices. The basic factors that will influence the qualities of the resulting nanoparticles at the end of a synthesizing include: nucleation rate, growth rate, presence of seeds, existence of any shapedirecting agent that guide growth in these paths due to selective binding or tempering effect of the crystallographic face, digestive maturation, and seed or intermediate coagulation. Diverse strategies are adopted for the controlled synthesis of metal nanoparticles in anisotropic form. Some of these strategies are: (i) micellar/surfactant solutions synthesis; (ii) synthesis of flexible, rigid templates; (iii) nanoparticular development utilizing physical confines; (iv) physical processes such as lithography of the nanosphere or deposition of vacuum vapor; (v) active solution synthesis in the presence or absence of additives; and (vi) morphological changes of the preformed nanopharmaceuticals [3]. The processes used to synthesize the metal and the monodisperse alloy nanocrystals are coprecipitation, microemulsification, synthesis of polyol, decomposition of hightemperature organic precursors, pyrolysis mist, pyrolysis laser, etc. During the last decade, efforts have been made to synthesize monodispersed metal nanoparticles with bulk particle size 2A SWNTs and MWNTs. Small angle neutron scattering is employed for SWNTs dispersed in water aided by surfactants which detect the optimal surfactant dispersion concentration. A SANDALS-type diffractometer is used for the structural investigation of the liquid and amorphous SWNTs [21,24,30].

2.9 X-ray diffraction (XRD) technique X-ray diffraction is a nondestructive method for analyzing matters ranging from liquids to crystals. This characterization method provides statistical information on interlayer multiple orientations of carbon nanomaterials. The parameters examined by this technique are structural strain, diameter, chirality distribution, and impurities in CNMs. Bragg’s law is applied for the X-ray diffraction pattern peak. X-ray diffraction profile does not differentiate microstructures but used for determining the sample purity. X-rays are impinged on the NPs which rotate in the collimated beam. The graphite oxidation process is determined by intercalation of oxygen species between interlayers. Moreover, growth of MWCNTs and bundle numbers in SWCNTs can also be monitored by using XRD [17,21,24,30,31,33].

2.10 Spectroscopic methods Electromagnetic radiations from various light sources have been applied for the interpretation of the characteristic profile of a carbonaceous nanomaterial. Information on aspects such as composition, size, and distribution of nanomaterials are investigated from spectroscopic analysis. Photon correlation spectroscopy (PCS), also termed as quasielastic light scattering, is used for the determination of size distribution and suspension aggregation of nanoparticles. Spectroscopic techniques include Raman spectroscopy, FT-IR spectrometry, UV-visible spectrophotometry, NIR, fluorescence spectroscopy, X-ray photoelectron spectroscopy, and photoluminescence [30].

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2.11 Raman spectroscopy Raman spectroscopy is applicable for morphological and molecular profiles of carbonaceous nanomaterials. It is a qualitative and quantitative analytical technique which utilizes Raman spectrum patterns within the molecules. Micro-Raman spectroscopy is a typical method for characterization of carbon nanomaterials at an excited wavelength. The SWCNT spectrum contains three main zones: low (breathing mode), intermediate (D-line), and high (G-band) frequency, whereas band length is reduced in MWCNTs. The radial breathing mode (RBM) explores the diameter of the carbon nanotubes at various frequencies such as 515, 548, and 584 cm1 [24,26,31]. Monochromatic light is used to investigate material vibrations of subcategory materials. This technique conveys both electronic and optical vibrational properties of nanomaterial by measuring the radiation spectra at 90°. Stokes and anti-Stokes scattering at an intensity of 0.001% denounce 99% of radiation [17]. A laser radiation source used for Raman scattering ranges from ultraviolet (UV) to near infrared (NIR). Charge-coupled devices (CCDs) and photomultiplier tubes (PMTs) have been used as detectors for this technique. A crucial application of this technique is that different properties of polycrystalline diamonds can be analyzed. Stress levels of carbon nanoplatforms can be attained in Raman spectroscopy. A geometrical property in the form of a 3D pattern is achieved at high resolution factors [34]. Raman spectroscopy is a meteorologically standardized instrument for quality control in industries. Advanced tip-enhanced Raman spectroscopy (TERS) has high resolution power that empowers the spectral fields. This technique is applied to crystallographic analysis [21,33].

2.12 Infrared (IR) and Fourier transform-IR (FT-IR) spectroscopy The use of infrared spectroscopy is limited for characterization of carbon-based nanomaterials due to its weak signal intensity. It is applied to detect the presence of oxygen functional groups and other functional moieties in carbon nanomaterials [31]. Single-walled carbon nanotubes depend on various factors like symmetry, chiral, armchair, and zigzag in the IR active modes. Impurities and molecular capping are observed in carbon nanoplatforms. A catalytic property and modifications in the nanomaterials was determined in the case of multiwalled carbon nanotubes. Fourier transform-IR (FT-IR) spectroscopy is a modified characterization technique applied for the determination of modifications like nitric oxide, nitrogen dioxide, nitrogen trioxide, and carbon nanotubes with the help of carbon signals [24]. Identification of organic functional groups has been done by measuring the characteristic vibrational factors. Quantitative measurement and concentration of the functional groups are not possible with this spectroscopic analysis method [21,25].

Functionalized carbon nanomaterials for biomedical imaging

2.13 Ultraviolet-visible and near-infrared spectroscopy Ultraviolet-visible (UV-vis) spectroscopy and near-infrared (NIR) spectroscopy are commonly used characterization techniques for carbon-based nanomaterials. Carbon nanoplatforms are strongly absorbed in the UV-vis and NIR regions because of the sp2 hybridization of carbon atoms. This is used for monitoring redox reactions and some morphological objectives. Distribution pattern of the bulk samples with their concentration has been analyzed in liquid solvents. In the case of conduction and semiconduction carbon nanotubes undergo three transitions: S11, S22, and M11, respectively.

2.14 Fluorescence spectroscopy Fluorescence spectroscopy is a tool for bulk sample characterization of carbon nanomaterials. Fluorimetric signal measurement provides quantitative abundance of carbonaceous nanomaterials. Fluorescence produced by individualized semiconducting SWCNTs containing surfactants has been applied for determination of the diameter and chirality of CNTs. Fluorescence has been observed between the bandgap of semiconducting nanotubes. NIR fluorescence spectroscopy is a powerful technique used to detect complex biological and environmental nanomaterial-based samples with the help of fluorophores [21].

2.15 X-ray photoelectron spectroscopy (XPS) X-ray photoelectron spectroscopy (XPS) is a prominently used characterization technique that reveals chemical and structural modification of carbon nanotubes, focusing on the photoelectron effect. The relative difference between graphite and carbon nanotubes can be studied with the help of binding energy capacity [24]. Characterization of nanomaterials has been determined after decomposition by heating the compound. Three factors that reveal characterization are change in weight, temperature change, and thermal reactions of the compound. Electron spectroscopy for chemical analysis (ESCA) and ultraviolet photoelectron spectroscopy are the two modified techniques of XPS [17]. The ejected photoelectron determines surface sensitivity and the peak-fitting X-ray photoelectron spectrum reveals the chemical environment of the nanoplatform [25].

2.16 Energy dispersive spectroscopy (EDS) Energy dispersive spectroscopy (EDS), also named dispersive X-ray analysis, involves analysis being done by the bombardment of electrons from a spectrum of X-ray beams. Both the qualitative and quantitative analysis of nanoparticles can be performed by using X-ray spectral lines. EDS is applied mainly for the analysis of elemental composition of the carbonaceous nanomaterials like CNTs with gold, silver, and palladium encapsulated nanoparticles [21].

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2.17 Thermal techniques Thermal analysis is the appropriate technique for characterization of carbon-based nanomaterials. Thermogravimetric analysis (TGA) and temperature programmed desorption (TPD) are the most commonly used techniques [25].

2.18 Thermogravimetric analysis Thermogravimetric analysis is applied for studying the thermal stability of CNTs. Analysis of both macro-scale (carbon-metal ratio) and nanoscale (SWCNT-MWCNT ratio) was carried out by using thermogravimetric analysis (TGA). Quantitative determination of carbon nanomaterials is based on the distribution of annealing temperature that gives a weight-loss curve with three different parameters: initiation temperature, oxidative temperature, and residual mass [21]. TGA provides information about CNT purity and concentration of organic groups in nanomaterials [25]. Oxidative temperature reveals the diameters, defects, and derivatization of CNTs. The higher the oxidative temperature is, the purer CNTs are, and vice versa. This technique is also applied for the determination of functionalization protocols [31]. Temperature programmed desorption (TPD) involves heating under a vacuum and is particularly applied for volatile products. Both identification and quantification of CNT functional groups can be determined by using TPD [25].

2.19 Separation techniques Separation techniques are powerful tools for the characterization of different CNTs which provide morphological properties after fractionization. Various approaches of separation techniques include ultra-centrifugation (UC), size exclusion chromatography (SEC), capillary electrophoresis (CE), and field flow fractionization (FFF).

2.20 Ultracentrifugation (UC) Ultracentrifugation is used for both size separation and characterization of CNTs based on the density gradient principle. The heavy water suspended CNTs initially undergo ultracentrifugation for several hours; after this, a supernatant solution is used for the characterization process. The buoyant density of CNTs is directly proportional to the surface-volume ratio and inversely proportional to the diameter. Density gradient ultracentrifugation is a frequently performed technique for SWCNTs with different chirality dispersed in sodium cholate solution [21].

2.21 Size exclusion chromatography (SEC) Size exclusion chromatography (SEC) is otherwise known as gel permeation chromatography. It is a type of liquid chromatography used for separation as well as characterization of carbon-based nanomaterials. Characterization is done by using controlled pore-sized

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columns (300 nm). Tetrahydrofuran (THF), Milli-Q water, and sodium dodecyl sulfate (SDS) are commonly used dispersion media used for the simple oxidation method [21].

2.22 Capillary electrophoresis (CE) Capillary electrophoresis is effectively applied for bulk samples of CNTs into different fractions with quasiuniform distribution using charge-size ratio phenomena. In this technique, surfactants like SDS are added above a critical micellar concentration. Apart from purification, characterization of CNTs is also determined with the help of CE [21].

2.23 Field flow fractionization (FFF) Field flow fractionization (FFF) is a separation method in which an external force is applied perpendicular to the direction of liquid phase flow in the sample. Separation of the SWCNT and MWCNT is done by an oxidative shortening process. Cross-flow filtration is a modified technique [21].

2.24 Other characterization techniques 2.24.1 Grazing incidence single angle X-ray scattering Grazing incidence single angle X-ray scattering (GISAXS) is an extended small angle X-ray scattering, semiquantitative technique which provides deeper knowledge about morphological and structural characterization. This supports real study with threedimensional images of CNTs [22]. 2.24.2 X-ray absorption near-edge structural elucidation An X-ray absorption near-edge structure (XANES), also termed as a near-edge X-ray absorption fine structure (NEXAFS), is an effective tool for the characterization of carbonaceous nanomaterials. In addition to morphological and topographical data, it provides absorption and adsorption of hydrocarbon molecules. This is because angular dependence of the absorption transition property correlates at an energy level of 50 eV above the absorption edge. Synchrotron radiation sources have been frequently used for analysis [22]. The sensitive photoelectron probes identify the charge distribution and arrangements of atoms in the chemical environment, which provides a successful spectroscopic footprint. The part of the spectrum at low-lying state with low-energy photons (ω) is XANES. Multiple scattering formalism and photon absorption crosssection are the two theories applied for characterization [34]. Surface composition and functional group identifications are information provided by using this technique, but it is not suitable for routine and large-scale analysis [25].

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2.24.3 Boehm titration Boehm titration is an analytical technique for CNT characterization that provides information about protic functional group quantification. It depends on the orders of magnitude of a neutralized CNT, whereas the aprotic compounds cannot be analyzed by this method [25]. 2.24.4 Chemical derivatization (CD) Chemical derivatization (CD) is a direct technique applied for the quantification of targeted functional group concentration in carbonaceous nanomaterials. Targeted oxygen containing functional species reacts with a specific derivatized reagent that has a specific chemical tag and then quantification of the carbon nanomaterials was processed. Depending on the nature of the tag, concentration of the chemical tag quantification techniques was selected. A fluorine atom has been used frequently as a chemical tagging element [25].

3. Applications of drug-loaded carbon nanomaterials for imaging Recent advancements in material designing and synthesis of nanomaterials such as carbon nanomaterials produced a robust electrochemical sensing system that displays a superior analytical performance [35,36]. Carbon nanotubes (CNTs) are impressive nanostructures because of their unique properties, such as electrochemical reactivity of biomolecules and electron transfer reactions [37]. Carbonaceous nanomaterials including CNTs, graphene oxide (GO), carbon nanohorns (CNHs), carbon nanoplatelets (CNPs), nanodiamonds (NDs), and graphene quantum dots (GQDs) have gained more interest in biomedical applications due to their intrinsic properties. Extensively investigated various biomedical applications are biosensing, drug delivery, functional imaging, cancer therapy, tuberculosis treatment, and synergistic combinational platforms. Other applications include drug carriers, imaging contrast agents, photothermal agents, photoacoustic agents, and radiation dose enhancers [38–40]. Carbonaceous nanomaterials are mainly used in gene delivery to cells or organs, tissue regeneration, biosensor diagnostics, and analysis [41]. An activated CNT from miscanthus may potentially be applied for recycling wastewater after activating with phosphoric acid and potassium hydroxide [42]. The entire biological tissue is prominently applied for biological imaging and drug detection [43,44].

3.1 Biosensors Biosensors are analytical devices used to identify an analyte that combines a biological moiety with the help of a physicochemical detector. The fluorescence ability of protein encapsulated nanotubes are implantable biosensors. Carbon nanotubes, graphene quantum dots (GQDs) and graphene oxide (GO) are potential platforms for developing

Functionalized carbon nanomaterials for biomedical imaging

biosensors due to their unique electrical, thermal, mechanical, and optical properties. Recently, diamond nanoparticles (DNPs) achieved excellent biocompatibility, reduced toxicity, and wide distribution pattern, and were found to be economical compared to other carbonaceous nanomaterials. DNPs employ the best platform for analyzing glucose, alcohol, nucleic acid, and redox enzymes [38,45,46]. Biosensor fabrication substrates consist of thick silicon with a thermal oxide layer using a high-density card-edge connector for impedance measurement by Ivium Technologies [47]. A significant advantage of carbon-based nanomaterials is that they act as electrochemical biosensors for DNA, pollutants, proteins, metal ions, gases, and immunosensors [35]. Radio isotope enzymes are also used as biosensors [37,46]. The different carbon nanomaterial-based biosensors and applications are shown in Table 2.

3.2 Carbon nanotube biosensors The unique properties of CNTs with their high chemical conductivity, stability, and sensitivity are applied in biosensing in which the biomolecules are immobilized on their surface, enhancing the signal transduction mechanism. Functionalized carbon nanotubes have a wide range of application in diagnosis and analysis [35,38].

3.3 Graphene oxide as a biosensor Graphene is composed of sp2-hybridized carbon atoms and it is capable of interacting with a probe or transduction of a specific response toward target molecules. This process is achieved by fluorescence, Raman scattering, and electro-chemical reaction. Functionalized graphene oxide (nanocomposite) is broadly used as a contrast agent for MRI. Polyethylene glycolated GO with fluoroscein isothiocyanate and NIR fluorophores labeled dyes were used in in vitro and in vivo imaging. A newly designed protein-based GO was used in photoacoustic (PA) and ultrasonic dual-modality imaging. A highly sensitive label-free DNA biosensor functionalized with single stranded probe DNA was used for detecting the limit of DNA oligonucleotides [38,48].

3.4 Fullerenes Functionalized fullerenes are also used as nanocarriers for drug and gene delivery because of their optimal size and hydrophobic surface, which supports easy crossing of cell membranes. Fullerenes show free radical scavenging activity and have the ability to sensitize the production of singlet oxygen (ROS), which is efficiently utilized for blood sterilization and photodynamic cancer therapy. Gadolinium metallo fullerene (gadofullerenes) with better relaxivity show promise for magnetic resonance imaging (MRI). The multifactorial applications of carbon nanomaterials in imaging are shown in Fig. 1 [48,49].

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Table 2 Carbon nanomaterial-based biosensors and applications. S. no.

1. 2 3 4 5 6

7

Biosensors type/ principle

Carbon nanoplatform used

Glucose oxidase biosensor Genosensors

Carbon nanotubes and diamond nanoparticles Carbon nanotubes with DNA, graphene oxide Multiwalled carbon nanotubes Single-walled carbon nanotubes Multiwalled carbon nanotubes Functionalized multiwalled carbon nanotubes MWCNT

Electrochemical biosensors SWCNT corona phases Enzyme biosensors MWCNT-modified glassy carbon electrodes 50 -Pyrene conjugate

Theranostic application

Key outcome

Ref.

Controls and detects blood sugar level To detect genetic diseases

Highly accurate and simple manipulation Improved sensitivity and cost-effective

[37]

Detects nitric oxide and sense ephinephrine Detects fibrinogen in human blood serum Detects arginase-I enzyme in E. coli Detect and quantify amino acids, albumin, and glucose RNA recognition

[35,37,48] [38] [38]

Ultrasensitive device

[38]

Potentially low for submicromolar concentration Improved selectivity

[35]

[35]

Functionalized carbon nanomaterials for biomedical imaging

CARBON NANOMATERIALS

Fig. 1 Application of carbon nanomaterials in multifactorial imaging.

3.5 Carbon quantum dots as biosensors The excellent photoluminescence, electrochemilumescence, and electrochemical behaviors of carbon quantum dots (CQDs) are widely applied in clinical analysis and diagnosis. They show better selectivity and sensitivity in detecting biomacromolecules like DNA, RNA, proteins, and glucose molecules. Carbon nanomaterials (CBNs) are effectively applied for photon imaging and also for therapeutics because of their unique properties, such as easy functionalization and high photon absorption with large surface area. The 3D spatial arrangement of CBNs is beneficial for fluorescence imaging systems. Two-photon fluorescence microscopy (TPFM) is an efficient technique for bioimaging and diagnosis [26]. In recent research, functionalized single-walled nanotubes (SWNTs) have been widely applied for bioimaging, ranging from single to multimodel imaging and also chemo-photothermal therapy. They possess various unique intrinsic optical properties like Raman scattering and photoluminescence in the near-infrared (NIR) region [50].

3.6 Fluorescence imaging and therapy Fluorescence is a type of luminescence that involves the absorption of radiation followed by the emission of light at certain wavelength by fluorophores. The basic principle involved in this technique is in-depth imaging of fluorescent proteins and dyes, which gives a detailed explanation of different molecular mechanism in living cells. Reducing the π-electron network connectivity of GQDs attracts more interest for implantation into bioimaging. The strong green fluorescence of GQDs synthesized

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by a one-step solvothermal method was applied for cellular imaging. This invasive technique serves as a potential biological tool in bioimaging and has been applied in a wide range of observations including gene expression, protein expression, and cellular interactions. Intrinsic and extrinsic are two types of fluorescence imaging which involve fluorescence emission by their concurrent fluorophoric species. Nanomaterials developed for conventional fluorescence imaging include quantum dots, metal nanoparticles, magnetic nanoparticles, silica nanoparticles, nanodiamonds, hydrogels, etc. [50,51]. The potential advantages of fluorescence imaging include high resolving power with target specificity and labeling concerned cellular physiology for bioimaging. The contrast of the targeted cellular image seems to be efficient and clear due to its super resolution capacity. The excellent photostability and aqueous dispersibility enable brilliant bright images to be achieved [51]. The different options of fluorescence imaging are shown in Fig. 2.

3.7 Magnetic resonance imaging and therapy Magnetic resonance imaging is a noninvasive bioimaging technique with zero ionizing radiation; it has the ability to penetrate deeper tissues and also characterize the healthy and tumor cells effectively, which initiates the pharmacotherapeutic application. It is used in surgical procedures (e.g., tumor resections) and for basic research purposes. The principles involved in MRI of the human body are detecting water proton density, velocity, and relaxation time (longitudinal T1 and transverse T2) by generating signals from a strong magnetic field. This is achieved by administering the contrast by an intravenous route that improves the tissue visualization clarity and shortens the relaxation time (T1 and T2). The imaging contrast may be T1 or T2, depending on the relaxation time of the water protons. Longitudinal (T1) contrast enhances the positive (bright) imaging whereas transverse (T2) improves negative (dark) imaging contrast. Gadolinium-loaded CBNs are a novel class of T1 contrast agents which have potent proton longitudinal relaxivity, improve diagnostic accuracy, and have an extraordinary positive safety profile. Different types of gadolinium contrasts are gadofullerenes, gadonanodiamonds, gadonanotubes, and gadographene. Recently, gadolinium has been upgraded by hyaluronic acid (HA). Modified SWNTs were synthesized to develop a targeted multifunctional theranostic system which is conjugated with DOX by disulfide bonds to achieve better imaging and therapy. Superior relaxivity of gadolinium is understood by SolomonBloembergen-Morgan (SBM) theory. Particular advantages of MRI are safety, accurate cellular labeling effect, and better biodistribution. Greater photon relaxivity provides easy biomolecular targeting with reliable images at a lower dose. Excellent penetration power across the cell membrane reduces the toxicity level. Both covalent functionalization and noncovalent functionalization are possible for combinational theranostics [50,52].

Functionalized carbon nanomaterials for biomedical imaging

Fig. 2 Different techniques of fluorescence imaging.

3.8 Raman imaging and therapy Raman imaging is based on the principle photon scattering process under light excitation, i.e., Raman spectra. The Raman scattering signal of GO is normally weak and modified with metals like gold (Au) and silver (Ag) for better sensitivity and intensity, which is termed as surface-enhanced Raman scattering (SERS). A Raman probe is used for bioimaging by the Raman mapping technique. SWNTs can generate van Hove singularities under the electronic density of states (eDOS) results in resonant Raman scattering. Thus, SWNTs produce stronger Raman peaks in tangential G bands than graphene. An intrinsic Raman character of SWNTs aids live cell imaging and also long-term biological tracking with DNA-modified SWNTs [50].

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3.9 Photoacoustic imaging and therapy (PA) Photoacoustic imaging is a biomedical, high-resolution volumetric optical imaging with acoustic waves produced by laser excitation on the target. Herein the detection and image visualization is achieved by penetration of the PA waves much deeper into the tissue. 3D PA images are depth-resolved images detected by ultrasound transducer through the waves. The basic mechanism involved is target site absorption by short pulsed laser light which gets converted into thermal energy with pressure change in the tissues. This pressure change initiates the tissue volume expansion and contraction that is being emitted as ultrasound waves. PA imaging system is of two types: photoacoustic microscopy (PAM) and photoacoustic computed tomography (PACT). Most of the scanning methods are done by PAM by the techniques of optical beam delivery geometrics and optical-acoustical focusing. In the case of PACT, multielement array type transducers and multichannel data acquisition boards (DAQs) were used to acquire data. The contrast used for imaging may be endogenous chromophores like hemoglobin, melanin, and glucose for imaging internal organs and blood vessels or exogenous contrasts such as dyes, metallic nanomaterials, organic nanomaterials, and carbon nanomaterials. Cycli peptide Arg-Gly-Asp (RGD) conjugated SWNTs through polyethylene glycol are applied for tumor targeting. Gold nanoparticles and organic dyes are widely used for clinical diagnosis of metastatic cancer by sentinel lymph node (SLN) mapping [53]. Safe and high photothermal conversion efficacy improves the broad optical absorbance spectrum for biphotonic diagnosis modality. Minimal damage of the normal surrounding cancer tissue enhances the efficacy for multimodel imaging [51,54].

3.10 Radionuclide imaging and therapy Radiopharmaceuticals are the combination of radionuclides and the pharmaceutical drug molecule developed for diagnosis or treating various diseases. A pharmaceutical molecule is labeled with a radionuclide for preferential localization in imaging techniques by emitting alpha, beta, and gamma particles on anatomic tissues. Radionuclides like technetium-99m, gallium67, 68, iodine123, 131, etc. have been used in radiopharmacy [49]. They show a strong impact in the field of cancer nanotechnology with some innovative radionucleotides like liposomes, dendrimers, quantum dots, and carbon nanotubes. Positron emission tomography (PET) and single photon emission computed tomography are two categories of radionuclide imaging. Site-specific passive tumor targeting and molecular affinity are the two basic mechanisms involved in radionuclide imaging for tumor diagnosis. First-generation nanocarriers are passively targeted and trapped in organs of the reticuloendeothelial system (RES), such as the spleen and liver. Second-generation nanocarriers are passively targeted by stabilization with PEGylated nanoparticles with enhanced permeability and prolonged circulation. The bioconjugated

Functionalized carbon nanomaterials for biomedical imaging

nanocarriers along with specific antibodies or peptides shown active targeted tumor specificity by molecular interactions. Radionuclide Iodine-131 emits beta type radiation used for the examination of “S” cluster tumor cells. Liposomal gamma imaging drug therapy monitoring is achieved by the radionuclides 99mTc, 111Inx, and 67Ga. 111 In-DTPAlabeled PEGylated liposomes are advanced encapsulated radionuclides for nuclear imaging [50,55]. Radionuclide imaging as various advantages like multifunctional and multimodel imaging, efficient target specificity at safe-level therapy, and low immunotoxicity. Radionuclide imaging has been applied with remarkable results for both preclinical and clinical imaging [55].

3.11 Multimodel imaging and therapy Multimodel imaging overcomes the limitations of the single model imaging with various merits. High-quality imaging and accurate diagnostic data are possible by combining MRI with PET and PA imaging system (Cu-rGO-IONP-PEG). Photosensitizer-loaded nano-graphene by π-π stacking is routed for synergistic therapy of multimodel imaging. Other novel multimodel imaging hybrids are PET-CT, PET-MRI, and SPECT-CT, which provide perfect picturization. The convenient approach in dual or multimodel imaging is the utility of diagnosis in a single probe. Multifunctional nanoparticles are engineered with ligand binding for multimodel imaging. General strategies applied for engineering this method are: (a) selection and fabrication of nanoparticles core; (b) shell structure synthesis; and (c) surface modifications. Fused imaging modalities SPECT-MRI/PET-MRI afford potentially high sensitive images. Recently, trimodal imaging probes have been developed, e.g., PET, MRI, and fluorescence imaging. Multimodel theranostics has vast potential advantages like high degree of internalization and ultrasensitivity. Well-organized interpretation of the biological and physiological visuals is possible. Due to its excellent profile, it is also applied for intraoperative imaging [50,56].

4. Carbon nanomaterial-based bioimaging using animal imaging system At present, the application of nanotheranostics has a smart role in diagnostics and therapeutics for various diseases. Biological imaging is the potential and unique identity of carbon nanomaterials which supports the early detection of diseases. Nanotheranostics release the therapeutic drug molecule by quantitatively monitoring the real-time response on targeted specific tissues. Powerful noninvasive techniques like radiolabeling of nanomaterials have been used for drug delivery monitoring. Imaging ability is achieved by using carbon nanomaterials as core materials. The animal imaging system uses nanomaterials for multifactorial diseases. Some of the nanoplatforms explored in

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biological assessments such as SWNT fluorophores in NIR fluorescence detection facilitate high throughput bioassays and immunoassays. CNTs have been intensively studied for multiple imaging models such as fluorescence, photoacoustic, Raman imaging, etc. MWCNTs are ultrasound contrast agents for large animal models such as pig, monkey, etc. In vivo trimodal imaging is performed using various novel hybrid nanomaterials [57–59].

4.1 Oncological bioimaging and radiopharmacy Biological imaging using carbonaceous nanomaterials shows greater and effective attention on cancer imaging. Since cancer is the second leading cause of death among diseases, early detection and timely therapy are of utmost importance. Advanced theranostics includes detection of tumor biomarkers by molecular diagnosis. Cancer cells are detected accurately by active targeting and passive accumulation by using probes. Molecular imaging is the method of depicting visual characterization and quantification of the biological processing at a cellular/molecular level. Currently, emerging molecular imaging techniques includes fluorescence, bio-luminescence, targeted ultrasound (US), molecular magnetic resonance (MRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging [58,60]. Tumor xenografted live mice showing SWNT Raman signals after intravenous administration of targeted SWNTs have been involved in the first in vivo tumor imaging via a carbon nanotube model. In the case of CNTs, drug carriers with doxorubicin are a common model by noncovalent interactions, and for hydrophilic drugs covalent binding is explored. Epidermal growth factor (EGF) is a targeting ligand selected for head and neck squamous carcinoma cells expressing EGF receptors. Regression of tumor growth was seen in mice treated with SWCNT-cisplatin conjugates. Intravenous injection of an SWCNT-cyclic Arg-Gly-Asp (RGD) peptide conjugate is a photoacoustic imaging contrast for malignant glioma tumors in mice which shows better imaging signals. Deep and disseminated tumors visuals are seen in ovarian cancer model used with SWCNTs. Recently, hybrid nanoplatform were developed for in vivo trimodal molecular imaging. Multimodel tumor ablation in mice has been studied using a C60-iron oxide nanoparticle functionalized by PEG and hybridized with folic acid [57]. In vitro dual-mode cellular imaging using human breast cell lines (T47D) and MTT viability assay (MDAMB-231 and T47D) has been determined by a hybridized 2D nanofiller GO-Fe3O4 aqueous suspension [61]. Luminescence imaging in mouse with persistent luminescent nanoparticles (PLNPs) showed excretion of α-fetoprotein during the growth of cancerous cells by peritoneal injection [62,63].

Functionalized carbon nanomaterials for biomedical imaging

4.2 Nanoplatform-based cardiovascular imaging Common cardiovascular disorders include congestive heart failure, myocardial infarction, hypertension, and cardiac inflammatory diseases. Potential application of carbonaceous nanoplatforms in the detection of chemical vapor deposition contributes to effective management. Nanoplatform animal models (both in vivo and in vitro) like Zr-based PET imaging in atherogenic ApoE mice by using dextran NPs functionalized with desferoxamine show prominent macrophagic plaques in the aortic vessels. Moreover, PEGylated gold NPs were 5-aminolevulinic acid photosensitized with porphyrin IX explored in bioimaging of atherogenic plaques in rabbits with atherosclerosis. Nanotheranostics has potential in terms of early diagnosis of CVD that concomitantly reducing mortality rate. Recently, intra-articular delivery of antisense oligonucleotides to chondrocytes in mice has been achieved by SWCNTs modified with PEG. A mouse angiogenesis model demonstrated by the administration of miR-503 bounded with functionalized CNTs reported reduced vessel formation [57,58,63]. SWNT fluorescence in NIR-short wavelength infrared range (SWIR) cameras provided visualization of the spatially magnified vascular anatomy of mice using IR-800 dye [64]. An atherosclerotic mice model was used for PET-CT imaging [65].

4.3 Neurological disorders bioimaging models Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease (HD) have been affecting globally. Despite the fact, degree of theranostics is lacking due to poor blood-brain barrier (BBB), penetration. PET, SPECT, MRI, and X-ray CT are some of the current detecting technologies for neurological problems. Nanomaterials are used as biosensing agents for biomarkers of neurological diseases. MWCNTs bioconjugated with AuNPs are electrochemical affinity biosensors that detect peptide biomarkers (Aβ40 and Aβ42) in the cerebrospinal fluid and brain tissues of AD rats. A novel nanocrystal, ceria and iron oxide, coated on mesoporous silica NPs functionalized with amino-T807 (PET tau tracer) and methylene serves as a diagnostic and therapeutic tool for Parkinson’s disease (PD) in mice and rats [58,66]. Stereotactic administration of MWCNTs in CNS directly delivering siRNA results in neuroprotective activity in mice and rats by the formation of a bio-corona over the surface of CNTs. Nanodiamonds provide a platform for neuronal growth, hybrids of graphene oxide, and silica nanoparticles (NPs) that promotes human neural stem cell growth with neuronal alignment [57].

4.4 Pulmonary bioimaging models Asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and pleural infections are the most common lung diseases. Moreover, pulmonary tuberculosis and lung cancer is one among wide spectrum of respiratory disorders. Even though nanoplatform

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bioimaging is quite difficult in terms of visualization, some researchers have developed novel nanosystems. Few animal models, such as an in vivo effect of COPD-induced lungs of mice after administration of superparamagnetic iron oxide NPs conjugated with biocompatible antibody, showed specific targeted macrophages [56,58]. Natural polymers such as gelatin and chitosan were used as nanocarriers for a pulmonary drug delivery system. Moreover, synthetic polymers like poly ethylene glycol, poly lactic-co-glycolic acid (PLGA), and poloxamers have also been used as pulmonary nanocarriers [67].

4.5 Hepatic bioimaging models Acute liver failure (ALF) is a globally challenging health issue characterized by hepatic cell necrosis. A carbonaceous nanoplatform provides multifunctional theranostic effects with increased specificity and bioavailability. Hepatocytic animal models include surgical and drug models in animals such as mice, dogs, and rabbits. Acetaminophen (APAP)-induced ALF is a widely used drug model for the experimental study of nanomaterials with appropriate clinical data. Carbon tetrachloride (CCl4)-induced ALF in an in vivo mice model is applied for fluorescence imaging of transplanted stem cells in the liver aided by quantum dots labeled with octa-arginine peptide, which may initiate an organ-specific accumulation imaging [68].

4.6 Biopharmaceutical analysis imaging models The unique identity of nanomaterials is in vivo imaging potentially applied in bioimaging functions coupled with a drug delivery system for evaluating biomedical parameters such as pharmacokinetic, pharmacodynamic, and toxicological imaging by various animal models [57,69]. Analyzing the immune system response is a key step in biocompatibility assessment, since functionalized carbon nanomaterials are immunostimulators. Both GO and CNTs have direct effects on macrophages. Subcutaneously implanted GO triggers an Ab-Ag reaction in mice. Single molecular tracking in living cell is the best model for investigating biopharmaceutical events at cellular level. This model is applied for tracking various receptors’ binding mechanism, plasma membrane lipids, aquaporins, and lipidraft diffusion dynamics. Real-time biodistribution evaluation significantly achieves a smart stimuli-responsive drug delivery process mechanism. Photodynamic activity of carbon 60 doped with iron oxide nanoparticles-PEGylated (C60-IONP-) has been studied by an in vivo murine tumor model [70].

5. Conclusion Carbon nanomaterials have been used for multifactorial applications. These nanomaterials have been utilized as drug delivery carriers and for imaging applications due to their physicochemical properties, biocompatibility, and surface derivatization. Carbon

Functionalized carbon nanomaterials for biomedical imaging

materials with versatile surface properties, size, shape, and functionalization capability provide the possibility of having multifunctional drugs in a single dose. Several chemical modification strategies have been developed concerning the toxic effect of carbon nanomaterials in the biological system for diagnostic applications including drug delivery and tissue engineering applications.

Acknowledgments The authors gratefully acknowledge the Department of Science and Technology (GoI), New Delhi supported National Facility for Drug Development for Academia, Pharmaceutical and Allied Industries (NFDD) (Ref No. VI—D&P/349/10-11/TDT/1 Dt: 21.10.2010) and National Facility for Bioactive Peptides from Milk (NFBP) Project (Ref No. VI—D&P/545/2016-17/TDT; Dt: 28.02.2017).

Conflict of interest The authors do not declare any conflict of interest.

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CHAPTER 17

Current advancement and development of functionalized carbon nanomaterials for biomedical therapy Shashi Chawla and Prateek Rai Department of Chemistry, Amity Institute of Applied Sciences, Amity University, Noida, Uttar Pradesh, India

1. Introduction Richard P. Feynman, Physics Nobel Laureate, gave a lecture in 1959 during the American Physical Society Meeting which was titled “There’s Plenty of Room at the Bottom” which gave inspiration to the scientific community about the future prospects in the field of nanotechnology [1,2]. Feynman said: A friend of mine (Albert R. Hibbs) suggests a very interesting possibility for relatively small machines. He says that, although it is a very wild idea, it would be interesting in surgery, if you could swallow the surgeon. You put the mechanical surgeon inside the blood vessel and it goes into the heart and looks around. It finds out which valve is the faulty one and takes a little knife and slices it out. Nanomaterials, defined in very layman terms as materials having at least one of its dimensions in nanometer scale, i.e., 1–100 nm (1 nm ¼ 1  109 m) [3–7]. The term “nanotechnology” was coined by Norio Taniguchi in 1974 [8]. Nanotechnology is based on the practice of manipulating a material’s characteristics at the atomic scale. It can be considered as a borderline between atoms and molecules and the macro world (see Fig. 1) [2,9–12]. Since their inception, nanomaterials have been part of a large amount of research, and their applications can be seen in numerous fields of science and engineering (see Fig. 2) [13–16]. Among their various important applications, the ability of nanomaterials and nanotechnology to influence healthcare systems is widely acknowledged as astonishing [17–21]. In the past few years, the employment of nanomaterials in biosensing technologies has grown enormously [22–27]. It has increased our ability to create molecules that only respond when they are bonded to a particular biological cell. For instance, nanowires [28,29] are used in the detection and tracking of various cells. They are coated with target-specific substances that only get attached or respond when in contact with a particular protein. The identification and labeling of the target cell are done with the study of change in the conductivity of the nanowire when it gets attached to the

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Fig. 1 Size comparison of nanomaterials [2,9].

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target protein molecule [30–34]. Drug delivery has always been a peculiar task in medicine and health care. Bioincompatibility, poor stability, and solubility in the biological environment, degradation, and side effects on other biomolecules are some of the major drawbacks of classical drug delivery systems. Nanomaterials generates a possibility of a more efficient target delivery of drugs which can be credited to their functionalization abilities, which can relate to their particle size, types, surface, and other properties [35–37]. Moreover, they can be designed in a way that they can exhibit biocompatibility within a biological environment. A large number of nanotechnology-based materials have shown various biomedical applications such as polymeric materials, lipid-based materials, metal-based materials, and others. Among these classes of nanomaterials, carbon nanomaterials have proved to be a highly beneficial class of which can be attributed to their unique structural and chemical properties. Carbon nanomaterials have a unique ability to cross cellular membranes thanks to their nanosized dimensions and high surface area. Herein, the focus is targeted on the biomedical uses of carbon nanomaterials and their specific properties which allow them to perform these functions [38].

Current advancement and development of functionalized carbon nanomaterials

2. Effectiveness of carbon nanomaterials in biomedical therapy From nanodiamonds to carbon nanotubes (CNTs) and graphene, carbon nanomaterials are a class of nanomaterials suitable for utilization in a large range of consumer and industrial applications [39–41]. In recent times, carbon nanomaterials have gained attention from the scientific community due to their potential application in biomedical therapy and diagnostics [42–46]. The distinctive chemical properties of carbon and its ability to exist in a diversity of possible nanostructures are major reasons for its broad application in commercial and medical uses [47]. The existence of different carbon-based nanomaterials may be due to variations in the hybridizations from sp. to sp3 [48]. The classical 2D hexagonal lattices of many carbon nanomaterials are based on sp2 hybridization having trigonal planar geometry. The cubic crystal structure of the diamond is due to the sp3 hybridization, where bonds are arranged in a tetrahedral arrangement. The transition from sp3 to sp2 carbons brings about a plethora of other carbon structures [49]. The ratio of sp/sp2/sp3 hybridization in different carbon nanomaterials determines the formation of dimensionally distinctive nanostructures. Most frequently, the classification of carbon nanomaterials is done on the basis of dimensional difference in their structures (see Fig. 3). This same ratio also decides the other properties, including their mechanical strength and electrical and chemical characteristics, which in turn contribute to the advantages of carbon nanomaterials toward different applications [49]. In terms of biomedical applications, the freedom to tune the dimensions of carbon nanomaterials and the potential to functionalize them make these materials a preferable therapeutic tool. In recent years, it has been discovered that carbon nanomaterials can directly influence the biological activities of living matter. For example, carbon nanomaterials are found to be able to stimulate the production of reactive oxygen species (ROS) when internalized in cancer cells [50].

0D Carbon Dots

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Fig. 3 Classification of carbon nanomaterials based on dimensions.

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Drug delivery systems refer to the designing of a biomedical tool which is capable of delivering drugs to a target molecule specifically and to enable the proper interaction of drugs with the target. Carbon nanomaterials have been shown to have great potential in novel drug delivery systems. The conjugation of drugs with these nanomaterials improves the drug absorption, distribution, and elimination. It also enables the function of bioimaging by which the interaction of the drug with biomolecules inside the body can be monitored and visualized [51,52]. Bone tissue engineering is another branch of biomedical therapy in which the use of nanomaterials is considered. Bone tissue engineering and tissue regeneration, both require the use of biological tools that can substitute the ill-functioning or infected tissues. Carbon nanomaterials have potential application in this field due to their excellent mechanical properties such as high strength, fatigue resistance, and biocompatibility [53–55]. Chemical functionalization is an essential step to make these carbon nanomaterials a more adaptable, multifunctional, better-performing theranostic aid. Moreover, it helps to reduce toxicity, increase water solubility, and to generate various specific functions. These functionalizations are based on various chemical transformations such as amidation, esterification, hydrogenation, halogenation, and oxidation. The use of carbon nanomaterials ranges from biosensing, effective carriers for targeted drug delivery systems to stem cell therapy and tissue regeneration [47,49,56].

3. Carbon nanotubes CNTs are one of the most prominent inventions in the field of nanotechnology whose applications ranges from capacitors and transistors, to nanomedicines and biosensors [49,57–59]. These applications are due to their inherent characteristics such as light weight, small size, high tensile strength, and high electrical and thermal conductivity. CNTs are a part of the fullerene family, which was discovered by Kroto, Curl, and Smalley in 1985 [60], although CNTs were developed in 1991 by a Japanese scientist, Iijima [61], by the simple arc-evaporation method [62]. Structurally, CNTs can be thought of as graphene sheets that are rolled upon themselves which makes them look like cylindrical or tubular structures made of sp2 hybridized carbon atoms. These tubes are nanometers in diameter and can be several millimeters in length [49,57,61,63,64]. CNTs are categorized mainly into two types on the basis of the number of tubes present: single-walled CNTs (SWCNTs), which are made up of a single graphene sheet rolled upon itself having an approximate diameter of 1–2 nm and multiwalled CNTs (MWCNTs), which are composed of multiple layers of rolled graphene sheets ranging from 2 to 50 nm (see Fig. 4) [49,57,65–68]. CNTs are already a part of a large number of biomedical applications like drug delivery systems, gene therapy, cancer therapeutics tools, tissue regeneration, biosensing technology, extraction and separation of chiral

Current advancement and development of functionalized carbon nanomaterials

Fig. 4 Structure of CNTs.

drugs, etc. The most prominent features that make them capable of these applications is the presence of a high surface area and the ability to adsorb or conjugate with a range of theranostic and diagnostic agents such as drugs, genes, antibodies, biomedical sensors, and vaccines [69–72]. Despite their promising features, CNTs in their original form have been found to aggregate in bundles because of van der Waals attraction between them, and are not easy to manage during their interaction with biomolecules due to their low solubility in an aqueous environment. Thus, functionalization is often necessary to tune the properties of CNTs according to our requirements. These functional modifications are done through covalent attachments of functional groups like dOH, dCOOH, etc. (see Fig. 5) as well as through some noncovalent attachments like coating a CNT with a surfactant molecule or polymer such as ethylene glycol (see Fig. 6). These functionalizations

Fig. 5 Covalent functionalization of CNTs.

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Fig. 6 Noncovalent functionalization of CNTs.

benefit CNTs in improving their biocompatibility and solubility, and lowers their toxicity as well. After this, they become hydrophilic and are ready to be conjugated with any drug or biomolecule for a particular therapeutic function [58,73–78]. • Functionalized CNTs for novel drug delivery systems CNTs are being largely used nowadays as drug carriers for target-oriented delivery of various pharmaceutical elements. Their distinctive hollow interior and presence of functional groups on their surfaces allow them to be loaded with drugs inside and on their surfaces as well [49,57,73,74]. Additionally, their ability to penetrate the cells and keep the drug attached without being metabolized by the body during its transport makes them more efficient and accurate vehicles for drug and gene delivery (see Fig. 7). Recently, efforts have been made to use CNTs for drug delivery in cancer therapy as well, which presently involves therapy through radiation, chemotherapy, and surgery.

Fig. 7 CNTs used in drug delivery.

Current advancement and development of functionalized carbon nanomaterials

The present methods of treatments are highly painful and have adverse side effects such as the killing of normal body cells in addition to cancer cells. CNTs have shown potential in cancer therapy due to their target specificity and lower dosage [37,71,79–82]. • Functionalized CNTs in bone tissue regeneration In order for a material to be chosen as a scaffold, it is essential to evaluate its biocompatibility, long-term safety, and degradability and its proper mechanism to biomimic the particular function. CNTs are being utilized as bone regenerative tools (see Fig. 8) because of their excellent strength, elasticity, and chemical stability with fatigue resistance properties. They can be used as scaffolds in which they provide a controlled release of growth factors and at the same time provide a place for the cells that form new bones to grow. In addition to these properties, it has been pointed out that scaffolds with good electrical conduction are more desirable since electric stimulation can increase cell growth [83–91]. • CNTs as biosensors A biosensor is an analytical tool capable of detecting an analyte which is attached to a biomolecule in a biological environment. The application of CNTs in biosensing technology is a very exciting improvement in the biomedical field [92–98]. For example, presently, blood glucose monitoring methods for diabetes patients involve the insertion of a needle under the skin to check the glucose levels. It was analyzed that 70% of these total reading shows an error of 10% [74,99]. In an attempt to find some improvements, some researchers conjugated CNTs with glucose-oxidase biosensors which can be made to interact with the body fluids such as saliva. It was found that the presence of a highly accessible electrochemical surface area and large electrical conductance help to produce more accurate results than the biosensor used alone, along with the benefit of eliminating the uncomfortable practice of finger pricking [94,96,100–103]. • Limitations in the use of CNTs in biomedical applications CNTs are part of a very large amount of research in the pharmaceutical and medical domains, which can be credited to their exceptional characteristic properties, but

Fig. 8 CNT as a scaffold for bone tissue regeneration.

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concerns remain [104]. Toxicity is a major concern related to CNTs and studies are being carried out to understand their cytotoxic effects and ways to reduce these [3,105–112]. In addition, the biodegradability [56,113] factor is important for maximizing the efficiency of CNTs to be used in biomedical therapy. Hence, it can be summarized that there are four major concerns in using CNTs as part of therapeutics: biocompatibility, solubility, biodegradability, and toxicity.

4. Carbon nanofibers Carbon nanofibers (CNFs) are often considered as a special form of CNTs in which the graphene layers are stacked upon themselves with a certain orientation with respect to the fiber axis (see Fig. 9). Different types of CNFs are categorized based on the angle (α) between the graphene layers and the fiber axis (see Fig. 10). In CNFs, the graphene layers are not continuous as in CNTs and are arranged in a random fashion [114–118]. Their therapeutic applications are similar to those of CNTs, apart from some exceptional applications, such as in deep brain stimulation [119,120]. • CNFs in neural applications Neural interfaces are used as links for communication between a malfunctioning nervous system and the outside world. CNFs have recently been used for the manufacturing of devices which can act as neural interfaces, due to their good electrical conductivity. They are widely used as interfaces to be applied as tools to input electrochemical signals for the stimulation of a specific region of the brain to restore sensing processes and to improve neural activities (see Fig. 11). For this process, CNFs are usually coated with polypyrrole films [121,122]. CNFs show excellent potential for a neuro-chemical interface due to their conical nanostructure composed of graphite layers, which makes them stable in a biological environment. In addition, they have large surface to volume ratios, with surfaces that can be functionalized with a huge number of organic functional groups and

Fig. 9 Structural difference between CNTs and CNFs.

Current advancement and development of functionalized carbon nanomaterials

Fig. 10 CNFs’ characteristic structure.

Fig. 11 CNFs as a neuronal interface.

active moieties that make them capable of biochemical sensing. This treatment is used on patients with neural disorder problems such as Parkinson’s disease, epilepsy, and Alzheimer’s disease [123–126]. CNFs are also used in bone regeneration techniques as scaffolds due to their excellent mechanical properties compared to polymer-based scaffolds [121,127–129]. • Limitations in the use of CNFs in neural applications For the clinical application of CNFs in this field, the following issues must be studied thoroughly: (a) the nucleation and growth mechanism of CNFs are still a topic of concern, which his why the yield of CNFs in synthesis is not satisfactory; and (b) due to their surface properties, some unwanted and toxic substances may get conjugated with them and could be transported to the cell, causing it to malfunction. Therefore, the selectivity of CNFs is also a major issue [121,122,130,131].

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5. Nanodiamonds Carbon nanodiamonds (NDs) are a class of carbon-based nanomaterials which are defined as single crystal diamonds with high physical and chemical properties [132–136]. They can be understood as a nanoscopic version of tetrahedral sp3 carbon atoms with a diamondlike structure (see Fig. 12), while CNTs and fullerenes have an sp2 configuration. They are exceptional because they inherit properties of diamond such as hardness and superthermal conductivity, and also have the advantages of nanomaterials such as high surface area and biocompatibility [137,138]. In addition, the synthesis of NDs is considered inexpensive, and can be done through the detonation of carbon-containing explosives in a closed chamber. The yield of the synthesis depends largely on the heat capacity of the cooling medium (water, air, CO2, etc.) inside the detonation chamber (see Fig. 13) [133,139–143]. Structurally, NDs have a diamond-based internal core, i.e., sp3 carbon atoms, and graphene-like external shell, i.e., sp2 carbon atoms having hanging bonds

Fig. 12 Structure of NDs.

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Fig. 13 Synthesis of NDs.

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Current advancement and development of functionalized carbon nanomaterials

which can be bonded with different functional groups (see Fig. 12) [144–148]. The surfaces of NDs can be chemically conjugated with carboxylic acid, hydroxyl, anhydride, and epoxide groups, which makes them soluble in water [149–153]. These functionalized NDs have the capability to be complexed with water-soluble drugs like dexamethasone [153,154] (an antiinflammatory agent) and purvalanol A [153,155] (a drug for liver cancer) [156]. NDs are an ideal candidate for drug and biomolecule carriers, which may be due to their large surface area and surface functionalities [50,134,139,153,156–169]. NDs show great potential as carriers for hydrophobic drugs, as they can enhance a drug’s dispersibility in the physiological environment [153,170]. Additionally, NDs have a lot of lattice defects in the diamond core due to their production procedures [133,153,171–173]. These lattice defects are utilized as fluorescence centers for bioimaging and labeling. • Application of NDs in optical bioimaging Bioimaging is used to visualize body parts, cells, tissues, or organs for therapeutic diagnosis and other clinical studies. The defects and impurities in the lattice structure of NDs provide them with exceptional optical properties. These vacancies act as color centers and exist in a large number of varieties; as a result, the emission covers almost the visible spectrum entirely. NDs thus can be conjugated with drugs and other molecules and released into the body, after which their interaction with the biological environment can be studied with excitation from radiation of almost any wavelength (see Fig. 14) [133,174–180]. • Antibacterial applications of NDs The goal of any antibacterial or antimicrobial agent is to prevent bacterial growth and its reproduction capacity. It has been found that NDs possessing surfaces which are partially oxidized or negatively charged and having an acid anhydride group attached to them show an antibacterial property [153]. Moreover, the conjugation of proteins on the surfaces of NDs enhances their antibactericidal property. For example, the antibactericidal property of NDs is utilized against Gram-negative bacteria, Escherichia coli [181–183].

Fig. 14 Bioimaging with NDs.

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NDs, in this case, are functionalized with a carboxylic acid group. The nanodiamond gets attached to the bacterial cell wall and destroys it [182,184–187]. • Limitations NDs show great potential for use in biomedical therapeutics but further research is required to make them more efficient [139,153]. There are certain drawbacks related to its applications, including: (a) the conjugation process of NDs with an active pharmacological substance is quite a complex process and the solvents used in the synthesis of NDs are difficult to eliminate [188,189]; (b) the traditional method used for their production requires very high pressure and temperature [190]; (c) NDs bounded with proteins may result in alteration of the protein structure’ [189,191,192] and (d) aggregation of NDs is a major issue due to their very small size of less than 50 nm [193].

6. Carbon dots Carbon dots are the newest addition to the family of carbon nanomaterials which have attracted enormous attention from the scientific community due to their special advantages such as facile synthesis procedure, simple surface functionalization, excellent water solubility, low toxicity, and unique photochemical properties [194–200]. The size of carbon dots is less than 10 nm. They can be used as an alternative to conventional inorganic quantum dots such as PbS and CdSe quantum dots [195,201–207]. Carbon dots are more biocompatible and there is less concern about their environmental effect, toxicity, and cost of production compared to other quantum dots [207–213]. It is reported that carbon dots have a quasispherical structure which is generally comprised of amorphous cores of sp2 hybridization, although some studies show the presence of an sp3 diamond-like structure as well (see Fig. 15) [197,214–216]. The rim of a carbon dot’s structure contains reactive groups which make it suitable for the possibility of functionalizations [217,218]. Water-soluble carbon dots can be developed through a very efficient

Fig. 15 Functionalized carbon dot.

Current advancement and development of functionalized carbon nanomaterials

procedure using Setcreasea purpurea boom [219,220]. The high water solubility of carbon dots is an exciting feature which has great significance for materials used in biological conditions [221,222]. • Carbon dots in the efficient delivery of drugs and fluorescence imaging Carbon dots have proved to be efficient in carrying some anticancer drugs [223–227] like oxidized oxaliplatin (Oxa), which is conjugated on its surface. In addition, the fluorescence property of carbon dots enhances therapy performance. It also provides the facility to control the optimum dosage of a drug and minimizes the side effects of anticancer drugs [228,229]. Similarly, another anticancer drug called cisplatin (IV) prodrug is conjugated covalently onto the carbon dot surface which develops into a theranostic system that displays an enhanced tumor-inhibition efficacy with minimal side effects [230,231]. Additionally, the fluorescence emission properties offer another advantage of bioimaging, and the magnetic properties of carbon dots can also be used for magnetic resonance imaging (MRI) [197,205,207,216]. For example, in a study of a chemotherapeutic drug doxorubicin (DOX), it was found that when the drug is loaded inside a hollow carbon dot, it enables the possibility of rapid internalization of the drug by the cells and can exhibit pH-controlled delivery of the drug. It was confirmed from fluorescence microscopy that the drug is internalized into the cytoplasm [207,208,232–234]. • Limitations Although smaller size is usually considered a plus point, for carbon dots it has been found that to enhance their functionalization, stabilization in physiological environments, and biocompatibility, the carbon dots must be covered with additional layers or shells so that their size falls in the range of 10–30 nm [211,217,235–237]. Another issue that needs to be overcome by the scientific community is to increase the luminescence of carbon dots as it still remains below 50% in comparison to that of other quantum dots [238].

7. Graphene Graphene is a hexagonal array of carbon atoms in a single layer of the graphite structure. It is a two-dimensional planar array of sp2-hybridized carbon atoms. Each of these carbons forms four bonds: three sigma bonds (one each with three neighbors) and one π-bond that is oriented out of the plane. The structure in graphene has a hexagonal pattern resulting in the formation of a honeycomb crystal lattice [239,240]. The Scotch tape method (mechanical cleavage), graphite oxide reduction, graphite fluoride reduction, liquidphase exfoliation, intercalation, and compound exfoliation are some of the methods to prepare graphene from graphite [241]. Graphene has high thermal conductivity, high intrinsic mobility, and a large specific surface area. Due to the absence of oxygen atoms, graphene is considered hydrophobic [239]. Graphene oxide (GO) is a hydrophilic derivative of graphene. It is hydrophilic due to the presence of oxygen atoms bound to carbon.

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COOH OH HOOC

OH O

O

O

O O

OH OH

O

OH

OH HO OH

Graphene

Graphene oxide

Reduced Graphene oxide

Fig. 16 Graphene derivatives.

Several functional groups such as hydroxyl, carbonyl, epoxide, oxygen, and phenol groups are present on the surface of GO. The sp3 (aliphatic) and sp2 (aromatic) domains are present on GO, which facilitates the interactions at the surface of GO (see Fig. 16) [239,241–245]. Reduced graphene oxide (RGO) has an intermediate structure between the highly oxidized GO and the ideal graphene sheet (see Fig. 16). It is prepared by chemical or thermal reduction of graphite oxide or graphene oxide [246,247]. Reducing agents such as sodium borohydride, L-ascorbic acid, hydrazine hydrate, and hydrazine are used for the preparation of RGO from GO [247]. The functionalization of GO creates surface sites for covalent and noncovalent interactions required for biomedical applications of graphene-based nanomaterials (GBNs). Through functionalization, biocompatibility, selectivity, and solubility are improved [248]. Noncovalent functionalization of GO improves biocompatibility, binding capacity, dispersibility, and sensing [245]. The formation of hydrogen bonds between water molecules and polar functional groups on the GO surface creates a stable GO colloidal suspension. Such noncovalent interactions help in potential biomedical applications of GO [249,250]. • Graphene-based materials in therapeutics Both reduced and oxidized graphene oxides are suitable for therapeutic applications and drug delivery. In comparison to other carbon-based materials, the main advantage of using GO is its colloidal and aqueous stability. A large surface by volume ratio and distinctive physiochemical properties make GO suitable for biosensing, imaging, cancer therapy, and a variety of other biomedical applications [249,250]. Graphene, GO, and RGO are suitable for theranostic therapy applications. This is due to the fact that they have been thoroughly investigated for their use in photo-ablation as photosensitizing agents, as they produce heat upon irradiation. In biomedical applications, GBNs are used for anticancer therapy, gene therapy, and drug delivery [251–255]. In therapeutics, GBNs are used as carrier molecules. A high specific area, π-π interactions, and attraction due to electrostatic or hydrophobic interconnections of GBNs help in installation of drugs with potency and high efficacy [244,256]. Chemotherapy drugs like paclitaxel and methotrexate packed on GO by amide connections or by π-π stacking exhibited a tremendous therapeutic effect on cancer cells found in lungs and breasts. As a result, hindrance in tumor growth was observed of 66%–90% [257–259].

Current advancement and development of functionalized carbon nanomaterials

Ibuprofen is being used as a nonsteroidal antiinflammatory drug (NSAID). When conjugation of ibuprofen with GO (functionalized by chitosan) linked by amide bonds was carried out, this functionalized GO showed 20% higher biocompatibility compared to GO sheets for human acute lymphoblastic leukemia cell lines (CEM) and Michigan Cancer Foundation 7 cell lines (MCF-7) [259]. • Graphene in phototherapy Graphene is considered firmly for targeted cancer cells phototherapy with the help of nanomaterials. GBNs are an ideal candidate for phototherapy because GO possesses excellent properties such as lower cost, large specific surface area, and higher photothermal conversion [260–266]. • Limitations The cytotoxic behavior of materials derived from graphene is a matter of study as some scientific communities, such as the European Scientific Community [267–269], have included graphene in their lists of hazardous materials [270–273]. The graphene family of nanomaterials has another disadvantage in that it differs in atomic composition from one material to another. Since it has been found that graphene-based nanomaterials can stay in the body for a long time, their long-term toxic effects must be studied [274]. In addition, in the synthesis of graphene-based materials, a large number of chemically hazardous and toxic substances are used and due to the planar nature of graphene, these contaminants may be present on the surface, which can hinder the interaction of these materials with biosystems [275,276].

8. Fullerenes From their inception, fullerenes are a part of a large number of researches in the biomedical field due to their size, dimensionality, electronic configuration, and hydrophobicity [277–281]. Their unique cage-like [282] structure (see Fig. 17) is also a critical advantage when it comes to studying their therapeutic applications [283,284]. Fullerenes are

Fig. 17 Fullerene derivatives.

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entirely composed of carbon atoms that can exist in the form of sphere, ellipsoid, or tube. Spherical fullerenes are famously referred to as buckyballs. One of the most magnificent properties of fullerenes is their high symmetry [285,286]. They were discovered in 1985 by Kroto et al., for which they were awarded the 1996 Nobel Prize in Chemistry [287,288]. Fullerenes can contain 60–70 carbon atoms with a diameter of about 1 nm. They have poor solubility in aqueous solvents [289,290] coupled with a disadvantage that they form aggregates [291]. However, this issue is resolved to a great extent by chemical conjugation to functionalize fullerenes, which enables them to dissolve in the polar solvents as well [292–294]. • Fullerenes as antiviral agents The replication rate of human immunodeficiency virus (HIV) can be reduced by the use of several antiviral agents which are effective in controlling, or in some cases delaying, the arrival of acquired immunodeficiency syndrome (AIDS). Fullerenes are capable of fitting inside the hydrophobic core of HIV proteases. Fullerenes and their functionalized derivatives have proven to exhibit antiviral properties which can have a strong influence on the biomedical treatment of HIV infection [279,295–298]. The first fullerene derivative that showed anti-HIV activity was reported in 1993. These antiviral properties are based on fullerenes’ numerous biological characteristics which include unique molecular architecture and antioxidant activity [299]. Dendrofullerene (see Fig. 17) has shown the highest anti-HIV protease activity [300]. • Fullerenes as neuroprotective therapeutics Carboxylic acid derivatives of fullerenes have been observed to have properties that can be employed in their use as neuroprotective agents (see Fig. 17) [301,302]. In 1997, Dugan et al. reported an article on “carboxyfullerenes as neuroprotective agents” [303]. They suggested that carboxyfullerenes are efficient against two forms of neural apoptosis. In addition, with the use of neuroprotective characteristics of fullerenes, the attack of  radical species such as superoxide (O 2 ) and hydroxy (OH ) on lipids, proteins, DNA, and other biomolecules can be restricted [277,278,304,305]. • Fullerenes exhibiting antimicrobial activity It has been reported that fullerenes have the capability of antimicrobial properties against many microbes such as Candida albicans and Bacillus subtilis [306–309]. • Limitations The issue of cytotoxicity of fullerene and its derivative is still a matter of concern for its use in biological systems. Even now, a large amount of research is required to understand the toxicity of each and every derivative. Secondly, the mechanism of the interaction of fullerenes with the biomolecules is still not clear. The optimal amount of solubility which is needed for a material in the biological system is also a point of issue for fullerenes, although it is somehow managed with the help of chemical functionalizations [310–313].

Current advancement and development of functionalized carbon nanomaterials

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Section E Functionalized carbon nanomaterials for bio-barcodes for clinical tests

CHAPTER 18

Functionalization of carbon nanotubes: A multifaceted and upcoming diagnostic tool in the clinical domain Shikha Gulatia, Nandini Sharmaa, and Kartika Goyalb a

Department of Biological Science, Sri Venkateswara College, University of Delhi, Delhi, India Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India

b

1. Introduction Contrary to popular belief, nanoscience wasn’t born in the 20th century from the minds of those such as Richard Feynman, but has been practiced since time immemorial in the form of dyes on monument windows, the Lycurgus Cup of Rome in the 4th century, ancient nanomedicine of Indian culture, etc. However, the form of nanotechnology that is seen in today’s scientific world is very different from the starting point of this domain. This scientific arena of utilizing formulations at the nanometer scale, which is a billionth of a meter (10
9 m), owes its terminology to the scientist Norio Taniguchi, who coined the term “nanotechnology” in 1974 [1]. Thus, nanomaterials are substances having at least one dimension in the nanoscale that renders them superior in function as well as structure. Nanomaterials having only one dimension in the nanometer scale include surface coatings, thin layers, and films, while the ones having two dimensions in the nanoscale involve nanofibers, nanowires, and especially nanotubes. The last dimensional classification entails all three parameters in the nanoscale that results in the formation of nanoparticles, nanospheres, nanorings, etc. Due to their unique size, nanoformulations develop a set of distinctive properties like exceptionally high surface area to volume ratio, chemical reactivity, quantum confinement, superparamagnetism, and many more, which render them better and more energy-efficient alternatives to their counterparts. Not all formulations at the nanoscale exhibit optimum properties which can be readily applied in the biomedical domain, but one type of nanomaterial that possesses highly promising properties and can be easily obtained for extensive research and applications is the carbon nanotube (CNT), which is the focus of this chapter.

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00010-8

Copyright © 2023 Elsevier Ltd. All rights reserved.

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The domain of CNTs was first discovered by Iijima [2], by employing the technique of transmission electron microscopy to detect the occurrence of these nanomaterials. Nanotubes, which are a promising category of nanomaterials, can be synthesized from various starting materials like boron, molybdenum, etc., but the most well-researched and diversely functional version is of nanotubes made of carbon. CNTs can be characterized as graphite sheets that are rolled in such a way to form open-ended or seamless cylinders with diameters up to 100 nm and lengths in micrometers, possessing a high aspect ratio. They can be considered as derivatives of both carbon fibers and fullerenes, and are classified into two types based on the numerical value of layers present: singlewalled carbon nanotubes (SWCNTs), which possess only one graphene of diameter ranging between 0.4 and 2 nm, with a conformation of hexagonal packed-bundles, and multiwalled carbon nanotubes (MWCNTs), which comprise of more than one graphene sheet cylinders, with diameters between 1 and 3 nm [3]. Their distinctive attributes encouraged extensive research in developing them as applicative mediums in various biomedical areas, e.g., therapeutics, drug delivery, and diagnostics, but their inadequate solubility, dispersibility, bundling effect of accumulation, and substantial toxicity inside living systems made them dysfunctional and inapplicable for such purposes. Therefore, to open the avenues of bio-applications for CNTs, several strategies were developed in order to make them more functional, which are referred to as functionalization (also called surface engineering) techniques. These procedures took advantage of the high surface area of CNTs and modified their surface properties by different chemical reactions, to overcome their disadvantages and make them more functionally efficient in terms of biocompatibility, dispersibility, reduced toxicity, etc. The functionalization strategies consist of techniques based on both covalent and noncovalent type linkages between nanotube surfaces and biological moieties, and are discussed in detail in the upcoming sections of this chapter. Functionalization grants many beneficial properties to CNTs, such as easy bioavailability, elasticity, photoluminescence, high mechanical strength, thermal and electrical conductivity, nonimmunogenicity, and deeper cell membrane penetration, that are exploited in wide-ranging applications, such as biosensing, bioimaging, cancer therapeutics, and drug delivery, to name a few (Fig. 1). In this chapter, the biomedical applications of FCNTs, using their multipurpose physicochemical attributes, are discussed thoroughly along with a background of their synthesis and functionalization strategies, giving an overview of FCNTs as promising bio-applicable mediums, especially as diagnostic tools in the clinical domain.

Functionalization of carbon nanotubes

Fig. 1 Wide-ranging biomedical applications and advantages of FCNTs.

2. Carbon nanotubes (CNTs) CNTs belong to a subfamily of bucky balls or fullerenes and are conceived as sp2hybridized distinct allotropes of carbon, having a CdC bond distance of around ˚ . These seamless rolled-up graphite cylinders are hexagonally arranged in a honey1.4 A comb lattice with distinctive qualities—for example, nanosized dimensions of diameter, high aspect ratio, large surface area, ultralightweight body, rich surface chemistry, exceptional thermal and electrical conductivities, neutral electrostatic potential, high drug loading capacity, and large mechanical strength. Such advantageous properties make them highly scientifically attractive and render them as potential candidates for many biomedical purposes, especially diagnostics. These third allotropes of carbon have a length-to-diameter ratio of approximately 2,80,00,000:1

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and each CNT is distinct from the other because of the number of carbon atoms, such as C20, C30, C70, etc., where every individual member is referred to as “graphene” [4]. The strength and flexibility of CNTs make them of potential use in controlling other nanoscale structures, which suggests they are an upcoming novel class of materials in nanotechnology.

2.1 Structure and types of CNTs CNTs come in two principal forms and this classification is based on the structure of their walls. (i) Single-walled carbon nanotubes (SWCNTs) comprise a unilayer graphene sheet rolled into a closed cylindrical model, and are arranged in a hemispherical array of networks made of carbon that are present in the single graphitic sheet. The dimensions of SWCNTs range from 0.4 to 3.0 nm in diameter and 20 to 1000 nm in length, with further distinctions based on the arrangement of carbon atoms into categories like zigzag arrangement, armchair arrangement, etc. Their remarkable electrical, chemical, and mechanical properties change with the degree of chirality present in the entire arrangement. (ii) Multiwalled carbon nanotubes (MWCNTs) generally tend to have around three to five sheets of graphene rolled and arranged to form a single multilayered nanotube, having dimensions ranging from 1 to 50 μm in length and 1.4 to 100 nm in diameter. An important subsegment of these are the double-walled carbon nanotubes (DWCNTs), which are morphologically related to SWCNTs but have exactly two concentric graphene sheets coaxially placed, which increase their stability, both thermally and chemically. Another subsegment of multiwalled CNTs occurs when only three graphene sheets, which are concentric, are arranged around one axis, which are consequently referred to as triple-walled carbon nanotubes (TWCNTs). The basic structures of both kinds of CNTs are portrayed in Fig. 2. Apart from the previously mentioned characteristics of SWCNTs and MWCNTs, a comparative and in-depth analysis of their properties is given in Table 1.

2.2 Synthesis techniques for carbon nanotubes There are five major approaches by which CNTs, both SWCNTs and MWCNTs, can be synthesized, which are: a. carbon-arc discharge; b. laser ablation; c. chemical vapor deposition; d. flame synthesis; and e. spray pyrolysis.

Functionalization of carbon nanotubes

Fig. 2 Carbon nanotube structures and types.

Table 1 Differences in properties of SWCNTs and MWCNTs. S. no. Single-walled carbon nanotubes

1. 2. 3.

4. 5.

6. 7.

8.

Multiwalled carbon nanotubes

Possess only one layer of graphene Possess multiple layers of graphene Require catalysts for synthesis Can be produced without catalysts Chances of occurrence of defects are higher Chances of defects occurring during during functionalization functionalization are low, but once formed, they are difficult to improve Purity is comparatively poor Purity is comparatively higher Easier process of bulk synthesis Tedious bulk synthesis as proper control overgrowth and the atmospheric condition is required Tend to get less accumulated inside the Tend to get more accumulated inside the body body Easy process of characterization and Complex structure means that evaluation characterization and evaluation processes are difficult Can be twisted easily and are very pliable Cannot be twisted easily due to complex formulation, so are less pliable

Among these, the three methods that are most widely employed as well as reported in the literature, due to the fact that they make stable CNTs, are as follows. • Chemical vapor deposition method: Vaporized reactants react chemically and form a nanomaterial product that is deposited on the substrate. The various prerequisites reported as crucial to this method are as follows [5].

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Sources for carbon

Substrate used

Catalyst used

Conditions maintained inside the furnace

Precursors for carbon nanotubes are hydrocarbon gases such as acetylene, ethylene, methane, etc.

Zeolite, silica, silicon plate coated with iron particles, etc.

Metal catalyst nanoparticles, e.g., iron, cobalt, nickel, molybdenum, ironmolybdenum alloys

Temperature: 500–900°C Inert gas atmosphere: Argon gas

• Electric arc discharge method: Here, a direct current traverses between two graphite rods that form the electrodes and the high current causes evaporation to take place and create carbon products which deposit around the chamber walls or over the cathode substrate [6]. Conditions maintained

Electrodes

Reactor

Pure graphite rods (both positive and negative electrode)

Has a quartz chamber connected to a vacuum pump and a diffusion pump for inert gas supply. The chamber is made a vacuum by the vacuum pump and then filled with helium gas, using a diffusion pump

Diameter of electrodes: 5–20 μm Gap between electrodes: 1 mm Current: 50–120 A Voltage: 20–25 V Inert gas pressure: 100–500 Torr Temperature: 3000–3500°C

• Laser ablation method/physical vapor deposition: This technique can be used to vaporize a material into gaseous form and then deposit it on the surface of a substrate [5]. Target source

Laser source

Substrate used

Inert gas atmosphere

Solid graphite

CO2 laser

Water-cooled copper collector

Argon gas

A holistic view of all the abovementioned synthetic techniques of CNTs is summarized in Table 2.

Functionalization of carbon nanotubes

Table 2 Some common methods of CNT synthesis used conventionally. Methods of CNT synthesis

Carbon arcdischarge Laser ablation Chemical vapor deposition Flame synthesis Spray pyrolysis

Underlying principle

Type of CNTs

CNTs’ growth on the negative end of the carbon electrode in an argon-filled vessel Fabrication of CNTs using continuous-wave 10.6 μm CO2 laser in the presence of metals (Ni and Co) CNTs’ growth achieved at 1000°C in the presence of irondoped alumina catalyst particles Co-flow diffusion flame type. Catalysts: metal nitrate + TiO2 Synthesis of CNTs using tire pyrolysis oil as a carbon precursor with ferrocene as a catalyst at 950 °C

SWCNTs SWCNTs SWCNTs and DWCNTs MWCNTs MWCNTs

3. Need for functionalization of carbon nanotubes Despite the fact that CNTs possess a myriad of useful assets, in terms of physical and chemical properties, they are still lacking in some areas, like their intrinsic nature of water insolubility in all types of solubilizing agents in the biological setting. There is a need to maintain an appropriate balance between the merits and demerits of CNTs so as to get the best outcomes in applications. The shortcomings can be overcome by engineering CNTs by chemical or bioactive molecules of differing functionalities, which allow surface modifications, and this process is referred to as “functionalization.” Here, a number of interactions like adsorption, hydrophobic, and electrostatic interactions come into play that give CNTs properties like hydrophilicity and biocompatibility (the ability to survive in a biological milieu without any toxic expression). Moreover, the tendency of aggregation of individual CNTs by van der Waals forces inside an aqueous solvent is also significantly reduced by functionalization. By attachment of multiple kinds of functionalities to the CNT surfaces, to form FCNTs, their cellular uptake and biocompatibility are enhanced and hydrophobicity and tendency of aggregate formation are reduced, thus making them ideal nano-candidates for wide-ranging biomedical applications [7]. For example, Chen et al. found that pristine CNTs inhibit the growth of Chinese hamster ovary cells. However, after modification with analogs of cell surface adhesive glycoproteins through noncovalent interactions, CNTs showed a minute influence on cell growth. Thus, making proper surface functionalization on CNTs to afford water solubility and biocompatibility is the most critical step to produce nanotube bioconjugates for desired applications.

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4. Functionalization techniques used in carbon nanotubes In usual practices, generally, two major methods of functionalization are utilized, based on both types of linkages (covalent as well as noncovalent) between the surface of nanotubes and the moieties of biological substances, which are: 1. covalent chemical functionalization and 2. noncovalent chemical functionalization.

4.1 Covalent functionalization This is a highly effective method of functionalization when the strong linkage between CNTs and biomolecules is required and depends on the grafting of chemically active molecular entities onto the inert sp2 hybridized structure of carbon, inside the π-conjugated skeleton. Keeping in mind the functional groups attached on the surface, this type of functionalization can be further divided into two strategies: “sidewall” functionalization and “end-defect” functionalization [8]. A. Sidewall covalent functionalization: This is a functionalization strategy to generate different functional groups on the sidewall surfaces of nanotubes, without losing van Hove singularities in the way. This can be achieved by techniques like gas-phase reaction with the nondestructible sidewall. By this process, the local chemical reactivity of CNTs is increased as there is the existence of sidewall defects, namely, pentagonheptagon pair, also known as Stone-Wales defect/vacancies. Usually, carbon sites with sp3 hybridization are formed as a result of covalent sidewall functionalization, which causes disturbance in the band-to-band transitioning delocalized electrons [9]. The employment of 1,3-dipolar cycloaddition reaction is an efficient method of covalently functionalizing the sidewalls of CNTs. Here, azomethineylide that comprises a carbanion next to an ammonium ion forms intermediates of pyrrolidine, in addition to dipolarophiles. This can be easily created via decarboxylating iminium salts which are obtained from the condensation of α-amino acids along with either aldehydes or ketones. The surfaces of CNTs possess amine functional groups that are introduced by 1,3-dipolar cycloaddition of azomethineylide [9]. Another type of reaction that can be employed for CNT sidewall functionalization is Diels-Alder cycloaddition. In this case, the SWCNTs that have been fluorinated undergo this cycloaddition with the help of several dienes, such as 2-trimethylsiloxyl, anthracene, and 2,3-dimethyl-1.3-butadiene, to become functionalized SWCNTs. The action of electron-withdrawing fluorine atoms on the surface of these nanotubes activates double bonds on the sidewalls, which in turn enhances the rate of cycloaddition reaction [9]. B. End-defect covalent functionalization: This alternative of covalent functionalization includes “end” extremity oxidation which is the generation of numerous functional groups containing oxygen, e.g., alcohol, hydroxyl, lactone, carboxylic, ketone, ester, phenolic, by the employment of sonication process and a combination of strong

Functionalization of carbon nanotubes

oxidizing agents. The variety of functional groups helps to enhance the property of solubility in CNTs by factors like temperature, presence of an acid, time, concentration, and sonication [10]. Among so many methods of functionalization, one of the most efficient and mainstream methods is carboxylation, which links CNTs with functional groups like amines and amides. To activate carboxylic acid before covalent functionalization, active ester, oxalyl chloride (C2O2Cl2), n-hydroxy succinimide (NHS), or thionyl chloride (SOCl2) are used, which results in the formation of largely reactive intermediate groups, causing a stable covalent linkage to be formed between CNTs and functionalizing agents. This method has comparatively high reactivity compared to the sidewall process of functionalization [11]. Another approach of obtaining FCNTs is by esterification-amidation reactions; these take into use the conversion of incorporated carboxylic groups in CNTs into amidated (by the help of ethylene-diamine) and acylated (by thionyl or oxalyl chloride) CNTs. Oxidized CNTs are employed on a large scale for further modifications and the chemical tetra chlorosilane is used for the activation of acyl chloride and oxidized CNTs [9]. Free radical grafting: This is a unique technique among covalent functionalization methods, where alkyl or aryl peroxides, substituted anilines, and diazonium salts are used as the starting substances. Results of the study suggest that free radical grafting of macromolecules onto the surface of CNTs can enhance the solubility of CNTs compared to conventional acid treatments which practice the adjunction of small molecules like hydroxyl onto the surface of CNTs. This is due to the fact that in the case of free radical grafting, large functional molecules facilitate the dispersion of CNTs in a variety of solvents, even at a low degree of functionalization. Recently, a novel, bio-based, environmentally friendly approach has been processed for the covalent functionalization of MWCNTs with the aid of clove buds. This approach is innovative and green because it does not use toxic and hazardous acids, which are typically used in common carbon nanomaterial functionalization procedures. These MWCNTs get functionalized in one pot using a free radical grafting reaction. The MWCNTs functionalized by clove are then dispersed in water, causing the production of a highly stable aqueous suspension (nanofluid) of MWCNTs.

4.2 Noncovalent functionalization In this form of functionalization, several agents are used to achieve noncovalent interactions, for example, van der Waals forces, hydrophobic interactions, and π-π stacking interactions. The numerous functionalities that can be used in this way include surfactants, DNA, fluorophores, aromatic organic molecules, proteins lipids, polymers, and endohedral functionalization. There are commonly three classes of molecules that are employed for the functionalization of nanotubes: (i) surfactants; (ii) polymers; and

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(iii) biopolymers, e.g., proteins, DNA, lipids. The basic mechanism used in this particular type of functionalization is self-assembly, with the aid of hydrophobic effects [12]. Regarding the dispersion of CNTs, surfactants of cationic, anionic, and nonionic origins are available. Multiple aromatic molecules are able to get adsorbed with fused benzene rings on the surface of CNTs, without any changes in the properties and functions, because of π-π stacking. The complex, which is supramolecular in nature, thus formed can be used to immobilize dendrimers on nanotube surfaces. The phenomenon of PEGylation of CNTs is crucial at times when long-circulating nanotube formulations are required. In this, the surface of CNTs gets strongly linked to hydrocarbon chains of the lipids by the hydrophilic chain of PEG that extends to the aqueous phase, providing biocompatibility and solubility. Such PEGylated nanotubes are highly stable as suspensions in serum and in highly saline solutions. Fig. 3 displays various methods of surface functionalization of CNTs, reported in the literature, which improve the processing and manipulation of insoluble CNTs, rendering them useful for synthesizing innovative CNT nano-fluids with impressive properties that are tuneable for a wide range of applications [13]. Side Wall Covalent Methods Ends and defects Functionalization Polymer wrapping Non-Covalent Methods Surface attachments of surfactants

(a) Side wall

(b) Ends and defects

(c) Polymer wrapping

Fig. 3 Methods of functionalization of carbon nanomaterials [13].

(d) Surface attachments of surfactants

Functionalization of carbon nanotubes

Reduced Bundling Effect

Enhanced Solubility

High Biocompatibility

Enhanced Dispersibility

Reduced in vivo and in vitro toxicity

Fig. 4 Merits of functionalized carbon nanotubes.

Therefore, we see the enhancement of multiple functionalities of CNTs after they are subjected to various methods of purification, characterization, and functionalization, in turn providing the most efficient and effective version, i.e., FCNTs. The merits of functionalizing CNTs are depicted in Fig. 4.

5. Biomedical applications of FCNTs 5.1 Drug delivery Compared with other traditional nanocarriers for drug delivery such as polymers and liposomes, CNTs have some unique and valuable features that make them appropriate for this application, as follows [14]: (1) CNTs exhibit high specific surface areas, which improves the loading efficiency of medicine. In addition, the high aspect ratio gives CNTs advantages over other types of spherical NPs in that the needle-like CNTs allow loading of large quantities of drugs along the longitude of tubes without affecting their cell penetration. (2) For molecules that tend to exhibit high stability in vivo, they can be loaded on the surface of CNTs externally, as this will give them enough exposure, while relatively fewer stable molecules in vivo can consequently also be hidden inside the internal cavity of CNTs so as to avoid the quick loss of their effective properties in transportation. (3) CNTs allow the installation of multiple types of molecules with different functions simultaneously to their surface, such as targeting and imaging moieties, thus enabling multifunctional effects. In an experimental study, CNTs were mixed into 1% tri-block copolymer pluronic F127 solution which was then put through bath-sonication for 30 min. Next, the mixture was added to doxorubicin (DOX) solution to produce a CNT-DOX complex. The cytotoxicity of the CNT-DOX complex against the human breast cancer cell line MCF-7 was higher than that of the pure DOX or DOX surfactant complex [15]. Fig. 5 displays the drug delivery action of FCNTs.

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Fig. 5 Schematic representation of drug delivery action shown by FCNTs.

5.2 Cancer therapy In addition to the delivery application, these CNTs have enormous potential for the treatment of the deadly disease of cancer. Out of the important studies conducted, it has been deduced that CNTs can generate site-specific heat when exposed to NIR radiation that induces cell death in a noninvasive manner [16]. In a study, single-walled CNTs (SWCNTs) were conjugated with cyclic Arg-Gly-Asp (RGD) peptides that are further utilized for photoacoustic imaging of tumors. The deduced result of the study suggests the potential of SWCNTs for cancer diagnosis [17]. Furthermore, Tosun et al. reported collagen conjugated SWCNTs for improved electrical activity. A study carried out at Stanford University states the unique thermal ablation of cancer cells. For the experimental study, they have first injected mice with human epidermal cancer cells and the size of the tumor was allowed to reach around 70 mm3. These functionalized CNTs were then injected into the desired tumors, which were consequently exposed to NIR radiation. The tumor was observed to disappear within 20 days after exposure to thermal treatment with CNTs under NIR [18]. Some instances of FCNTs being employed in cancer therapeutics are listed in Table 3. Such a CNT-mediated thermal therapy is a novel complementary tool to the currently available treatment regime. Moreover, thermal ablation can also be combined with other kinds of therapies for synergistic effects by loading effective therapeutic molecules on FCNTs. Fig. 6 shows a schematic representation of cancer therapy carried out by FCNTs.

Functionalization of carbon nanotubes

Table 3 Significant role of CNTs in cancer therapy. S. no. Type of CNTs Model/cell line

1.

2.

3.

4. 5.

6.

Singlewalled CNTs Singlewalled CNTs Singlewalled CNTs Multiwalled CNTs Multiwalled CNTs

Multiwalled CNTs

CNTs dosage Results

Higher cytotoxic action 12.67 and toward cancer cells 5.49 μg/ mL 3.125, 6.25, Induction of death of cancer cells under NIR12.5, and irradiation 25 μg/mL 4, 8, 12, 16, Delivery of curcumin to cancer cells; induction and death and apoptosis in 20 μg/mL cancer cells HeLa cells/mice 5 mg/kg In vitro and in vivo cancer cell inhibition 0.1, 0.2, 0.4, Effective delivery of MCF-7 and docetaxel and its release 0.6, 0.8, MDA-MB-231 and human breast 1 mg/mL cancer cells/rats HeLa cells 1.67 μg/mL Enhancement of antitumor activity of camptothecin

Human breast cancer cells (MCF-7) MDA-MB-231 human breast cancer cells A549 and NIH 3 T3 cells

Fig. 6 Schematic representation of FCNT action on cancer cells.

Reference

[19]

[19]

[19]

[19] [19]

[19]

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6. Diverse applications of functionalized CNTs in diagnostics Overexpression of human epidermal growth factor receptor 2 (HER2), also known as c-erbB-2 or HER2/neu, is responsible for approximately 20%–25% of invasive breast cancer. Liu et al. studied SWNT delivery of paclitaxel (PTX) into xenograft tumors in mice with higher tumor suppression efficacy than the clinical drug formulation taxol. The PTX conjugated to PEGylated SWNTs showed high water solubility and maintains the same toxicity to cancer cells as taxol in vitro. SWNT-PTX affords a much longer blood circulation time of PTX than that of taxol and PEGylated PTX, leading to high tumor uptake of the drug through the EPR effect. The strong therapeutic efficacy of SWNT-PTX is shown by its ability to slow down tumor growth even at a lower drug dose [20]. Pan et al. investigated the efficiency of MWCNTs to deliver the gene to the tumor cell for cancer therapy. In this research work, the scientists fabricated MWCNTs that were modified with polyamidoamine dendrimers which were further in conjugation with FITC-labeled antisense c-myc oligonucleotides (asODN). In the human breast cancer cell line of MCF-7 and MDA-MB-435, cells were incubated with modified MWCNTs (asODN-dMNTs), as per the above conditions. The emission of fluorescence developed by the FITC revealed the phenomenon of cellular uptake of asODN-dMNTs within 15 min. These composites inhibited the cell growth in time and dose-dependent means and downregulated the expression of c-myc gene (overexpression of this gene amplifies the expression of HER2) and C-Myc protein.

6.1 Biosensing technology Ever since the conception of CNTs, the major application which was probed for these nanomaterials was the field of diagnostics, especially the area of biosensing. As early sensing of complications is essential for the treatment of diseases, it is vital to look for better and more efficient ways of diagnostics. The analysis of in vitro biomarkers is widely used, but there is a huge problem of the excessive requirement of biological samples and even the present methods are very time-consuming. Thus, by exploiting the electrical and chemical properties of FCNTs, scientists have utilized them in electrical sensors and unique label-free biosensors. The initial research on this topic was about the modification of biosensor surfaces for detecting proteins binding to fullerenes and CNTs [19]. The last few years have experienced the development of DNA-biosensor containing MWCNTs covalently functionalized by carboxylation, for covalent DNA immobilization and enhanced detection of hybridization [21]. When this newer FCNT-based biosensor was compared with conventional ones, it was observed that the former significantly enhanced the sensitivity and increased the quantity of DNA being attached, making it the first application and demonstration of FCNTs serving as DNA biosensors for fast, specific, and reliable detection. The recent focus of this technology is to enhance the DNA sensitivity by optimization of CNTs, and such a nanotube-based system has been

Functionalization of carbon nanotubes

fabricated which has potential for detection of anticancer drug, mercaptopurine, or 6-MP in biological samples, by employing immobilized DNA present on MWCNTs [22]. Another example of an electrochemical DNA biosensor was developed by Shahrokhian’s group, who incorporated π-stacking interaction between single-stranded DNA and MWCNTs. The final biosensor was a stable, cost-efficient, and sensitive alternative for the detection of sequence-specific, mismatched, and noncomplementary DNA. For the detection of viral pathogenic DNA from the hepatitis C virus and genomic DNA tuberculosis-causing pathogen, Mycobacterium tuberculosis, FCNT-based biosensors have been developed which can be utilized as a point-of-care device for multifaceted target diagnostics in hospitals [23]. There has also been research into detecting Escherichia coli by using DNA-wrapped MWCNTs. This nano-hybrid system provided enhanced signals with exceptional sensitivity [24]. Apart from a plethora of DNA-detection biosensing technology, FCNT-based biosensors have also been actively researched for other possible diagnostic applications, employing the principle of biosensing. These are the detection of pesticides, cholesterol, glucose, lactate, reactive oxygen species, anticancer drugs, nucleic acids, malarial parasites, and many more such pathogenic microorganisms [25]. Table 4 lists some biosensors that utilize the properties of FCNTs for diagnostic outcomes.

6.2 Bioimaging technology In addition to having unique electrical, chemical, and mechanical properties, CNTs possess optical properties which are very useful in applications such as biomedical imaging. SWNTs comprise strong optical absorption from ultraviolet (UV) to regions of nearinfrared (NIR) and are particularly useful in a range of different imaging techniques. These techniques incorporate photoacoustic imaging, fluorescence imaging, and Raman imaging, and with functionalization of the CNTs, there is also positron emission tomography (PET) imaging and even magnetic resonance (MR) imaging [20]. Dai et al. researched the CNTs which were functionalized with a specific receptor for internalization into a specific cell type, as a result imaging these cells with a very low background of autofluorescence. In an in vivo study, the biodistribution of SWNTs in live drosophila larvae was monitored by fluorescence imaging [19]. Through photoacoustic imaging, deeper and better tissue penetration can be achieved compared to other conventional optical imaging techniques. This technique makes use of certain specific light-absorbing molecules (like CNTs) which convert laser pulses delivered into the biological tissue into heat energy. Consequently, transient/temporary thermoelastic expansion is induced, in turn giving rise to wideband emission of ultrasonic waves which can then be detected by an ultrasonic microphone that shows high optical absorption in the NIR range. SWNTs make a useful contrast agent in this kind of biomedical imaging [25]. Some bioimaging instances where FCNTs are employed are listed in Table 5.

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Table 4 Some FCNT-based biosensors used for diagnostic purposes in the biomedical industry. Type of S. no. biosensor

1. 2. 3.

4.

5.

Principle

Electrochemical Uses MWCNTs/AuNPs along with Mannan-Os adducts Electrochemical Uses MWCNTs and coalesced Ru-TiO2 nanoparticles Electrochemical Used MWCNTs with glassy carbon as sensor along with phosphate buffer solution (PBS) at pH ¼ 9.0 Electrochemical Uses MWCNTs and copper microparticles dispersed in polyethyleneimine Gas

Target molecule

Reference

Dopamine

[26]

Cetirizine

[27]

Methdilazine [28]

Glucose and amino acids Uses MWCNTs along with tungsten oxide Ammonia nano bricks gas

[29]

[30]

Table 5 Some FCNT-based bioimaging tools used for diagnostic purposes in the biomedical industry. S. no. Bioimaging modality

1. 2. 3.

4. 5.

6.

7.

Type of CNT employed

Near-infrared (NIR) photoluminescence Raman imaging

Pl-PEG-NH2 functionalized SWNTs Lipid-polymer functionalized SWCNTs/MWCNTs Photoacoustic imaging SWNTs functionalized by Dye (QSY21)-cyclic Arg-GlyAsp peptide formulation Visible imaging NH3+ functionalized SWNTs

Photoacoustic imaging MWCNTs functionalized by RGD-conjugated and silica-coated Au nanorods Magnetic resonance MWCNTs functionalized by (MR) imaging gadolinium (III) chelate

Nuclear imaging

SWCNTs functionalized by radioisotope of iodine 125I

Disease visualized

Reference

Cells of breast cancer Ovarian cancer cells αvβ3 integrin protein

[31]

Human lung carcinoma In vivo cells of gastric cancer

[34]

MRI contrast agents weighted by T1 and T2 Biodistribution of various animal tissues

[36]

[32] [33]

[35]

[37]

Recently, CNT research in the field of diagnostics has revealed that CNTs have the potential to generate and behave as quantum dots (QDs), which are semiconductor crystals at the nanoscale and can emit light in various wavelengths. CNTs have the capability to mimic these light-emitting particles and can help in revolutionizing bioimaging. Scientists have conducted experiments with cisplatin and epidermal growth factors (EGFs)

Functionalization of carbon nanotubes

Fig. 7 FCNT applications in clinical diagnostics involving bioimaging and biosensing.

attached to SWCNTs so as to target squamous cancer cells, and have also observed that bioconjugates of SWCNT-QD-EGF portray better cell internalization when compared with plain CNTs [38]. The holistic representation of FCNT applications in the diagnostics and clinical domain is shown in Fig. 7.

7. Concluding remarks and future outlook There is no doubt that the scientific community has experienced a boom pertaining to research and development in the domain of nanotechnology, and a significant contribution comes from a special type of nanomaterial called CNTs. These CNTs have demonstrated unique properties and functionalities in a multitude of areas, especially the biomedical arena. After functionalization, the properties of these unique nanomaterials, which can be single-walled or multiwalled, are enhanced manifold, making them their best versions and ready to be employed in areas like cancer targeting, antibacterial therapy, drug delivery, biosensing and bioimaging, and most importantly clinical testing and diagnostics. In this chapter, we have tried to explain the growing importance of FCNTs in the field of diagnostic approaches in biomedicine, through which it is predicted that the clinical impact of nanomaterials will increase significantly, along with the precision

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and sensitivity of disease diagnosis. Although FCNTs display extraordinary performance in the biological milieu, there are still some limitations when it comes to cytotoxicity, large-scale production, and cost of fabrication of these mechanically, chemically, and physically sound nanomaterials. Thus, adequate evaluation of such parameters along with further in-depth research of CNTs is required so that these promising nanoformulations can be fully utilized to their best extent and be ideally enhanced to become one of the most well-developed and efficient solutions in biomedical research, particularly in the domain of clinical diagnostics.

Important websites 1. https://www.remedyspot.com/bhasmas-the-nano-medicine-of-ancient-times. 2. https://en.wikipedia.org/wiki/Carbon_nanotube. 3. https://www.nanowerk.com/nanotechnology/introduction/introduction_to_ nanotechnology_22.php. 4. https://nano-c.com/technology-platform/what-is-a-nanotube. 5. https://www.britannica.com/science/carbon-nanotube. 6. https://www.azonano.com/article.aspx?ArticleID¼5833. 7. https://news.mit.edu/2021/carbon-nanotube-covid-detect-1026. 8. https://web.ornl.gov/geohegandb/tubemain.html. 9. https://tuball.com/articles/single-walled-carbon-nanotubes. 10. https://today.oregonstate.edu/archives/2012/mar/nanotube-technologyleading-fast-lower-cost-medical-diagnostics.

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Section F Functionalized carbon nanomaterials for point-of-care applications

CHAPTER 19

Innovative progress in functionalized carbon nanomaterials, their hybrids, and nanocomposites: Fabrication, antibacterial, biomedical, bioactivity, and biosensor applications Shadpour Mallakpoura, Elham Azadia, and Chaudhery Mustansar Hussainb a

Organic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ, United States

b

1. Introduction Carbon, a multipurpose element that is ubiquitous in our lives, can form diverse allotropes due to the capability for hybridization in sp/sp2/sp3 configurations. Nano-carbon materials are becoming very appealing substances in the science and technology fields. Concerning the dimensionalities, many categories of carbon nanomaterials can be achieved including 0D such as carbon quantum dots and fullerene, 1D like carbon nanotubes (CNTs), 2D including graphene, and 3D such as diamonds and graphite [1–4]. Each category displays inimitable features and applications in diverse areas such as environmental sciences, biosensing, medicine, imaging, biology, etc. Investigations in the Scopus database indicate a developing trend in the utilization of nano-carbon materials in diverse domains in the last decade. The results of these searches are shown in Fig. 1. However, nonmodified carbon nanomaterials have many disadvantages, including an affinity for the formation of stable aggregations due to robust intermolecular attractions like dipole-dipole, van der Waals, and so on. These aggregations cause undesirable changes in the physiochemical features and reduce their performance [5]. The best performance of nanomaterials is achieved when the particles are well-dispersed and free of accumulation. Hence, surface functionalization of nano-carbon materials is a significant subject for nano-chemists and the introduction of appropriate modifiers is an essential step. The functionalization of nano-carbon materials can be performed via covalent or noncovalent modification using a range of numerous materials such as biomolecules and macromolecules [5,6]. The following are some of the types of nano-carbon materials. Graphene, a carbon allotrope with exceptional characteristics, is the most advanced and engineered in diverse areas of applications among new generations of nano-carbon-based Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00017-0

Copyright © 2023 Elsevier Ltd. All rights reserved.

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Fig. 1 A number of publications on the “Scopus website” with the keyword of “carbon nanomaterials” in June 2022.

materials. It is the thinnest, lightest, and strongest compound known, with the best conductivity of electricity (15,000 cm2 V
1 s
1) and heat (5000 W/mK). It is a relatively stable compound that is 300 times stronger than steel and 0.35 nm thickness (1/200,000th human hair diameter) [1,7–9]. The unparalleled electrical and chemical behaviors along with biocompatibility, flexibility, and easy surface functionalization of this valuable material, provide opportunities for utilization of it and derivatives in a variety of domains, including drug delivery [10], biosensors [11,12], diverse polymeric nanocomposites for remediation and catalysis, and other uses [13–16]. This compound exists in many forms such as nanosheets, nano-plates, and 3D graphene, all of which present amazing utilization. Structurally, in graphene construction with 2D honeycomb lattice, each carbon atom with sp2 hybridization has three σ bonds with neighboring atoms with 0.142 nm length. These robust connections in each lattice form a hexagonal construction. Graphene’s stability and electrical conductivity are attributed to the tightly packed atoms in sp2 hybridization and vertical π bond [1,7,9]. CNTs and carbon quantum dots (a class of nano-carbon materials below 10 nm in size) are other allotropes of nano-carbon materials with a cylindrical nano-construction and unparalleled features such as remarkable surface area, high reactivity, biocompatibility, outstanding thermal and chemical stability, mechanical strength, and ultra-lightweight. These characteristics have attracted attention in terms of research and industry, and have led to innumerable utilizations of CNTs in electronic devices, biomedicine, sensors, nanocomposites, environmental applications including water and soil treatment, antimicrobial agents, energy fields, catalysis, and so on. For more than 20 years, these compounds have

Innovative progress in functionalized carbon nanomaterials

Fig. 2 Diverse applications of carbon nanomaterials in biomedical, antibacterial, biosensor, and bioactivity areas.

been the main subject of research. Carbon quantum dots can be applied in numerous fields including optronics, solar cells, light-emitting devices, and so on [1,4,17–32]. Considering the great features and importance of carbon nanomaterials, this study illustrates the recent developments of carbon nanomaterials in biomedical, antibacterial, biosensors, and bioactivity fields (Fig. 2).

2. Biomedical utilization of functionalized carbon nanomaterials 3D printing is a new technology that is advancing rapidly and has utilizing in diverse fields including biomedical and bone tissue engineering for developing implantable scaffolds. Based on different studies, a nerve cell is sensitive to CNTs as conductive substrates. These electrically conductive layers (CNTs) stimulate neurite extension as well as being able to grow the nerve cells. In addition, to prevent the aggregation and precipitate of CNTs, their surfaces can be modified by water-soluble constituents such as single-strand DNA (ss-DNA). In this regard, Liu and coauthors [33] reported 3D-printed scaffolds employing functionalized CNTs for application in tissue engineering. For this aim, CNTs and ss-DNA were mixed via a sonication process to produce a nano-complex (ssDNA/CNT) that was negatively charge. On the other side, a 3D-printed scaffold by poly(propylene fumarate) (PPF) was prepared by the stereolithography method and ammonolyzed with hexamethylenediamine for introducing NH2 groups that in water could take on a positive surface charge. After that, via electrostatic force and a simple

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Fig. 3 Schematic illustrations: (A) fabrication of ssDNA@CNT by ultra-sonication of ssDNA and CNTs. (B) 3D scaffold-printing and subsequent ammonolysis and functionalization by ssDNA@CNT through electrostatic forces between positively charged 3D scaffold surfaces and negatively charged ssDNA@CNT composites. CNT, carbon nanotube; ssDNA, single-strand DNA. (Adapted from X. Liu, M.N. George, S. Park, A.L. Miller II, B. Gaihre, L. Li, B.E. Waletzki, A. Terzic, M.J. Yaszemski, L. Lu, 3D-printed scaffolds with carbon nanotubes for bone tissue engineering: fast and homogeneous onestep functionalization, Acta Biomater. 111 (2020) 129–140 with kind permission of Elsevier.)

one-step process, an ssDNA/CNT complex was coated on the scaffold (Fig. 3). This work resulted in many advantages such as simplistic and fast surface functionalization of CNTs with uniform and nontoxic coating, which meaningfully enhanced the adhesion, proliferation, and differentiation of preosteoblast cells. In addition, this conductive coating based on CNTs caused cellular proliferation and gene expression through electrical stimuli. Fig. 4A shows the functionalized polymeric scaffolds with ssDNA, CNT, and ssDNA/CNT composite through soaking them in individual media of modifiers. The photographs of each kind of functionalized-scaffold are shown in Fig. 4. Based on the outcomes, the pristine ammonolyzed-PPF and ammonolyzed-PPF/ssDNA scaffolds show clear construction. Ammonolyzed-PPF/CNTs show nonhomogeneously dark dots in the scaffold. However, ammonolyzed PPF/ssDNA/CNT indicates homogeneous thick-dark covering of the surface of the scaffold with a CNT composite layer in the surfaces. In addition, SEM pictures of nonfunctionalized as well as functionalized scaffolds can be seen in Fig. 4B. The outcomes showed the significant development in cell adhesion as well as spreading in the ssDNA/CNT-functionalized scaffolds. These results clearly indicate that

Innovative progress in functionalized carbon nanomaterials

Fig. 4 (A) Photographs of 3D-PPFA scaffolds before and after functionalization with ssDNA, CNT, and ssDNA@CNT materials. (B) SEM images of 3D-PPFA scaffolds before and after functionalization. (Adapted from X. Liu, M.N. George, S. Park, A.L. Miller II, B. Gaihre, L. Li, B.E. Waletzki, A. Terzic, M.J. Yaszemski, L. Lu, 3D-printed scaffolds with carbon nanotubes for bone tissue engineering: fast and homogeneous one-step functionalization, Acta Biomater. 111 (2020) 129–140 with kind permission of Elsevier.)

ssDNA/CNT composite modification negates the CNTs’ cytotoxicity, improves conductivity and compatibility, and efficiently helps preosteoblast cell proliferation [33]. Graphene and its derivatives can bind to viruses and bacteria through electrostatic and hydrophobic attractions and deactivate them by rupturing and destroying their membranes. However, the type and number of functional groups in graphene are effective factors in killing bacteria. Indeed, for improvement of the antimicrobial behavior of graphene sheets, they must be equipped with robust functional groups that are needed for a strong connection to the pathogenic membranes [34]. On the other side, boronic acid, as a boron derivative with remarkable biological features comprising antimicrobial

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behavior, vascularization, and growth factor expression, improves the extracellular matrix turnover through increasing the collagen and proteins, and keratinocyte migration and proliferation, and increases the wound healing process (especially of diabetic wounds) proficiently. Boronic acid functional groups can bond covalently to the glycoprotein with cis-diol functionality (suitable targets) in the cell membrane and speed up the healing of wounds. In this regard, Beyranvand and coauthors [34] prepared boronic acidfunctionalized graphene platforms and investigated the antiparasitic and antibacterial behaviors for bacteria and nematodes as well as their proficiency as wound-dressings in diabetic wounds. In this study, 1% phenytoin cream, as a commercially available drug, was utilized as a positive control. For preparation of boronic acid-functionalized graphene, first, reduced graphene oxide was prepared and dopamine was polymerized onto it. Then it was mixed with boronic acid solution, and finally, a black solid was obtained. The schematic illustration and MIC (laboratory measurement) values of the boronic acidfunctionalized graphene interaction for bacteria are shown in Fig. 5A. Optical and microscopic pictures of the surface of untreated and treated nematodes are also presented in this figure (B–G). Based on the outcomes, boronic acid-functionalized graphene wrapped bacteria and destroyed them in a short time. Moreover, after 1 day of nematodes’ incubation with the modified graphene, their bodies were ruptured as well as the viability having reduced to 30%. In vivo tests on rats showed the efficiency of graphene platforms compared to phenytoin drug for diabetic wounds in 10 days. Based on the outcomes for 10 days, a control (untreated rates) group, drug-treated group, and a functionalized graphene-treated group showed wound contractions of 43%, 66%, and 93%, respectively. Graphene oxide (oxidized form of graphene) is a photothermal agent in the nearinfrared light region, and by producing heat from the light, it can be used to kill cancer cells. In fact, graphene oxide-based nanomaterials are photosensitizing materials and can enter tumor cells for generating heat from light absorption. Graphene oxide can selectively release the drugs inside the cancer cells and cause photothermal ablation of tumors. Thus, Mauro et al. [35] developed nano-sized folic acid-treated nano-graphene oxide sheets, as a helpful platform for combination photothermal therapy and stimuli-sensitive chemotherapy to develop a cancer treatment while decreasing the side effects. The treatment of graphene oxide with folic acid comprising poly(ethylene glycol) supplied tumor cell recognition capabilities as well as causing high quantities of loading (>33%, w/w) of the drug doxorubicin. The prepared nano-platform was selectively capable of entering and killing breast cancer cells. The in vitro cytotoxicity of the prepared platform was assessed on human breast cancer cell lines (MDA-MB-231 and MCF7) as well as healthy human fibroblast. The outcomes showed higher (3–12 times) cytotoxic effect on breast cancer cells than that measured for healthy cells such as fibroblasts. In another study by Yan et al. [36] bioactive scaffolds incorporated of p-phenylenediamine-functionalized carbon quantum dots into silk fibroin/poly(L-lactic acid) nano-fibrous for cardiac tissue engineering. Silk fibroin has many features like biocompatibility, striking mechanical

Innovative progress in functionalized carbon nanomaterials

Fig. 5 (A) Schematic representation of the interaction between G-BA sheets and bacteria and MIC values of G-BA for E. coli and B. cereus. (B–G) Optical and SEM images of the surface of (B), (E) untreated, (C), (F) GPDA treated, and (D), (G) G-BA treated nematodes. BA, boronic acid; G, graphene. (Adapted from S. Beyranvand, Z. Pourghobadi, S. Sattari, K. Soleymani, I. Donskyi, M. Gharabaghi, W.E.S. Unger, G. Farjanikish, H. Nayebzadeh, M. Adeli, Boronic acid functionalized graphene platforms for diabetic wound healing, Carbon 158 (2020) 327–336 with kind permission of Elsevier.)

behavior, oxygen and humidity permeability, and increases human skin fibroblasts and keratinocytes. It is thus an important material for scaffold preparation. Microscopic examination was performed to study the morphology of the fabricated scaffold (Fig. 6). Based on micrograph results, spherical modified-carbon quantum dots were equally distributed in scaffolds. The prepared scaffolds showed a highly porous structure,

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Fig. 6 The morphology of synthesized CQD@SF/PLA: (A) nanofibrous bioactive scaffolds under SEM. TEM images of synthesized SF/PLA: (B) and CQD@SF/PLA (C and D) nanofibrous bioactive scaffolds. CQD@SF/PLA, carbon quantum dots/silk fibroin/p-phenylenediamine; SEM, scanning electron microscopy; TEM, transmission electron microscopy. (Adapted from C. Yan, Y. Ren, X. Sun, L. Jin, X. Liu, H. Chen, K. Wang, M. Yu, Y. Zhao, Photoluminescent functionalized carbon quantum dots loaded electroactive silk fibroin/PLA nanofibrous bioactive scaffolds for cardiac tissue engineering, J. Photochem. Photobiol. B Biol. 202 (2020) 111680 with kind permission of Elsevier.)

effectively improved young modulus, improved swelling asset for effective implantation efficacy. After 7 days of culture of scaffolds in rat cardiomyocytes, all pores in the scaffolds were overflowing with cardiomyocytes. Cardiomyocytes in the prepared scaffolds had significantly higher metabolic activity as well as viability in comparison to the pristine silk fibroin/poly(L-lactic acid) scaffolds. Recently, graphene oxide has been one of the most promising materials for uses in biomedicine due to its good features such as biocompatibility, easy chemical modification, low cost, abundance, water solubility, and great optical absorption in the nearinfrared spectroscopy region. In addition, natural polymers such as chitosan, with biocompatibility, biodegradability, and low-cost characteristics, are a good choice for biomedicine. Thus, in a study by Jun and coauthors [37], graphene oxide was functionalized with chitosan and the conjugated to folic acid molecules to prepare multifunctional nanomaterial photothermal therapy of tumors. The reason for using folic acid is that it is a significant ligand with excellent attraction for folate receptors on human cancer cell surfaces. In this study, chitosan-functionalized graphene oxide was formed via a

Innovative progress in functionalized carbon nanomaterials

robust interaction between chitosan (with reactive -OH and -NH2 groups) and graphene oxide (with negative charge surfaces) through electrostatic connections and hydrogen bonding. In addition, covalent bonds were created between chitosan and folic acid via carbodiimide chemistry. In vitro outcomes indicated that the fabricated nanomaterial could destroy tumor cells completely under laser radiation. In vivo experiments exposed complete inhibition of tumors without recurrence in 20 days. After 24 h of the platform injection in mice tumors, high photoacoustic signals were sensed. Overall, the resultant theranostic agents exhibited an extraordinary tumor-targeting proficiency and powerful photothermal influence. As mentioned earlier, for chemotherapy, the development of nanocarriers using functionalization of them with folic acid is a promising approach for efficient delivering drugs. Thus, Sousa et al. [38] functionalized graphene oxide using folic acid to achieve successful chemotherapy drugs delivery. For this aim, folic acid molecules were linked to poly(ethylene glycol), subsequently coupling with the surface of graphene oxide. The drug camptothecin was adsorbed on the graphene oxide. The thermogravimetric analysis specified high treatment of graphene oxide (20%) with folic acid-poly(ethylene glycol) and 37.8% of camptothecin was loaded on it. In vitro investigations demonstrated the prolonged release of camptothecin (more than 200 h). At pH ¼ 5.0 (acidic media), the releasing of camptothecin from nanocarrier was slower than that at pH ¼ 7.4 (physiological pH). The antitumor screening examinations specified that the treated graphene oxide was proficiently internalized through tumor cells and powerfully adhered to the cell surfaces. The designed nanocarrier increased the death of tumors by apoptosis; thus, folic acid is significant in promoting apoptosis in cancer cells. Mahajan et al. [39] studied bio-functionalization of graphene oxide using a natural biopolymer (chitosan) to achieve sustainable delivery of famotidine. This drug was loaded onto graphene oxide and then inserted in a biopolymer. The interaction of famotidine with chitosan and graphene oxide was performed via amine functionalities. The in vitro drug release studies at pH ¼ 4.5 revealed a sustainable release of famotidine (extended up to 12 h) that was better than the market product with a whole release in a short time (2 h). Moreover, the resultant nanocarrier indicated a 56% release in the first hour, which was a significant feature for quick and successful therapy. A large number of patients suffer from bone defects due to tumors or other diseases, and many of these defects do not heal easily and have become a challenge around the world. Numerous researchers are trying to improve this problem by providing biodegradable and biocompatible scaffolds as temporary templates for development of bone regeneration. In this regard, a nanohybrid scaffold for bone regeneration by employing chitosan/functionalized graphene oxide was designed by Mahanta et al. [40]. Sulfonated graphene oxide was applied for developing the nanohybrids. Through diverse spectroscopic methods, the interactions between chitosan and nano-filler were investigated. In addition, the mechanical stability, biocompatibility, drug release capabilities, and

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efficiency of the hybrid scaffold were examined. Considering the outcomes, the prepared nanohybrid scaffolds with porous construction exhibited highly hydrophilic behavior, superior mechanical features, and better biocompatibility in comparison with pristine chitosan. They also showed sustained release of the tetracycline hydrochloride drug. An in vivo investigation demonstrated the potential of developed nanohybrid scaffolds in faster bone healing with no side effects compared to the pristine scaffolds. One effective approach to treating cancer is the induction of mitochondria-mediated apoptosis. However, penetration into mitochondria is difficult due to the double and dense membrane. A series of ligands can be used to deal with this issue, but these mitochondria-targeting ligands have several drawbacks such as high cost, limited diversity, and nonspecific toxicity. Recently, attention to natural products has increased. Hypericin, as a natural antitumor material, produced from Hypericum perforatum L., is a proficient mitochondria-targeting ligand (Fig. 7A). In this regard, Han and coauthors [41] prepared functionalized graphene oxide using a hypericin photosensitizer and loaded doxorubicin, a chemotherapeutic drug, to improve mitochondria targeting and synergistic anticancer influence. The synergistic mechanism of the prepared system is shown in Fig. 7B. Hypericin/graphene oxide/doxorubicin enhanced the synergistic antitumor efficiency of chemotherapy and phototherapy without any side effects. In vitro and in vivo examinations showed that the proposed platform caused apoptosis of breast cancer cells. Moreover, graphene oxide displayed low toxicity to normal cells, which demonstrated its safety for antitumor therapy. In another study, [42] in a single-step, bio-facile production, plant extract polyphenols (Memecylon edule leaf ) were used for the functionalization of graphene nanosheets as photothermal therapeutic agents for ablation of lung tumors. This procedure did not involve the deployment of any harmful or toxic reductant. The prepared polyphenol anchored graphene oxide and presented excellent near-infrared radiation of the lung tumor cells directed in vitro for cytotoxicity delivery. The photothermal cytotoxicity of the prepared platform was examined on A549 and MDCK cells. The outcomes showed excellent behavior in this system for lung tumor cell ablation. To develop the drug delivery proficiency, graphene oxide was modified with natural peptide (protamine sulfate) and biopolymer (alginate) through electrostatic interaction at every stage of adsorption according to layer-by-layer self-assembly [43]. The surface of graphene oxide was negatively charged so it was accessible for the immobility of cationic peptide and anionic polymer by electrostatic interactions. Then, the as-prepared sample was loaded with doxorubicin for estimation of its potential as a nanocarrier. The drug-loaded nano-system revealed outstanding pH-sensitive release behavior. The modification of graphene oxide with alginate and protamine sulfate could improve stability and dispersibility (in physiological pH), as well as quenching the protein adhesion. Drug loading/release analyses revealed high loading capability

Fig. 7 (A) The natural product hypericin (HY) from Hypericum perforatum L. was used as an efficient mitochondria-targeting ligand. (B) Illustration of the synergistic anticancer mechanism of GO-PEG-SSHY/DOX mediated by the mitochondrial-mediated apoptosis pathway: (i) entering blood circulation after intraperitoneal injection; (ii) accumulation at the tumor site through passive and active targeting effects; (iii) endocytosis by tumor cells; (iv) transport into endo-lysosomes; (v) endolysosomal escape; (vi) glutathione-triggered HY release and HY targeting to mitochondria; (vii) release of cytochrome c from mitochondria into the cytosol after stimulation with singlet oxygen; (viii) activation of caspases by cytochrome c; (ix) pH-triggered DOX release and DOX targeting to the nucleus; (x) DNA damage-mediated activation of caspase; and (xi) stimulation of caspase-mediated apoptosis by enhanced synergistic anticancer treatment. GO, graphene oxide; DOX, doxorubicin; HY, hypericin; PEG, poly(ethylene glycol). (Adapted from C. Han, C. Zhang, T. Ma, C. Zhang, J. Luo, X. Xu, H. Zhao, Y. Chen, L. Kong, Hypericin-functionalized graphene oxide for enhanced mitochondria-targeting and synergistic anticancer effect, Acta Biomater. 77 (2018) 268–281 with kind permission of Elsevier.)

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and rapid release action at low pH. Due to the small particle size and high water dispersibility, the prepared nano-system could be uptaken by MCF-7 cells. In addition, this composite displayed no clear cytotoxicity toward MCF-7 cells, while the drugloaded composite showed better cytotoxicity than the graphene oxide/drug. Hence, this composite was feasible as a means of delivery for doxorubicin. In a study by Homaeigohar et al. [44], a hydrogel nanocomposite based on alginate and modified graphite nanofilaments was designed to be applied in neural tissue engineering use. For this aim, citric acid, in a simple and green methodology, was employed for the functionalization of graphite nanofilaments to develop the biological and mechanical features of the hydrogel. Fig. 8 illustrates the schematic preparation of hydrogel samples, with in vitro and in vivo examinations. Functionalization of graphite nanofilaments with citric acid induced the creation of oxygen-comprising groups on the nanofilaments surface, thereby assuring their homogenous distribution in the matrix. Using conductive nanofilaments, local conductive zones were provided, thus enabling intercellular signaling and optimizing the activities of neural cells. Durability and degradation rate were improved by this electrical conductivity, and nerve cells could regenerate and grow on the fabricated hydrogel. The mechanical stability of hydrogel was increased by the homogeneously dispersed nanofilaments. In vitro tests verified the hydrogel’s biocompatibility, and in vivo studies also showed the applicability of the prepared hydrogel for implanting in the body without any adverse reaction or inflammatory reactions (after 14 days in the animal model tissue). As mentioned before, among carbon nanomaterials, graphene oxide, with unique features like impressive flexibility, large surface area, high hardness and Young’s modulus, simplistic surface functionality, good thermal and electrical conductivity, and suitable processability in an aquatic environment, is a good candidate in diverse biomedical utilizations. Thus, in a study by Olad et al. [45], the influence of amine-modified graphene oxide nanosheets on the characteristics of chitosan/gelatin scaffolds was examined and investigated for the use of these materials in tissue engineering. For this aim, first, by Hummers’ method, graphene oxide was synthesized and modified with -NH2 functionality. The modified graphene oxide was covalently incorporated into the chitosan/gelatin chains using a glutaraldehyde cross-linker. Enhanced physicochemical features for chitosan/gelatin/NH2-graphene oxide included larger pore size, shape retention, high water absorption, water retention ability, higher bio-mineralization, and better stability in buffer media. In addition, cell viability for functionalized graphene oxide-incorporated scaffolds was developed because of the high surface, hydrophilicity, and existence of pendant groups in scaffolds. Overall, the outcomes indicated that introducing NH2-graphene oxide into polymeric material can result in satisfactory products for tissue engineering uses. The employing of surface-treated CNTs with diverse chemical moieties, such as carboxyl, hydroxyl, amine, and sulfide groups, in the scaffolds’ construction cause them to be more bioactive and neuro-friendly due to efficient interactions with biological

Innovative progress in functionalized carbon nanomaterials

Fig. 8 (A) Schematic illustration of the preparation cycle of the CAGNF/alginate films and their structural, in vitro and in vivo characterization. (B) Camera images of the hydrogel implants (embedded within a guinea pig’s skin) harvested on days 7 and 14. The arrows mark the samples, for better identification. Both samples have clearly biodegraded after 14 days, with a lower degradation rate for the nanocomposite hydrogel. The inflammation red tissues (day 7) become noninflamed, and the white ones (day 14) over a longer time. The area surrounding the implantation sites for the alginate and CAGNF/alginate samples show no particular reddening and inflammation, implying a comparable in vivo performance for both samples after 14 days. CA, citric acid; GNF, functionalized graphite nanofilaments. (Adapted from S. Homaeigohar, T.Y. Tsai, T.H. Young, H.J. Yang, Y.R. Ji, An electroactive alginate hydrogel nanocomposite reinforced by functionalized graphite nanofilaments for neural tissue engineering, Carbohydr. Polym. 224 (2019) 115112 with kind permission of Elsevier.)

molecules (e.g., enzymes, proteins, and extracellular matrix). Hence, nano-fibrous bioscaffolds based on functionalized CNTs can support many roles of nerve cells for biological uses. In this regard, Shrestha et al. [46] functionalized CNTs using silk fibroin and prepared electrospun composite mats based on polyurethane and silk-modified CNTs for neuronal growth. The prepared bio-scaffolds showed specific characteristics such

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as high porosity, strong biocompatibility, improved hydrophilicity and mechanical behavior, and outstanding electrical conductivity. With the stimulation of the neuronal cells, and upregulating of protein expression, these scaffolds amplified the activation capability of the neurotrophins. In an investigation by Wu et al. [47], carbon nanodots were postmodified by catechol-borane moieties as ultrafine fluorescent nanocarriers for delivery of the drug doxorubicin. The prepared nanocarrier loaded the drug through noninvasive adsorption about 84.28% (w/w). In addition, due to the catechol/boronate-interaction reversibility, in cancer cells with acidic pH, boronic acid was exposed and helped the nanocarrier to bind to glucosamine in the cell. Thus, the prepared nanocarrier was capable of selective presentation of its bioactivity so as to enter the cell and release directly drug into nuclei. Furthermore, the intrinsic green fluorescence of the drug delivery system makes the nanocarrier trackable for cell imaging. Likewise, the selective binding of the nanocarrier to the nuclear pore complex was confirmed. Every year, thousands of patients undergo neurosurgery. However, in medical science, one of the most difficult issues is related to nerve damage and nerve regeneration. Researchers are therefore creating artificial neural channels as an alternative to nerve tissue. These neural channels must have good strength and flexibility, as well as being compatible with the body and the physiological environment. Carbon nanomaterials with conductive features, such as CNTs and graphene sheets, have been used for nerve regeneration. Liu et al. [48] reported the growth and strengthening of nerve cells and neurons with the help of these carbon compounds. In this study, electrically conductive hydrogels by insertion of functionalized CNTs and graphene oxide within the oligo [poly(ethylene glycol) fumarate] hydrogels were produced by a molding method and investigated as a promising nerve conduit. Based on Fig. 9A, the fabricated conduit displayed good thickness, homogeneous diameter and wall thickness that indicated adequate mechanical strength. The nonstructural morphology of the as-fabricated examples was examined via a microscopic investigation as can be seen in Fig. 9B. In addition, a schematic illustration of the application of the prepared conduit in nerve growth and repairing the damaged nerves is provided in Fig. 9C. Based on the results, this nerve conduit exhibited respectable biocompatibility and outstanding improvement for the proliferation of PC12 cells as well as the spreading of them.

3. Antibacterial utilization of functionalized carbon nanomaterials Infectious disease caused by bacteria is a severe risk to human health. In recent decades, with the help of mineral nanomaterials as well as metal oxides, affordable and high-performance bacterial-resistant materials with the least harmful effects on the environment have been prepared. In this way, Liu et al. [49] fabricated a water-soluble composite using functionalized-graphene quantum dot and nano-ZnO particles (antibacterial ingredient). Firstly, a graphene quantum dot was manufactured through citric

Innovative progress in functionalized carbon nanomaterials

Fig. 9 (A) Photographs of the fabricated tubular conduit. (B) SEM images of freeze-dried conduits at different angles. (C) Schematic view of conduit mediated stimulation of nerve growth aiming at repair of damaged nerves. (Adapted from X. Liu, A.L. Miller, S. Park, B.E. Waletzki, Z. Zhou, A. Terzic, L. Lu, Functionalized carbon nanotube and graphene oxide embedded electrically conductive hydrogel synergistically stimulates nerve cell differentiation, ACS Appl. Mater. Interfaces 9 (2017) 14677–14690 with kind permission of American Chemical Society.)

acid pyrolysis (at 200°C). Then, polyethylenimine was applied for functionalization of this, and by a sol-gel procedure, ZnO/functionalized-graphene quantum dot composite was developed. Due to the nanosized and enhanced adsorption of the composite onto the surface of bacteria, excellent antibacterial performance was observed. The morphology of bacteria (E. coli) after using the as-prepared composite was examined by microscopic measurements. Based on Fig. 10, after 10 h (ambient condition) of using ZnO/ graphene quantum dot or ZnO/functionalized-graphene quantum dot, number of E. coli cells reduced obviously, and the cell membranes were apparently damaged (Fig. 10B and C). In addition, obvious apoptosis was observed after treating process. However, the functionalized composite had superior antibacterial behavior compared to the ZnO/graphene quantum dot counterpart (Fig. 10C and F). Fig. 11 schematically illustrates the antimicrobial action of the prepared composite toward E. coli. Polyethylenimine enhanced the distribution of composite in water. In addition, robust electrostatic interactions assisted the composite adsorption onto the surface of cells. After the accumulation of composite on the bacterial surface, their physical mobility was hindered, and membrane injury and cytoplasm leakage occurred. Furthermore, with formation of ROS and releasing Zn2+ outside as well as inside the cells, and interaction with proteins and nucleic acids, bacterial cells were destroyed.

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Fig. 10 Structural changes of (A, D) untreated E. coli cells and E. coli cells after the treatment of (B, E) ZnO/GQD nanocomposites and (C, F) ZnO/GQD-PEI nanocomposites. (Adapted from J. Liu, J. Shao, Y. Wang, J. Li, H. Liu, A. Wang, A. Hui, S. Chen, Antimicrobial activity of zinc oxide-graphene quantum dot nanocomposites: enhanced adsorption on bacterial cells by cationic capping polymers, ACS Sustain. Chem. Eng. 7 (2019) 16264–16273 with kind permission of American Chemical Society.)

Innovative progress in functionalized carbon nanomaterials

Fig. 11 Schematic of the antibacterial process of ZnO/GQD-PEI nanocomposites against E. coli. (Adapted from J. Liu, J. Shao, Y. Wang, J. Li, H. Liu, A. Wang, A. Hui, S. Chen, Antimicrobial activity of zinc oxide-graphene quantum dot nanocomposites: enhanced adsorption on bacterial cells by cationic capping polymers, ACS Sustain. Chem. Eng. 7 (2019) 16264–16273 with kind permission of American Chemical Society.)

Recently, Ag NPs have been broadly utilized for the preparation of antibacterial materials. However, due to the aggregation and easy oxidation of these NPs, their practical uses are limited. To address these drawbacks, CNTs are useful candidates to support them to improve their stability and antibacterial performance. In this regard, in an investigation by Xia et al. [50], functionalized CNTs with open tips were employed as supports and nano-reactors for encapsulation of Ag NPs for biomedicine uses. For this aim, firstly, CNTs were modified with nitric acid; then, in the presence of silver nitrate (Ag salt) and glucose (protecting and reducing agent), nano-Ag (4 wt% and 8 wt%) was encapsulated in CNTs and the antibacterial activity of the samples was investigated and compared with blank CNTs. Based on microscopic investigations, nano-Ag (black dots) of 6–10 nm were homogeneously distributed and well-dispersed into CNT channels. Besides, owing to synergism between well-encapsulated Ag and CNTs, the robust antibacterial performance was observed (Fig. 12).

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Fig. 12 (A, B) TEM images of the as-synthesized Ag-NPs@CNTs with 4 wt% and 8 wt% silver loading. (C, D) STEM images of the as-synthesized Ag-NPs@CNTs. CNTs, carbon nanotubes; NPs, nanoparticles; TEM, transmission electron microscopy. (Adapted from L. Xia, M. Xu, G. Cheng, L. Yang, Y. Guo, D. Li, D. Fang, Q. Zhang, H. Liu, Facile construction of Ag nanoparticles encapsulated into carbon nanotubes with robust antibacterial activity, Carbon 130 (2018) 775–781 with kind permission of Elsevier.)

In another study, glycine, as an amino acid with N, C, and H groups, was applied for the functionalization of CNTs [51]. Fluorine-doped TiO2 with antibacterial capability was doped with functionalized CNTs and their antibacterial behavior was evaluated. Inhibition zones for P. aeruginosa and S. aureus bacteria were 11 mm and 15 mm, respectively. This robust antibacterial behavior for this product can be ascribed to the synergistic performance of antibacterial features of nano-TiO2, modified CNT, and fluorine. Recently, antibacterial Ag/graphene nanocomposites have been employed in diverse applications. Modified graphene oxide can be used as a substrate for the fabrication and stabilization of Ag NPs. Silane ligand acts as a modifier for the functionalization of graphene oxide for the construction of materials with innovative physiochemical characteristics. The silanization of graphene oxide is a good technique to produce monodispersed nano-Ag particles due to diverse benefits. With the creation of chemical attraction among -OH and -(OR)3 groups of graphene oxide and silane, distance between layers in the

Innovative progress in functionalized carbon nanomaterials

composite can be higher compared to in pure graphene oxide, and can prevent the accumulation of nanosheets of graphene oxide. In addition, this functionalization provides appropriate media for the presence of nano-Ag. Many active groups in modified graphene oxide (hydroxyl, thiol, carbonyl, thiocarbonyl, and amide) with Ag ions can interact simply by covalent connections for formation of a complex. In a study [52], nano-Ag particles of 8 nm were dispersed on the silane-modified graphene oxide’s surface. Silane groups successfully prevented the accumulation of particles and layers. The antibacterial performance of a silane-functionalized graphene oxide/Ag composite was tested on S. aureus and E. coli, and the results indicated great antibacterial influence. Pathogenic microorganisms cause infections and endanger human health. Thus, progress in innovative antibacterial nanomaterials is a significant subject in recent scientific investigations. Numerous examinations have focused on the deposition of nano-Ag particles on the graphene oxide surface for the production of Ag-containing nanoantimicrobial agents. Zhou and coauthors [53] treated the surface of graphene oxide with catechol-terminated polymers via a mussel-inspired approach. In this strategy, adhesion capability is mostly due to catechol segments. Covalent or noncovalent attractions such as -H bonding, π-π stacking, complexation, and charge transfer can produce adhesion between catechol and the surface of graphene oxide. Then, Ag NPs were prepared on the polymer-modified graphene oxide support. Fig. 13 illustrates the fabrication process of this antibacterial nanohybrid. The fabricated nanohybrid with hydrophilic and positive charge features displayed great effectiveness as well as long-term antimicrobial behavior. The proposed mechanism for the prepared nanohybrid is shown in Fig. 14, which involves damage of cell membrane and generation of reactive oxygen species. Hydrophilicity and positive charge of nanohybrid enhance the connection of composite with the negative surface of bacteria. Then, with releasing and penetration of Ag+ ion into the cell membrane, the prepared nanohybrid persuaded to reactive oxygen species creation and bacteria death (Fig. 14). In another study, [54] tannic acid, as a green and renewable polyphenol, was used to functionalize graphene oxide. In an alkaline environment (pH ¼ 8.5) and the presence of polyethyleneimine, tannic acid-modified graphene oxide was cross-linked. In an alkaline medium, via Schiff-base and/or Michael reaction, catechol and amine groups reacted together. The fabricated sample exhibited outstanding antibacterial performance against E. coli due to the inherent bactericidal features of tannic acid segments. Polyethyleneimine, having inherent polycationic behavior, high isoelectric point, and charge density, is a good candidate for surface modification of graphene oxide. Thus, Jiang et al. [55] prepared a novel antibacterial agent containing very low doses of tetracycline antibiotics to suppress bacterial activity and combat microorganisms. Polyethyleneimine was employed for the functionalization of graphene oxide, and the antibacterial behavior of a tetracycline/polyethyleneimine-modified graphene oxide nanocomposite was finally estimated. As demonstrated in Fig. 15, bacteria (Gram-negative and Gram-positive) with rod and round shapes have an intact and

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Fig. 13 Schematic illustration of the preparation and antibacterial application of rGO-QCP-Ag nanoantibacterial agent. QCP, quaternized polymer; rGO, reduced graphene oxide. (Adapted from S. Zhou, H. Ji, Y. Fu, Y. Yang, C. L€ u, Mussel-inspired fabrication of cationic polymer modified rGO supported silver nanoparticles hybrid with robust antibacterial and catalytic reduction performance, Appl. Surf. Sci. 506 (2020) 144655 with kind permission of Elsevier.)

smooth surface. After they have been exposed to the prepared nanocomposite, their shapes are wrinkled and their membranes are damaged. Graphene oxide can be simply modified with diverse organic compounds for developing properties and utilizations comprising medicinal ones, due to many active groups like epoxy, hydroxyl, carboxyl, and carbonyl. Biologically active components such as amines [56] with antiinflammatory features were utilized for the modification of graphene oxide, and their antimicrobial performance was tested against planktonic microorganisms. For the functionalization, a suspension of graphene oxide in dichloroethane was prepared in the presence of dimethylformamide and thionyl chloride. After reflux, amines were added and left overnight. Finally, the suspension was washed with methanol and dichloromethane and dried. The prepared samples presented antimicrobial features.

Innovative progress in functionalized carbon nanomaterials

Fig. 14 Bactericidal mechanism of rGO-QCP-Ag nanohybrid. (Adapted from S. Zhou, H. Ji, Y. Fu, Y. Yang, C. L€ u, Mussel-inspired fabrication of cationic polymer modified rGO supported silver nanoparticles hybrid with robust antibacterial and catalytic reduction performance, Appl. Surf. Sci. 506 (2020) 144655 with kind permission of Elsevier.)

Fig. 15 The morphologies after treatment with TC/PG nanocomposites. White arrows indicate the damaged cells. TC/PG, tetracycline/polyethyleneimine-modified graphene oxide [55].

Gold nanostructures have various biomedical uses due to their unique optical feature, intrinsic antibacterial behavior, and biocompatibility. In an investigation by Feng et al. [57], gold nanostar-functionalized graphene oxide was prepared via a seed-mediated growth technique. Gold nanostars grew on the nanosheet surfaces of graphene oxide by electrostatic attraction between gold nanoparticles (with a positive charge) and graphene oxide (with a negative charge). Through optimizing the amount of graphene

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oxide, excellent graphene oxide/gold nanostar nanocomposites with ideal morphology and good photothermal conversion proficiency were obtained. Feng et al. anticipated that because of the prickly nano-gold structures as well as the softness and sharp edges related to the 2D nanosheet in graphene oxide, the prepared sample could show excellent antimicrobial action toward bacteria. Thus, for investigation of this mechanism, microscopic analysis was performed to study the interactions of the prepared composite with bacteria, as shown in Figs. 16 and 17. However, single gold nanostars showed relatively weak interaction with bacteria. Hence, a 2D construction of a nanocomposite assisted the robust binding attraction to bacteria.

Fig. 16 TEM images of MRSA (A), MRSA incubated with rGO/AuNS0.02 (B) and AuNS (C) after 808 nm NIR irradiation for 6 min, and MRSA incubated with rGO (D). MRSA, methicillin-resistant Staphylococcus aureus. (Adapted from Y. Feng, Q. Chen, Q. Yin, G. Pan, Z. Tu, L. Liu, Reduced graphene oxide functionalized with gold nanostar nanocomposites for synergistically killing bacteria through intrinsic antimicrobial activity and photothermal ablation, ACS Appl. Bio Mater. 2 (2019) 747–756 with kind permission of American Chemical Society.)

Innovative progress in functionalized carbon nanomaterials

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Fig. 17 SEM images of MRSA (A), MRSA incubated with rGO/AuNS0.02 (B) and AuNS (C) after 808 nm NIR irradiation for 6 min, and MRSA incubated with rGO (D). MRSA, methicillin-resistant Staphylococcus aureus; NIR, near-infrared. (Adapted from Y. Feng, Q. Chen, Q. Yin, G. Pan, Z. Tu, L. Liu, Reduced graphene oxide functionalized with gold nanostar nanocomposites for synergistically killing bacteria through intrinsic antimicrobial activity and photothermal ablation, ACS Appl. Bio Mater. 2 (2019) 747–756 with kind permission of American Chemical Society.)

4. Biosensor utilization of functionalized carbon nanomaterials Coronavirus diseases 2019 (COVID-19), as a pandemic disease with a high prevalence rate has recently spread around the world and so far, it has caused the death of countless people. This disease is transmitted by touching contaminated surfaces as well as through respiratory droplets [58]. Thus, it is very important to recognize and control it. Recently, graphene has been used to control COVID-19 [59], and respectable viral inhibition capacity of graphene has been confirmed. For example, in 2020 [60], many recyclable as well as reusable graphene-based masks were prepared with exceptional superhydrophobic and photothermal behaviors for better protection. In addition, this valuable material can be applied to produce diverse biosensors to recognize COVID-19. Seo and coauthors [61] reported a biosensing device based on field-effect transistor (FET) using functionalized graphene to detect COVID-19 in clinical settings. By applying an interfacing molecule (1-pyrenebutyric acid N-hydroxysuccinimide ester) as a probe linker, this antibody was immobilized on the surface (Fig. 18). This biosensor was prepared through covering graphene sheets of the transistor with a particular spike antibody. The behavior of the biosensor was tested by employing a cultured virus, antigen protein,

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Fig. 18 Schematic diagram of COVID-19 FET sensor operation procedure. Graphene as a sensing material is selected, and a SARS-CoV-2 spike antibody is conjugated onto the graphene sheet via 1-pyrenebutyric acid N-hydroxysuccinimide ester, which is an interfacing molecule as a probe linker. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 [61].

and samples from people with COVID-19. The fabricated biosensor could successfully detect the spike protein at 1 fg/mL concentration. The limits of detection in the culture medium and clinical specimens were 1.6  101 pfu/mL and 2.42  102 copies/mL, respectively. Based on the outcomes, the functionalized graphene-based sensor platform provided fast, simple, and highly responsive detection of the SARS-CoV-2 virus in clinical samples. Graphene, with great characteristics such as 2600 m2 g
1 surface area, high electrocatalytic activity, and excellent electronic transport features (20,000 cm2 V
1 s
1), along with metal oxide NPs effectively forms promising nanocomposites for sensing performances. Recent studies revealed that TiO2/graphene composites have potential as materials for the preparation of biosensors. For example, in an investigation by Liu et al. [62], TiO2-functionalized reduced graphene oxide microspheres were manufactured and utilized for immobilization of hemoglobin (as a redox protein) for creation of a biosensor for H2O2 detection. Hemoglobin ordinarily displays electrocatalytic action for H2O2. For this aim, graphene oxide was organized from graphite through a modified Hummers’ process. The preparation stages of TiO2/graphene oxide microspheres and corresponding microscopic pictures of the prepared samples at several steps can be seen in Fig. 19. The production steps were generally as follows: first, TiO2 microspheres were prepared; then, using graphene oxide nanosheets, the prepared microspheres were wrapped directly for construction of TiO2@graphene oxide. Lastly, in hydrothermal conditions, the hollow microspheres were synthesized via hydrochloric acid etching reaction. The outcomes of electrochemistry and spectroscopy studies indicated the excellent behavior of a hollow microsphere with stability, biocompatibility for redox protein, and providing

Innovative progress in functionalized carbon nanomaterials

Fig. 19 Schematic illustration of synthesis steps for hollow TiO2-rGO microspheres and corresponding SEM or TEM images. (A) Synthesis steps for hollow TiO2-rGO microspheres. (B and C) SEM images of bare TiO2 microspheres. (D and E) SEM images of TiO2@GO microspheres. (F and G) TEM images of as-prepared hollow TiO2-rGO microsphere. (Adapted from H. Liu, K. Guo, C. Duan, X. Dong, J. Gao, Hollow TiO2 modified reduced graphene oxide microspheres encapsulating hemoglobin for a mediatorfree biosensor, Biosens. Bioelectron. 87 (2017) 473–479 with kind permission of Elsevier.)

respectable protein bio-activity. The reaction mechanism for the hemoglobin-based electrode was suggested as follows: (1) hemoglobin (FeIII) + e
Ð hemoglobin (FeII); (2) hemoglobin (FeII) + H2O2 + 2H+ ! hemoglobin (FeIII) + 2H2O. Some advantages of this work were low detection limit (10 nM), wide linear range (0.1–360 μM), and outstanding long-term stability. Ascorbic acid, as a biological and nutrient molecule with antioxidant properties in human blood, plays an important role in human body functioning. The body needs 100 mg of ascorbic acid daily. Its deficiency has negative effects on the body and its careful evaluation is essential for metabolism. To detect ascorbic acid in the blood plasma, Hashemi and coworkers [63] designed a biosensor by electrochemical approaches using decoration of exfoliated graphene oxide with nano-Ag and Fe3O4 nanoparticles. Active sites in graphene oxide construction (such as carboxyl and hydroxyl) provide uniform

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distribution of particles and significantly enhance the bonding of nanoparticles with surface of graphene oxide; thus, surface treatment of glassy carbon electrode with functionalized-graphene oxide is a promising approach for developing sensitivity as well as capability of electrodes and enabling accurate detection of ascorbic acid. Fig. 20A shows a view of graphene oxide integration with Ag or Age/Fe3O4 core-shell to detect the ascorbic acid. The results indicated significant improvements in sensitivity/selectivity

Fig. 20 (A) A view of integration of GO with either Ag or AgeFe3O4 toward precise detection of AA within diverse media. (B) Oxidation mechanism of AA that leads to its electrochemical sensing. (Adapted from S.A. Hashemi, S.M. Mousavi, S. Bahrani, S. Ramakrishna, A. Babapoor, W.H. Chiang, Coupled graphene oxide with hybrid metallic nanoparticles as potential electrochemical biosensors for precise detection of ascorbic acid within blood, Anal. Chim. Acta 1107 (2020) 183–192 with kind permission of Elsevier.)

Innovative progress in functionalized carbon nanomaterials

of electrodes after modification of functionalized graphene oxide. The sensitivity and detection limit of the sensor were 1146.8 mA mM
1 cm
2 and 74 nM, respectively. In addition, after 15 days, this biosensor retained about 91% of its performance, and continued to show great selectivity and stability. The oxidation apparatus of ascorbic acid that enables electrochemical detecting is shown in Fig. 20B. At pH ¼ 7, ascorbic acid is usually an ascorbate anion (pKa ¼ 4.2). The oxidation mechanism depends on the pH, and with increasing pH goes to negative values. The ascorbate anion oxidizes in two stages: the first one includes one H+ and one e
, and the next step involves a single electron oxidation procedure. Via electro-chemical manner, dehydroascorbic acid can be formed that furtherly causes irreversible hydrolytic process and generates electro inactive 2,3diketogluonic acid specie. In another investigation, [64] a biosensor based on poly(ethylene glycol)functionalized graphene oxide was designed for the profenofos sensing in milk, cabbage, and water. In comparison with traditional detection approaches, this strategy was a sensitive, convenient, simple, and fast method. In addition, by grafting poly(ethylene glycol) onto the surface of graphene oxide, biocompatibility, detection performance, stability in physiological solutions, and adsorption capacity were enhanced. This strategy showed a 0.21 ng/mL detection limit, which was excellent in comparison with the functionalized graphene oxide sensor. Phenolic compounds are extremely dangerous to humans and animals but are widely utilized in many industries including pharmaceuticals. Thus, the determination of them is a significant tissue. In this regard, [65] an amperometric biosensor based on coupling laccase enzyme to modified CNTs was developed to detect phenolic compounds. The resulting sensor demonstrated good sensitivity, which was based on the cyclic enzymatic oxidation of phenol under oxygen consumption and product reduction. Furthermore, the distinctive chemical, electronic, and mechanical features of the CNTs facilitated phenol regeneration at promising low potential. The prepared sensor was significantly stable whereby after 4, 8, and 10 cycles, 99.5%, 82%, and 77% of the catalytic action was retained. Augustine et al. [66] developed a rapid, ultrasensitive, and label-free immunosensor based on MoO3 metal oxide and reduced graphene oxide for the detection of breast cancer. In this study, 1D MoO3 was anchored onto the 2D reduced graphene oxide through hydrothermal production and further functionalized with 3-aminopropyltriethoxysilane. The nanohybrid-based immunosensor displayed developed sensitivity (13 uA mL ng
1 cm
2), low detection limit (0.001 ng mL
1), good surface area (2.58  102 m2 g
1), and high selectivity. Different functional groups and mesoporous construction of this sensor resulted in exceptional stability and reusability. Fattah et al. [67] prepared an inexpensive biosensor to detect a special antigen using antibody-functionalized CNTs. With immobilization of CNTs with an antibody, a selective biosensor for detection of a special antigen can be designed, since antigenantibody complexes on the surface of CNTs can moderate the current flow. For this

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aim, CNTs were functionalized twice, first with Fe3O4 nanocrystals and subsequently with the antibody. A biological ink comprising functionalized CNTs was synthesized. Then, this magnetic ink by a pipette and under an external magnetic field was printed and self-organized into an electrical-conductive strip and served as a biosensor for the determination of a specific antigen (Fig. 21). This detection system was simpler, faster, and less expensive than cyclic voltammogram analysis. Monitoring of glucose levels in the blood is vital for human health. It is estimated that by 2030, approximately 439 million people will have diabetes. One method to monitor the glucose level in plasma involves employing enzyme-based glucose sensors. In a study, [68] to achieve fast determination of glucose, modified aligned CNT arrays were applied for the preparation of a highly sensitive biosensor. By the chemical vapor deposition method, carbon nanotube arrays were grown on a composite substrate composed of silicon, alumina, and iron. Then, on the CNTs, electro-deposition of conductive polyaniline and covalent attachment of glucose oxidase were performed. The prepared pointof-care sensor was used effectively for glucose detection in plasma. Some results of this method were 1.1 μM detection limit and 620 μA mM
1 cm
2 sensitivity in a 2–426 μM linear range. Phosphorus is a nutrient that plays a beneficial role in the human body. This substance is converted to phosphate in the presence of oxygen in the body after consumption. Phosphate has a significant character in the synthesis of coenzymes and phospholipids, and also the metabolism of carbohydrates. The imbalance of phosphate in the body ( 20), comprising of carbon atoms on a spherical surface. Carbon atoms are generally positioned on the surface of the sphere at the vertices of pentagons and hexagons. In fullerenes, carbon atoms commonly exist in the sp2-hybrid form and are interconnected by covalent bonds. The fullerene C60 is the most recognized and best-explored fullerene. It has a unique cage structure with a three-dimensional complex. Their unique physical and chemical characteristics may be due to the distinct molecular stereotype. The three-dimensional space assembly and several double bonds of C60 offer a broad space for the progress of fullerene science [2]. The sphere-shaped molecule is highly symmetric and comprises of 60 carbon atoms, situated at the vertices of 20 hexagons and 12 pentagons. The diameter of the fullerene C60 is 0.7 nm (13). Fullerene has a property of radical scavenging, due to which it has applications in cosmetics and antiaging [14]. Furthermore, due to its unique physical and chemical characteristics, fullerene can be extensively and essentially used in many areas [15], including biomedicine [16,17], photocatalysts [18], electronic devices [19], the environment [20], and many more.

2.2 Carbon nanotubes (CNTs) Carbon nanotubes (CNTs) are one of the carbon allotropes among other carbonbased nanomaterials with unique properties suitable for technical applications. They were described in 1991 by the Japanese researcher S. Iijima. CNTs consist of cylindrically rolled (graphene) GRA sheets with fullerene covered in the ends with a diameter of several nanometers. CNTs vary in chirality (symmetry of the rolled graphite sheet), diameter, length, and the number of layers. According to their structure, CNTs are categorized into two main categories: single-walled nanotubes (SWCNTs) and multiwalled nanotubes (MWCNTs). Additionally, some researchers isolate double-walled carbon nanotubes (DWCNTs) as a separate group of CNTs. Usually, SWCNTs have a diameter of around 1–3 nm and a length of a few micrometers. Multiwalled CNTs have a diameter of around 5–40 nm and a length of approximately 10 μm. The structure of CNTs indicates remarkable properties with an exceptional combination of rigidity, strength, and elasticity in comparison to other fibrous materials. For example, CNTs show significantly greater aspect ratios (length to diameter ratios) than other materials, and higher aspect ratios for SWCNTs in comparison to

Regulatory and toxicological perspectives of carbon nanomaterials

MWCNTs because of their smaller diameter. Furthermore, CNTs exhibit high thermal and electrical conductivity in comparison to other conductive materials. The electrical characteristics of SWCNTs depend on their chirality or hexagon orientation of the tube axis. Hence, SWCNTs are categorized into three subgroups: (i) armchair (electrical conductivity > copper), (ii) zigzag (semiconductive properties), and (iii) chiral (semiconductive properties). In comparison, MWCNTs, constituted of several carbon layers, usually with variable chirality, can demonstrate outstanding mechanical characteristics instead of extraordinary electrical properties. In the last few years, CNTs have drawn great attention due to their unique characteristics and application aspects in several prospects of nanotechnology. CNTs exhibit remarkable optical and electronic properties, due to their distinct one-dimensional nanostructures which vary from other carbon materials and other kinds of nanoparticles [21]. Additionally, CNTs exhibit small size, good surface function, good biocompatibility, and high reactivity. Thus, they can be used extensively in the areas of biomedicine [22], energy [23], electronics [24], analysis and catalysis [25], and photoelectricity [26].

2.3 Graphene (GRA) Graphene (GRA) is a single plane hexagonal or multislice two-dimensional allotropic form of carbon. It is composed of sp2 bonded C-atoms [27] connected by σ- and π-bonds with a distance of 0.142 nm between neighboring atoms of carbon hexagons. GRA also demonstrates similarities in the structure and properties of some other carbon allotropes, such as graphite, fullerenes, and carbon nanotubes. Since the carbon atoms of GRA are bonded by carbon bonds and hence the bond energy is large, the mechanical characteristics of GRA are enhanced than those of ordinary nanomaterials, which can be utilized to fabricate high mechanical strength complexes. GRA has variable sizes ranging from nanometers to microns. Furthermore, its chemical characteristics will vary according to its size [27]. GRA exhibits a physical structure with a layer of carbon atoms packed in a honeycomb lattice, which is quite inexplicable [28]. It is a singlelayer complex with low-dimensional physics [29] and demonstrates unique physical characteristics such as excellent conductivity, mechanical flexibility, optical transparency [22], high thermal stability, and low coefficient of thermal expansion [30]. Moreover, the electric properties of GRA vary from the properties of three-dimensional substances. Hence, GRA has extensive applications in batteries [3], electronic devices [31], sensors [1], and wastewater treatment. GRA also has a wide range of derivatives, such as GRA nanoribbons, graphene oxide (GO), reduced graphene oxide (RGO), fluorographene, and many more. The existence of these derivatives extends the scope of applications of GRA [32,33] (Fig. 2).

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Fig. 2 Structure of carbon-based nanoparticles.

3. Synthesis of carbon nanomaterials Carbon Nanotubes: For the synthesis of CNTs, the methods usually employed are laser ablation, arc discharge, and chemical vapor deposition (CVD) [34]. Currently, CVD is one of the most studied and commonly employed methods for CNT synthesis [35]. The CVD method of synthesis uses simpler equipment, and the conditions of pressure and temperature are milder in comparison to the other two methods, making it favorable for synthesizing CNTs on a large scale [36]. CVD involves hydrocarbon decomposition to produce carbon and utilizing several substrates containing catalysts on which the nanotubes are growing to generate carbon nanomaterials. Generally, reaction chambers, inert gas-filled tubes, and hydrocarbon are the reactor components for the synthesis of CVD. Ethylene or acetylene is usually employed for the

Regulatory and toxicological perspectives of carbon nanomaterials

synthesis of MWCNTs, whereas methane is employed for SWCNTs. In the process, the substrate is subjected to the heat, until its temperature rises to 550–700°C for MWCNTs and to 850–1000°C in the case of SWCNT synthesis. Thermal decomposition of hydrocarbons results in the production of carbon and it dissolves in the metal nanoparticle catalyst. A semifullerene cap is formed after reaching a threshold of carbon concentration. It is an initial structure for the generation of a cylindrical shell nanotube, which is formed by a consistent flow of carbon from the hydrocarbon source to the catalyst particle. Final removal of the catalysts from the tips of the nanotubes and further purification is still under development and optimization in order to yield CNTs of higher quality [37,38]. Graphene: Research on graphene has been greatly advanced and several methods for synthesizing graphene are employed [39]. Graphene sheets were produced for the first time via mechanical splitting of graphite with adhesive tape [30]. A range of chemical and physical techniques are used, involving cutting or splitting materials to obtain nanoscale graphene sheets, such as nanotubes or graphite [40]. Laser ablation and CVD synthesis can also be employed for generating graphene sheets. Depending upon the applications, qualities of the obtained reduced graphene oxide sheets or graphene are different according to the different methods used. For structural applications, low-cost, moderate-quality graphene can be obtained in bulk amounts. On the other hand, graphene of high quality that is created in smaller amounts is more expensive. Commonly employed techniques for obtaining graphene in bulk are CVD synthesis, synthesis on silicon carbide, liquid phase, and thermal exfoliation of graphite [39]. Fullerenes: Carbon vapors are the components that are generally used for the synthesis of carbon nanomaterials. Evaporation of graphite electrodes in a helium atmosphere was the pathway through which fullerenes were synthesized for the first time in 1990 [41,42]. An electric arc was later created between two graphite electrodes for modifying the reactor. The soot which is thereby formed is captured and processed in benzene, boiling toluene, xylene, or other organic solvents after it condenses on the cold surface of the reactor. Formation of a black condensate takes place after evaporation of the solvents, which consists of 10%–15% of C60 and C70 fullerenes and small amounts of higher fullerenes. The ratio between the C60 and C70 fullerenes is variable, but generally C70 is formed in a smaller fraction in comparison to C60. The arc discharge method is one of a larger group of plasma methods that are most preferred and are usually employed in comparison to other methods [43]. However, due to lesser productivity of the available synthesis methods and high costs, the practical application of fullerenes is restricted.

4. Toxicity investigations for carbon nanomaterials Carbon Nanotubes: For evaluating the harmful effects of CNTs’ administration on human health and the environment, various animal models have been employed (Table 1). Nonfunctionalized CNTs were tested upon animals by employing them

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Table 1 Various toxic effects produced by different types of carbon nanomaterials. Carbon S. no. nanomaterial

Toxic effect

Reference

1.

Pulmonary toxicity

[44]

Pathogenicity in mice Inhibition of HEK 293 cell line proliferation

[45] [48]

Apoptosis of T-lymphocytes Cell death in bacteria Disruption in the cell structure along with toxic effects toward proteins DNA damage Lung injury

[49] [50] [51]

4. 5. 6.

Nonfunctionalized CNTs MWCNTs SWCNTs and MWCNTs MWCNTs SWCNTs Fullerenes (C60)

7. 8.

Fullerenes (C60) Graphene

2. 3.

[52] [53]

intratracheally, which resulted in the accumulation of raw CNTs in lung airways, leading to pulmonary toxicity [44]. These instances indicate that aerosol vulnerability of nonfunctionalized CNTs should be avoided to ensure the safety of human health at workplaces. In addition, a study demonstrated that on exposure of the mesothelial lining of the body cavity of mice to MWCNTs with diameters of 80–160 nm and lengths of 10–50 nm, pathogenicity was caused which was similar to that of asbestos [45]. Yet the conclusion from this study was not enough to determine the harmful effects of CNTs on human health. The MWCNTs employed in this research were nonfunctionalized. On the other hand, MWCNTs of diameter 10–14 nm and length 1–20 nm exhibit no significant toxicity, indicating that the toxicity profiles of various CNTs depend on their sizes. Functionalized SWCNTs have completely different characteristics from MWCNTs, which have diameters of 1–2 nm and lengths of 50–300 nm [45]. In vivo toxicity of covalently and noncovalently PEGylated SWCNTs have been evaluated [46]. Mice were infused with PEGylated SWCNTs intravenously and were observed for more than 4 months. It was reported that the blood biochemistry and tissue evaluations were normal. Therefore, it was indicated that functionalized SWCNTS were more biocompatible and favorable for biological applications. PEGylated SWCNTs are also known to be eliminated from the body in mouse models and not cause any significant toxicity issues [47]. The toxicity caused by CNTs also requires attention in the context of in vitro cell culture experiments. Different studies found that the application of SWCNTs [54] and MWCNTs resulted in inhibition of cell proliferation in HEK 293 cell line along with high necrosis/apoptosis of human skin fibroblasts [48]. It should be noted that CNTs employed in those studies were nonfunctionalized. Oxidized MWCNTs in a study were able to cause apoptosis of T-lymphocytes [49]. Sayes et al. indicated that the density of

Regulatory and toxicological perspectives of carbon nanomaterials

functionalization also influenced the toxicity of CNTs. CNTs functionalized with high density of phenyl-SO3X groups exhibited insignificant levels of toxicity [55]. CNTs without functionalization possess a hydrophobic surface due to which they accumulate during the experiments. This further results in their interactions with various biological entities such as proteins, thereby causing cellular toxicity. There are other factors that might play a vital role in the toxicity exhibited by CNTs in vitro. Surfactants are one such example; their excessive use in CNT suspensions leads to high cellular toxicity [56]. Analysis should also be carried out regarding the metal catalyst used during CNT production [57]. In addition to these, bacteria can be used to observe the effects caused upon CNTs application [58]. In the case of both deposited and suspended bacteria, SWCNTs demonstrate a strong antimicrobial effect through interrupting the formation of bacterial films. Cell death is thereby caused via interaction between bacteria and SWCNTs [50]. Higher physical perforations in bacterial membranes result in the application of individual SWCNTs that are well-dispersed, due to which they are even more toxic than the agglomerates [59]. In comparison to SWCNTs, MWCNTs are less toxic toward bacteria [50] because of fewer interactions between them. The reason for this can be lesser van der Waals forces on the surface of MWCNTs and higher rigidity. MWCNTs with smaller diameters are more toxic to bacteria [60]. Fullerenes: The surface charge is the main characteristic feature that determines the toxicity of C60. It is an aquatic pollutant (aqu-C60) because of its stably dispersed nature in water. Aggregates of C60 were found to be cytotoxic when tested on proteins, and could even disrupt the structure of the cell [51]. C60 is also known to be harmful to DNA [61]. Toxicity in cells can be induced via translocation of BAX proteins caused by C60, which is in turn related to apoptosis in mitochondrial membranes. These cytotoxic effects are produced by C60 because it is relatively light-sensitive, and light excitation can be used to easily form excited fullerenes. Organisms can experience a range of changes caused by exposure to the reactive oxygen species (ROS) that have the potency to attack directly. These changes include membrane degradation, DNA damage, and oxidation of proteins [62]. The damage caused to the DNA by unmodified C60 molecules is because they can accept and exchange electrons with nucleotides [52]. Graphene: Among carbon nanomaterials, graphene has optimum biocompatibility. However, it is found to exert cytotoxic effects, as concluded by some research studies. The physical and chemical properties of graphene primarily determine its cytotoxicity along with some correlation to its dosage. Graphene might ultimately find its way into the environment, thereby increasing risks to both to the environment and human health on account of its increasing production and usage. In the context of embryology, nutrients and metabolites are exchanged at a maternal-fetal level via the placental barrier. It has been found that the growth of the fetus is affected by nanomaterials having size less than 100 nm, which can enter the fetal blood by crossing the placenta [63]. A range of toxic

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effects can be produced by graphene in addition to penetrating the barrier. Graphene nanoparticles accumulate in the lungs after passing through the upper respiratory tract once inhaled [64]. The primary symptom of toxicity in animals is identified as lung injury caused by graphene [53]. The toxicity produced by graphene also affects the reproduction in animals along with causing harm to their central nervous systems.

5. Ecotoxicity of carbon nanomaterials Nowadays, research on carbon nanomaterials (CNMs) is concentrated on development of novel CNMs or their utilization in different areas such as biomedicine and agriculture. However, concerns have emerged about the presence of CNMs in the environment (Table 2). As CNMs are involved in a latest technology and existing properties varying from common contaminants of larger dimensions, the risks of CNMs have to be evaluated. Due to the greater increase in the production volume and widespread applications of CNMs, they can pose threats to the environment and human health. The toxic characteristics of engineered carbon nanomaterials (CNMs) rely sharply on the structure and shape of NPs, size, surface area and charge, the adsorption properties of the nanomaterial, and abiotic factors that include pH, ionic strength, water hardness, solubility, and the existence of natural organic matter (NOM) [65]. NOM is a heterogeneous composition Table 2 Ecotoxicological impact of various carbon nanomaterials. Materials

C60 GRA GRA SWCNTs

Results

ROS produced by C60 can attack organisms directly Graphene’s sharp edge can cut the cell wall of the algae cell Affects the metabolic activity of fish cells SWCNTs have a great effect on the development of Artemia salina in seawater SWCNTs Hormone regulation affecting the brain of zebrafish GRA Neurotoxicity to zebrafish embryo development GO Reduces the fecundity of Spodoptera litura C60 Produces inflammation in rat lung tissue nC60 Can produce acute and chronic toxicity to large cockroaches GRA Causes chronic toxicity to large leeches C60 C60 can cause toxic effects on Escherichia coli, and charge transfer occurs between the two MWCNMs CNMs can inhibit the growth of certain bacteria and fungi MWCNTs High concentration of MWCNTs inhibit the biomass and activity of microorganisms in the soil SWCNTs Concentration of SWCNTs was negatively correlated with the biomass of soil microbial community CNMs Biomass and community structure affect microbial communities

References

[52] [67] [68] [69] [70] [71] [72,73] [74] [75] [76] [77] [78] [79] [80]

Regulatory and toxicological perspectives of carbon nanomaterials

of decomposed animals and plants which is a major pollutant-bearer in nature [66], and can interact with CNMs, resulting in NOM-modified nanomaterials that may be a threat to ecological species through physical, chemical, and biological processes. Scientists have studied the ecotoxicological influence of CNMs, namely fullerenes, graphene, and carbon nanotubes, on algae, fungi, and plants. Accumulation of CNMs in photosynthetic organs increases hindrance in stomata and foliar heating as well as giving rise to modification in physiological processes. More studies on plants and algae, as parts of the food chain, are needed to understand profoundly the toxicity and health risks of CNMs as ecotoxicological stressors. Correct and detailed physical and chemical characterization of CNMs is very important to establish the exposure conditions matching the realistic ones. Ecotoxicological evaluations include examination of both short- and longterm effects. Popularly, CNMs have been regarded as nonpotential contaminants because they comfortably aggregate due to their hydrophobicity and poor dispersion in water [81] According to some of the theoretical calculations, carbon nanotubes (CNTs) cause no significant environmental risk. Nowadays, tons of chemical agents are utilized for agricultural use, and CNMs are considered to be nontoxic novel delivery agents for agricultural chemicals as some of these chemical compounds are highly adsorbed by organic carbon [82]. However, some studies have illustrated that CNTs give rise to toxicity in several organisms, such as protozoa (Stylonychiamytilus), copepods, mice, and rainbow trout, as well as genotoxicity in lymphocyte cell cultures [83–85], although the procedure by which CNTs become a toxic substance is still not clear. Manna et al. [86] and Cui et al. [54] have reported that these CNTs can merge with the plasma membrane elements as well as causing cell destruction via lipid peroxidation and oxidative stress [87] (Fig. 3). Special attention is paid to the surface characteristics of CNMs, which are vital for their aggregation behavior, their mobility in aquatic systems, their interactions with aquatic species, and their viable entry into the food chain. Interactions with NOM and other interactions can alter their aggregation behavior in water. Since CNMs vary in origin, size, and material, they are anticipated to exhibit different biological outcomes. In addition, CNMs of the similar bulk material but with the distinct crystal structure, surface coating, or size can exhibit different effects. For instance, the toxicity of CNTs is influenced by the degree and the order of agglomeration [88]. As only biological impacts of CNMs have been investigated and no data on the presence of CNMs in the aquatic environment are available, their environmental risks are difficult to predict. Initial simulations of three nanomaterials (silver, titanium dioxide (TiO2), and CNTs) have been reported [4]. From the calculations, CNTs appeared to exhibit no significant environmental risk [89]. Ecotoxicological evaluation of fullerenes and CNTs is challenging using existing tools. In addition, the hydrophobicity and van der Waals interactivity of CNTs may insinuate aggregation and sedimentation in aquatic systems, whereas surface functionalization (e.g., functional groups and coating) employed to improve their properties may improve their stability in aqueous systems, hence influencing their

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Intentional

Natural

Nanomaterials

Anthropogenic

Non-intentional

Air

Surface water

Wastewater treatment plants (WWTP)

Remediation of soil and water

Sediment

Sewage Sludge

Effluent

Drinking water

Landfill site

Ground water

Drinking water facility

Soil

Fig. 3 Fate of carbon nanomaterials in the environment.

environmental fate and ecotoxicology. Although fullerenes and CNTs are regarded as engineered nanoparticles (ENPs), they are also natural particles (fullerenes) or have direct relatives in the environment (CNTs) [90]. Despite being classified together in terms of anatomy, it is clear that fullerenes and CNTs may behave very differently in the environment. In an aqueous environment, both tend to be cumulative and therefore more efforts are made to modify the surfaces of CNTs to enhance their stability in aqueous suspensions [91].

6. Issues and research needs in carbon nanomaterial toxicology There is a general consensus among researchers, who represent both academia and industry, that further work is required on all of the novel carbon nanomaterials (CNMs) to assess their toxicity and health risks sufficiently. Another common issue is the requirement for awareness while interpreting data attained by utilizing these highly composite bio/nanomaterial systems. The contributing authors also cite a wide-ranging number of specific issues and research requirements that may be useful to readers entering this new field of research. We highlight a few of these in the following sections.

Regulatory and toxicological perspectives of carbon nanomaterials

6.1 Necessity for detailed material characterization There exists extensive agreement that future investigations should impose more emphasis on detailed characterization of test nanomaterials. Most pragmatic carbon nanomaterials (CNMs) are now recognized to be complex combinations having multiple carbon forms and metal remnants of different chemistry, particle size, and mode of attachment with carbon. In several cases, the discovered toxicity indices may consider these by-products or remnants rather than the elementary material structure. Encountering these needs requires collaboration between toxicologists and materials scientists.

6.2 Necessity for methods to track nanomaterials in biomaterials investigations Light microscopies are preferred techniques in the life sciences, but are challenging to adapt for nanomaterial studies as the materials’ composition in examination lies under optical resolution limits. Thin section TEM analysis could be very effective but is challenging and time-consuming. Fluorescence detection has been revealed to be achievable, but research is necessary for identifying the optimum ways of covalently or adsorptively connecting fluorophores to nanomaterials as well as complementary studies to evaluate whether these fluorophores modify nanomaterial surface chemistry and consequently alter their toxicity and transport in organisms. Secondary variation of the chemical or surface characteristics of CNMs by host cells or tissues should be considered in the investigational design. Nanoparticles may be transferred from the site of entrance, and sensitive approaches of detection are required to measure the level of systemic transport and tenacity at distant organs following dermal exposure, inhalation, ingestion, injection, or implantation. This part of the field is wide open for the progress of new experimental tools at the interface of biotechnology and materials science [92].

7. Biodegradation of carbon nanomaterials The biodegradation practices of CNMs mainly comprise of enzymatic degradation, cell degradation, and bacterial degradation. Among these, enzymatic degradation is an intensively studied topic in the biodegradation of CNMs (Table 3), and we can see the key process of catalytic degradation of CNMs. The biodegradation of CNMs employing bacteria is mainly associated with electron transfer. The transmittance of electrons causes the CdC chemical bond to disrupt, making numerous pores, in turn affecting the surface structure of the CNMs to be damaged and degraded.

7.1 CNT biodegradation The study of CNT biodegradation is always related with several types of enzymes. Scientists have verified that CNTs can be biodegraded in the natural environment via

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Table 3 Enzymatic degradation of carbon nanomaterials. Enzyme CNMs

MPO HRP HRP

LPO

MnP HRP LiP

Principle

SWCNTs, Degradation of CNTs by MPO mainly depends on the GO hypochlorite produced in vivo MWCNTs MWCNTs is oxidized by HRP and H2O2, which leads to many defects SWCNTs There is a strong interaction between SWCNTs and proteins which makes the active sites of HRP close to the carboxylated SWCNT substrates SWCNTs LPO combination with NaSCN and H2O2 can form hypothiocyanous acid which is capable of modifying the phospholipids adsorbed to the SWCNTs SWCNTs Conformational change in MnP can be enhanced by SWCNTs GO There is electron transfer between graphene and bacteria GRAs LiP is a peroxidase with stronger redox properties than HRP and MPO

References

[93] [94,95] [96]

[97–99]

[100] [101] [102]

enzyme catalysis [103,104]. The deterioration of SWCNTs is comparatively simple. Myeloperoxidase (MPO) in human neutrophils boosts the biodegradation of SWCNTs, as it comprises of hypochlorite and reactive free radical intermediates. It can be understood that both the human eosinophil peroxidase (EPO) (in vivo) as well as EPO activated in vitro can also catalyze the oxidative degradation of SWCNTs. Furthermore, Chen et al. [100] employed two distinct enzymes, manganese peroxidase (MnP) and ligninperoxide (LiP) to examine the molecular foundation of SWCNTs degradation, where MnP was capable of degrading SWCNTs as it can undergo a conformational transition which plays a key role in the biodegradation of SWCNTs. LiP could not degrade the original SWCNTs, but was capable of degrading the treated carboxylated SWCNTs. Chen et al. [99] also studied the molecular basis of CNT degradation by employing functionalization with the help of two known biodegradative enzymes, horseradish peroxidase (HRP) and lactoperoxidase (LPO). The results revealed that the functionalization energy can enhance the stability of the complexes produced by enzyme and substrate reactions through carboxylation. The degradation of MWCNTs is not the same as SWCNTs because SWCNTs have only single layer, while MWCNTs are made up of multiple layers, which would disturb the secretion of HRP. The degradation level of MWCNTs is associated to their carboxylation degree. In comparison with SWCNTs, it takes longer to reduce MWCNTs with HRP. Distinct cells have distinct principles to be employed for the degradation of CNTs. Some cells reduce CNTs via their self-peroxidase, while the phagocytic cells reduce CNTs via phagocytosis accompanied by a series of reactions. After their primary structures are reduced, MWCNTs are more vulnerable to degradation by phagocytic cells [105]. Bacteria are extensively found in

Regulatory and toxicological perspectives of carbon nanomaterials

nature, and the degradation of CNTs by the help of bacteria takes a longer time as CNTs are biocompatible and can adsorb bacteria on their surface, and the reaction of bacteria with CNTs begins at their defect, edge, or surface. Bacteria can pressurize MWCNTs and then yield peroxidase. The conformation of their active site has a strong connection, which increases the ability of bacteria to degrade MWCNTs [106].

7.2 Graphene biodegradation Regarding the biodegradation of graphene (GRA), some researchers have discovered that microbial bacteria are capable of oxidizing GRA materials. There is electron relocation in GRA; consequently, there is reduction in the volume of the material and subsequent degradation of the material. Furthermore, numerous enzymes can degrade GRA. HRP was formerly employed to degrade carbon materials and then used in biodegradation of CNTs and GRA. GO oxidation reaction damaged the crystal arrangement, resulting in defects which promoted the biodegradation of GO. HRP can also degrade 3D GRA materials in engineering applications. Thereafter the GRA sheet is slowly corroded into a single layer; the edges slowly dissolve and eventually degrade to CO2. The degradation of GO by MPO in myeloid cells principally depends on the generation of strong oxidant hypochloric acid, which then reacts with the functional group in GRA to disrupt it, thus achieving the purpose of degradation. The almost certain area for degradation of GRA materials remains on the oxygen-containing groups on its surface [107]. Furthermore, LiP produced by white rot fungi can also degrade GRA materials. Peroxidase has stronger redox properties than HRP and MPO, which can effectively degrade GRA, and is widely present in the environment [102]. Some scientists have also analyzed a new “design degradation” procedure, which has been employed for GO degradation. Several molecules are combined to the surface of GO to intensify its attraction to the enzyme near the active site, or to increase the oxidation speed of the enzyme by controlling the electron transfer between GO and the enzyme. The results indicated that covalently bound GO is more easily biodegradable. The biodegradation of GO chiefly depends on the functional groups binding to its surface. The degradation methods of CNMs by cells and bacteria are comparable. After the bacterial degradation reaction of GO, many pores are formed on the surface. As the chemical bond is broken, CO2 is produced during the degradation procedure, and GO gradually becomes fragmented as the degradation reaction proceeds [101]. Both E. coli and Shewanella bacteria can efficiently vitiate GO, providing electrons and transferring them extracellularly to restore GO [108].

7.3 Fullerene (C60) biodegradation Presently, there are not many studies on C60 biodegradation, and the predominantly reported ones are related to bacteria. C60 can be mineralized in soil, specifically clay and organic blower soil, which can enhance the quick and complete mineralization of

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C60. In the existence of soil bacteria, C60 is challenging to degrade [109]. In the organicrich clay, the presence of agricultural soil bacteria greatly improves the mineralization degradation rate of C60 [110]. Moreover, Chae et al. utilized the strain of the genus coriobacter to disrupt C60. It was discovered that the volume of C60 aggregates decreased under the state of microorganism [111]. As the surface of CNMs is negatively charged, bacteria can perform as electron acceptors whereas when their surface is positively charged, bacteria can transmit electrons to CNMs [101]. On the verge of electron transfer, bacterial degradation of CNMs is caused to undergo oxygen intervention [112]. The enzymes that degrade CNMs are mostly HRP, MPO, MnP, and LiP. These four enzymes need H2O2 to take part in the degradation of CNMs. The negatively charged functional group on the surface of CNMs is crucial for its binding to the enzymes. The enzyme consists of positively charged amino acid remnants, which are destined by electrostatic interaction. Nonfunctionalized CNMs may not be degraded, and their degradation arises at the defect. The treated CNMs have more defects, which is more favorable for the arrangement with the enzyme. Biodegradation is an environmentally friendly degradation technique. Nevertheless, a gap persists between experimental research and actual conditions. CNMs are simply adsorbed along with various other pollutants in the environment, which makes it complex for the practical degradation of CNMs in the environment. Therefore, further research is still required to study the degradation of CNMs [113].

8. Conclusion In recent years, apart from the applications of carbon nanomaterials, various studies have been conducted to analyze their toxicity. These nanomaterials can cause toxic effects for humans, animals, and the environment. Due to this nature, their use in vivo is restricted. However, it has been emphasized that appropriately functionalized carbon nanomaterials with suitable agents were able to reduce their toxic effects significantly on human health and were much more apt for biomedical applications in comparison to those that were nonfunctionalized. These aspects should be studied in future even more deeply to identify more of such agents which can help to decrease the cytotoxicity of these nanomaterials. Toxicology studies have many areas of improvement when it comes to carbon nanomaterials, including research on more methods which could efficiently track the performance and effects of these nanomaterials during biomedical applications. An overview of the biodegradation processes of carbon nanomaterials was also discussed, as these also play a significant role in reducing CNMs’ toxicity in an efficient manner. The future applications of these nanomaterials can be significantly enhanced by having defined control over their toxicity profiles and by developing effective regulatory methods for them.

Regulatory and toxicological perspectives of carbon nanomaterials

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[94] G. Modugno, F. Ksar, A. Battigelli, J. Russier, P. Lonchambon, E.E.D. Silva, C. Menard Moyon, B. Soula, A.M. Galibert, M. Pinault, A comparative study on the enzymatic biodegradability of covalently functionalized double- and multi-walled carbon nanotubes, Carbon 100 (2016) 367–374. [95] Z. Yong, B.L. Allen, S. Alexander, Enzymatic degradation of multiwalled carbon nanotubes, J. Phys. Chem. A 115 (2011) 9536. [96] B.L. Allen, G.P. Kotchey, Y. Chen, N.V.K. Yanamala, J. Klein-Seetharaman, V.E. Kagan, A. Star, Mechanistic investigations of horseradish peroxidase-catalyzed degradation of single-walled carbon nanotubes, J. Am. Chem. Soc. 131 (2009) 17194–17205. [97] Bhattacharya et al., 2015. [98] M. Chen, X. Qin, G. Zeng, Biodegradation of carbon nanotubes, graphene, and their derivatives, Trends Biotechnol. 35 (2017) 836–846. [99] M. Chen, G. Zeng, P. Xu, Y. Zhang, D. Jiang, S. Zhou, Understanding enzymatic degradation of single-walled carbon nanotubes triggered by functionalization using molecular dynamics simulation, Environ. Sci. Nano 4 (2017) 720–727. [100] M. Chen, X. Qin, J. Li, G. Zeng, Probing molecular basis of single-walled carbon nanotube degradation and nondegradation by enzymes based on manganese peroxidase and lignin peroxidase, RSC Adv. 6 (2016) 3592–3599. [101] L. Liu, C. Zhu, M. Fan, C. Chen, Y. Huang, Q. Hao, J. Yang, H. Wang, D. Sun, Oxidation and degradation of graphitic materials by naphthalene-degrading bacteria, Nanoscale 7 (2015) 13619–13628. [102] K. Zhao, Y. Hao, M. Zhu, G. Cheng, A review: biodegradation strategy of graphene-based materials, Acta Chim. Sin. 76 (2018) 168. [103] B.L. Allen, P.D. Kichambare, P. Gou, I.I. Vlasova, A.A. Kapralov, N. Konduru, V.E. Kagan, A. Star, Biodegradation of single-walled carbon nanotubes through enzymatic catalysis, Nano Lett. 8 (2008) 3899. [104] J. Russier, C. Menardmoyon, E. Venturelli, E. Gravel, G. Marcolongo, M. Meneghetti, E. Doris, A. Bianco, Oxidative biodegradation of single- and multi-walled carbon nanotubes, Nanoscale 3 (2011) 893–896. [105] D. Elgrabli, W. Dachraoui, C. Menard Moyon, X.J. Liu, D. Begin, S. Begin-Colin, A. Bianco, F. Gazeau, D. Alloyeau, Carbon nanotube degradation in macrophages: live nanoscale monitoring and understanding of biological pathway, ACS Nano 9 (2015) 10113–10124. [106] R.S. Chouhan, A. Qureshi, B. Yagci, M.A. G€ ulg€ un, V. Ozguz, J.H. Niazi, Biotransformation of multi-walled carbon nanotubes mediated by nanomaterial resistant soil bacteria, Chem. Eng. J. 298 (2016) 1–9. [107] R. Kurapati, J. Russier, M.A. Squillaci, E. Treossi, C. Menard-Moyon, A.E. Del Rio-Castillo, E. Vazquez, P. Samorı`, V. Palermo, A. Bianco, Dispersibility-dependent biodegradation of graphene oxide by myeloperoxidase, Small 11 (2015) 3985–3994. [108] O. Akhavan, E. Ghaderi, Escherichia coli bacteria reduce graphene oxide to bactericidal graphene in a self-limiting manner, Carbon 50 (2012) 1853–1860. [109] R. Avanasi, W.A. Jackson, B. Sherwin, J.F. Mudge, T.A. Anderson, C-60 fullerene soil sorption, biodegradation, and plant uptake, Environ. Sci. Technol. 48 (2014) 2792–2797. [110] T.D. Berry, T.R. Filley, A.P. Clavijo, M.B. Gray, R. Turco, Degradation and microbial uptake of C-60 fullerols in contrasting agricultural soils, Environ. Sci. Technol. 51 (2017) 1387–1394. [111] S.-R. Chae, D.E. Hunt, K. Ikuma, S. Yang, J. Cho, C.K. Gunsch, J. Liu, M.R. Wiesner, Aging of fullerene C-60 nanoparticle suspensions in the presence of microbes, Water Res. 65 (2014) 282–289. [112] E.C. Salas, Z. Sun, A. Luttge, J.M. Tour, Reduction of graphene oxide via bacterial respiration, ACS Nano 4 (2010) 4852–4856. [113] Z. Penga, X. Liu, W. Zhang, Z. Zeng, Z. Liu, C. Zhang, Y. Liu, B. Shao, Q. Liang, W. Tang, X. Yuan, Advances in the application, toxicity and degradation of carbon nanomaterials in environment: a review, Environ. Int. 134 (2020), 105298.

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Perspectives for the toxicological and biodegradation field of carbonaceous nanomaterials and their hybrids Shadpour Mallakpoura, Vajiheh Behranvanda, and Chaudhery Mustansar Hussainb a

Organic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ, United States

b

1. Introduction As can be seen in Fig. 1A, attention to the use of carbon materials for various applications is rapidly increasing. These materials are containing carbon nanotubes (CNTs), carbon black, fullerenes, carbon-based quantum dots (QDs), graphene, etc., which are in various forms such as cylindrical, particles, soccer balls, dots, and sheets (Fig. 1B). Increasing worldwide manufacture of carbon-based nanostructures has led to their increasing discharge into the environment, which may affect microorganisms, plants, or animals. In addition, they may pose a toxicity risk to human health if they enter the body by skin contact, inhalation, ingestion, or injection. This becomes even more important when these materials are used in biological fields and biomedical applications. Physicochemical physiognomies, in vitro assays (cellular and noncellular), and in vivo assays are three key rudiments of the screening strategy of toxicity. Numerous factors, such as the particle size, surface area, and charge, porosity, and functional groups, play significant roles in nanomaterials’ toxicity [1–5]. With these points in mind, this chapter presents a summary of the characteristics of carbonaceous materials such as structure and surface chemistry, and then focuses on their toxicity and factors that affect toxicity.

2. Different kinds of carbon nanomaterials 2.1 Carbon nanotubes (CNTs) CNTs, as one of carbon’s important allotropes, which are about 100 times stronger than steel, are classified as single-walled CNTs (SWCNTs) and multiwalled CNTs (MWCNTs). Through rolling one sheet of graphene into a cylinder, SWCNTs are

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00022-4

Copyright © 2023 Elsevier Ltd. All rights reserved.

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Fig. 1 (A) Obtained documents from Scopus using the keywords “Carbonaceous materials.” (B) Various carbon-based nanomaterials reported to induce cytotoxicity. (Adapted from X. Yuan, X. Zhang, L. Sun, Y. Wei, X. Wei, Cellular toxicity and immunological effects of carbon-based nanomaterials, Part. Fibre Toxicol. 16 (2019) 1–27 with kind permission of Springer.)

shaped with a typical diameter of approximately 0.8–2 nm. The stacking of multiple sheets of graphene provided MWCNTs with diameters of about 5–20 nm. CNTs exhibit high electrical conductivity, high tensile strength (100
stronger than steel), and surface-to-volume ratio. In addition, they are fairly low-cost and can be functionalized easily [6–10].

Perspectives for the toxicological and biodegradation field

2.2 Fullerene Carbon atoms can create a hollow sphere like a soccer ball, which is identified as C60 fullerene, an amazing stable compound. C60 is also well-known as buckminsterfullerene or buckyball. The fullerene molecule is extremely active and presents high antioxidant properties due to a large quantity of resulting free bonds with different radicals [11,12].

2.3 Graphene A two-dimensional and single-layer honeycomb carbon nanostructure, which is obtained from the isolation of crystalline graphite, represents graphene. This can be employed in different bio-fields, for instance, drug delivery, tissue engineering, bio-electronics, antibacterial materials, etc., due to the possibility of adjusting mechanical features and also the addition of binding sites for functionalization with biomolecules [13,14].

2.4 Carbon-based quantum dots (CQDs) Carbon-based quantum dots (CQDs) are a new advanced class of zero-dimensional carbon nanomaterials, which are classified as particles with a diameter of less than 10 nm known as CQDs, and nanosheets of graphene generally less than 10 nm, so-called graphene QDs (GQDs). There is a significant difference in morphology of CQDs and GQDs; a CQD is a spherical particle, while a GQD has a disk-like structure. Excellent dispersion in water, having many functional groups, and the ability for functionalization with various biological materials have contributed to their use in biomedical applications [15,16].

2.5 Carbon black Carbon black (CB) is a kind of material that contains more than 90% of the pure form of elemental carbon; it is spherical with diameters ranging from 10 to 500 nm. Thanks to facile functionalization, excellent electrical conductivity, the ability of dispersion in solvents, low-cost, and high surface area, CB nanostructures have been paid attention [17,18].

3. Effect of CNTs on biological cells As has been mentioned, the cytotoxicity of carbon-based nanomaterials can be influenced by several factors such as length, size, shape, defects, surface chemistry, metal impurities of carbon nanostructures, etc. [3,19]. According to the literature, CNTs’ toxicity appears to be influenced by many factors such as metal impurities, surface chemistry, degree of aggregation, pretreatment processes, physical form, etc., and different experimental reports have proposed that certain levels of toxicity can be produced by CNTs in different organs [20–22]. One of the important factors that affect the toxicity of CNTs is

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surface functionalization. Because of the hydrophobicity of unfunctionalized CNTs, their stability is low in biologic media. The surface carboxylation’s level on MWCNTs’ cytotoxicity and a threshold level of carboxylation that has proinflammatory influences have been reported [23]. The results showed that only MWCNTs with high-COOH content exacerbated DNFB-induced CHS ear swelling, and they also reduced the cell viability of cultured keratinocytes more than its pristine or low-COOH counterpart. More than 20% surface carboxylation was chosen as a threshold level that deteriorates DNFB-induced CHS responses in contrast to less oxidized MWCNTs. A physicochemical factor that influences the inflammatory response and lung clearance is the rigidity of MWCNTs. Male Sprague Dawley rats were subjected to MWCNTs for 28 days to examine not only pulmonary inflammatory response but also the hematology, blood biochemistry, and histopathology of the lungs [24]. Findings demonstrated that flexible or tangled MWCNTs are less inflammogenic and toxic, and have a shorter release half-time than rigid MWCNTs. Another report examined diameter size and cobalt content as important factors for the toxicity of MWCNTs for lungs [25]. Studies on 11 kinds of MWCNTs with various physicochemical properties showed that these nanomaterials are bio-persistent 1 year after lung exposure. In comparison to the thinner MWCNTs, their needle-like counterparts induce fewer histological changes, and no effect on pulmonary histopathology was observed by surface hydroxylation. The toxicity of carboxylic acid functionalized multiwalled carbon nanotubes (F-MWCNTs) and benzo a pyrene (BaP) in human lung adenocarcinoma cells was examined both individually and combined [26]. The outcomes showed that F-MWCNTs and BaP diminished cell viability and boosted reactive oxygen species (ROS) generation, apoptosis, and oxidative DNA damage, individually, whereas the combined exposure to BaP and F-MWCNTs reduced their toxicity, which may be due to limitation in BaP bioaccessibility to the cells. The level of toxicity and the mechanisms of toxic action of carbon nanofibers, carbon nanotubes, and silica nanotubes using four microalgae species have been reported [27]. The results showed the dependence of silica’s toxicity on its surface area, size, and other surface features. The similarity of the hydrophobic surfaces of carbon and some microalgae cells facilitates adhesion and physical damage of cells. However, CNTs did not have a noteworthy toxic influence on the growth rate of microalgae species; however, due to the presence of heavy metal impurities in their structure, inhibition of high esterase activity and depolarization of cell membranes were observed (the effects were lower in the case of nanofibers due to dissimilar physical availability of toxic impurities from various kinds of NPs to microalgae cells).

Perspectives for the toxicological and biodegradation field

4. Effect of fullerene on biological cells Different physical properties (size and shape), fabrication methods, and surface functionalization have effects on the cytotoxicity of fullerene materials. The hydrophobic nature of fullerene raises the chance of absorbing biological species or accumulating in lipid membranes, which can be avoided by modification with biocompatible moieties. Fullerenes are effective free radical scavengers and can simply react with free radicals. They are known as “radical sponges,” which protect living organisms against damage caused by free radicals [28,29]. Dextran, a natural polysaccharide, was used for the stabilization of fullerene according to the procedure of Fig. 2A and B to study the associated neurotoxicity [30]. The consequences revealed upgrading in fullerene’s solubility in water. According to the transmission electron microscopy (TEM) image (Fig. 2C), spherical particles with sizes in the range of 20–40 nm were obtained, and the surface charge was negative (Fig. 2D).

Fig. 2 (A) Experimental setup for making Dex-C60. A coating of C60 using dextran was produced by mixing a dextran solution under constant stirring, heating, followed by dialysis. (B) Schematic representation of Dex-C60 with C60-dextran bonding. (C) TEM image showing the size distribution of Dex-C60. (D) Zeta potential of Dex-C60 exhibiting potential difference between the particle and water. Dex-C60, dextran-C60; TEM, transmission electron microscopy. (Adapted from T.E. Biby, N. Prajitha, D. Sakthikumar, T. Maekawa, P.V Mohanan, Cellular toxicity on C6 glial cells induced by dextran stabilized fullerene C60, Brain Res. Bull. 155 (2019) 191–201 with kind permission of Elsevier.)

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A

B

Fullerene soot (FS)

Dextran Dex-Fs

100 nm

Fig. 3 (A) Schematic representation of bonding between fullerene soot and dextran polymer. (B) TEM image of dextran functionalized fullerene soot showing an average size of 30.29 nm. TEM, transmission electron microscopy. (Adapted from S.S. Athira, T.E. Biby, P.V. Mohanan, Effect of polymer functionalized fullerene soot on C6 glial cells, Eur. Polym. J. 127 (2020) 109572 with kind permission of Elsevier.)

By increasing the dextran-C60 concentration, cell viability diminished, and ROS production increased. According to the outcomes, the penetration of dextran-C60 into the cells can occur, and cause dose-dependent cellular toxic responses. The in vitro toxicity of fullerene soot as one of the highly exposed forms of fullerenes was examined [31]. In order to increase the stability and dispersion of fullerenes, they were functionalized by dextran molecules, as shown in Fig. 3A. Spherical particles (around 30.29 nm in size) were observed in the TEM image of dextran-fullerene soot (Fig. 3B). Cells in the central nervous system were exposed to the obtained particles, and observations showed by increasing the dose of dextran-fullerene soot toxicity increases (at 160 μg/mL) so that almost half of the exposed cells missed their viability. Thus, the study showed that NPs of fullerene soot are toxic in neuronal tissue.

5. Effect of graphene on biological cells It has been established that there are different mechanisms for cytotoxicity of graphene family nanomaterials (GFNs), as illustrated in Fig. 4. They can hurt cells via physical destruction and releasing intracellular components and ROS production, leading to mitochondrial damage, oxidative stress, DNA damage, etc. [32]. As GFNs are commonly used in tissue engineering, drug delivery, bioimaging, and antibacterial activity, evaluation of the level and degree of the toxicity for their biomedical applications is essential [33,34]. As was mentioned, one of the reasons for the toxicity of carboneous materials is impurities such as metallic species; therefore, purification is an important step in the oxidation process. In 2020, salt-washing (sw) as a new purification technique was introduced and

Perspectives for the toxicological and biodegradation field

Fig. 4 Schematic diagram showed the possible mechanisms of GFNs’ cytotoxicity. GFNs get into cells through different ways, which induce ROS generation, LDH and MDA increases, and Ca2+ release. Subsequently, GFNs cause kinds of cell injury, for instance, cell membrane damage, inflammation, DNA damage, mitochondrial disorders, apoptosis, or necrosis. GFNs, graphene family nanomaterials; LDH, lactate dehydrogenase; MDA, malondialdehyde; ROS, reactive oxygen species. (Adapted from L. Ou, B. Song, H. Liang, J. Liu, X. Feng, B. Deng, T. Sun, L. Shao, Toxicity of graphene-family nanoparticles: a general review of the origins and mechanisms, Part. Fibre Toxicol. 13 (2016) 57 with kind permission of Springer.)

the correlation between the purity of the samples and cytotoxicity was examined [35]. The cytotoxic effect of the samples of graphene oxide (GO), swGO, swGO coated with pluronic F-127 (swGO-F12), and reduced swGO (rswGO) was reported as follows: GO > swGO > swGO-pluronic F-127 > rswGO on noncancer cell lines. By the sw technique, removal of Mn2+ and considerable reduction of the amounts of Al-, K-,

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S-, and Si-containing ions were provided. The findings showed, however, that toxicity of graphene by this technique decreased, but swGO still exhibited toxicity, and for using GO in biomedical applications such as drug carriers, serious limitations should be considered.

6. Effect of carbon-based QDs on biological cells Studies have revealed that carbon-based QDs have excellent biocompatibility, and their in vivo and in vitro toxicities are fairly low in comparison to the conventional semiconductor QDs, GO, and CNTs. The toxicity of these kinds of materials depends on a combination of several factors such as shape, surface chemistry, dose, size, ligand chirality, etc. [36,37]. For the examination of the effect of surface chemistry and charge on the CQDs’ toxicity, various types were selected, such as pristine CDs with negative charge due to carboxylic groups, polyethyleneglycol modified dots with a neutral charge (CDs-PEG), and polyethyleneimine coated dots with a positive charge (CDs-PEI) [38]. The results were interesting as CDs-PEI and pristine CDs exhibited high and medium toxicity, respectively, while CDs-PEG showed the lowest toxicity, which indicates that the latter are the best candidate for cell labeling without influencing cellular processes. There is a strong electrostatic interaction between charged CDs and the cellular membrane, which intensely affects their uptake and more toxicity. CQDs’ toxicity to three freshwater species (zebrafish (Danio rerio), zooplankton (Daphnia magna), and phytoplankton (Scenedesmus obliquus)) were evaluated [39]. The results showed negligible toxicity of CDs (up to 200mg/L) for Danio rerio. Instead, CDs induced mortality and immobility in Daphnia magna with values of 48-h EC50 and LC50 of 97.5 and 160.3mg/L, respectively. The most sensitive organism to CDs’ exposure was Scenedesmus obliquus; the algae’s growth was repressed with a 96-h EC50 value of 74.8mg/L, and water acidification and oxidative stress could be the mechanisms underlying the CDs’ toxicity to Scenedesmus obliquus. In 2014, GQDs’ toxicity was examined in vitro and in vivo, and the tests showed that GQDs, due to their ultra-small size and high oxygen content, revealed very low cytotoxicity, while GO appeared toxic [40]. In 2019, in vitro influences of GQDs (with diameters of around 3nm) on the gene expression of primary human cells (blood-derived CD34+ cells) were assessed [41], and the outcomes showed only marginal influences of GQDs on the transcriptome, along with low toxicity.

7. Effect of carbon black on biological cells The ultrafine sizes of the primary particle (10–500 nm) and their aggregates (80–800 nm) can be key worries about exposure to carbon black (CB). A comparative study about the toxicity of micro- and nano-carbon black presented size-dependent cytotoxicity, and the outcomes showed greater toxicity and inflammatory response in human monocytes for nano-carbon black than micro-carbon black [42,43]. It has been reported that CB does

Perspectives for the toxicological and biodegradation field

not interact with DNA directly, and intracellular ROS generation reduces the cell’s activity [44,45]. ROS generation and the involvement of systemic immune response are two main mechanisms for the toxicological behavior of CB. Its toxicity can lead to cancer, respiratory, and cardiovascular diseases [46]. A comparison study on the toxicity of CB and TiO2 NPs was performed, and similar influences (inflammation, apoptosis, genotoxicity, etc.) were observed; however, the mechanism of toxicity was different [47]. Distinct cellular-induced toxicity mechanisms are the internalization of NPs, which could lead to lysosomal destabilization or accumulation, ROS production capacities, and protein interactions, which the internalization of NPs has a key role for TiO2 toxicity. In contrast, ROS production is the main mechanism for the toxicity of CB NPs. It has been reported that by increasing dose and exposure time, the number of cells filled with CB increases and the extreme particles’ phagocytosis causes cell swelling and lysis [48]. As CB’s toxicity is related to its large surface area, coated CB showed lower biological effects, and the hypothesis for this phenomenon was the reduction of surface area, which leads to ROS reduction [49].

8. Biodegradation of carbon nanomaterials As has been mentioned, carbonaceous materials and their derivatives are extensively employed in various fields, such as biosensors, adsorbents, drug carriers, electronics, and fuel cells, due to their many attractive properties. Thus, their entry into the environment increases because of their extensive application, and due to their toxicity, it is necessary to identify an effective and safe technology for their elimination from the environment. Biodegradation by fungi, bacteria, plant, animal, and microbial enzymes can be introduced for this issue [50]. For CNTs, low thickness, a higher degree of incorporated defects, and short length increase the rate of degradation. Fig. 5 shows a summary of the biological path of CNT degradation in macrophages. Activation of NADPH oxidase happens when CNTs are engulfed by macrophages, inducing the formation of O• 2 . Conversion of superoxide is done by superoxide dismutase (SOD) into H2O2, or by its reaction with free radical nitric oxide (NO•), ONOO is formed. A combination of H2O2 with Cl is made by myeloperoxidase (MPO) enzyme, and hypochlorite is produced; also, H2O2 is changed to OH• in the presence of Fe3+. Produced active species can attack unsaturated carbon bonds and CNT defects, which create holes in the graphitic structure of CNTs and lead to the CNTs’ degradation to carbon dioxide [51,52]. Three different GO samples containing different percentages of the carboxylic group degrees on their surface (GO1 (3.0%), GO2 (1.5%), and GO3 (1.0%)) were selected, and the degradation ability of the enzyme on them was evaluated [53]. After 40 h of the

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Fig. 5 A scheme of CNT degradation in macrophage. CNT, carbon nanotube. (Adapted from M. Yang, M. Zhang, Biodegradation of carbon nanotubes by macrophages, Front. Mater. 6 (2019) 1–7 with kind permission of Frontiers.)

treatment with the enzyme, all samples of GO1, GO2, and GO3, especially sheets of GO1 and GO2 (Fig. 6B, E, and H) totally missed their original morphology in comparison to their control. Altering of most of the sheets of GO1 and GO2 into nanoscale fragments can be observed after 90 h of eosinophil peroxidase (EPO) treatment as well (Fig. 6C, F, L). Overall, the number of degraded fragments for GO3 was lower in comparison to GO1 and GO2 because of fewer defects and the lower amount of oxygenated functions. The mechanism of GO and G biodegradation by blood plasma is shown in Fig. 7 [54]. OH• and O• 2 present in plasma, attack on the carbon-carbon bonds, and the defect sites or nanoholes are created in GO. Multiple attacks lead to collapse and formation of small products (Fig. 7A). About G (Fig. 7B), in the first step, epoxy groups were the main sites of attack, and slight biotransformation occurs for G due to very few active sites. In fact, defects, neighboring CdC/C]C bonds, and oxygenic groups on GO’s surface contributed to GO’s biodegradation, and this caused less stability of GO in blood plasma rather than G. Lipase enzyme degradation of CDs in the presence of hydrogen peroxide (H2O2) was examined, and the results demonstrated that diverse degradation profiles could be obtained with various surface functional groups on CDs. PEG, phospholipids, polyethyleneimine (PEI), and PEG phosphate (PEG-PO4) were employed for the functionalization of CDs and the production of neutral, zwitterionic, positive, and negative NPs, respectively, and their degradation behavior was compared with that of bare CDs [55]. The mechanism of enzymatic actions in the CDs’ metabolism is shown in Fig. 8. By sequential oxidation and CDs’ degradation, fluorescence

Perspectives for the toxicological and biodegradation field

Fig. 6 TEM images of EPO-catalyzed degradation of GO at three time points: control (in DI water, t ¼ 0), t ¼ 40h, and t ¼ 90h; images (A–C) correspond to GO1, (D–F) correspond to GO2, and (G–I) correspond to GO3. Scale bar represents 500 nm. EPO, eosinophil peroxidase; GO, graphene oxide; TEM, transmission electron microscopy. (Adapted from R. Kurapati, C. Martìn, V. Palermo, Y. Nishina, A. Bianco, Biodegradation of graphene materials catalyzed by human eosinophil peroxidase, Faraday Discuss. (2020). https://doi.org/10.1039/C9FD00094A with kind permission of the Royal Society of Chemistry.)

properties decreased, and for all samples, the common by-product from the degradation of different CDs was hydroxymethylfurfural. The rate of degradation of samples was as follows: CDs-PEG > CD-PEI > CD-PEG-PO4 > CD-phospholipid. Fullerene’s degradation by human myeloperoxidase was assessed [56] and the results showed that fullerene is degraded significantly and forms some benzene derivatives under

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Fig. 7 Schematic representation of a proposed mechanism of GFN biodegradation. (A) GO nanosheet; (B) G nanosheet. The sites of GFNs attacked by blood plasma are marked by green dotted circles. G, graphene; GFN, graphene family nanomaterials; GO, graphene oxide. (Adapted from D. Li, X. Hu, S. Zhang, Biomaterials biodegradation of graphene-based nanomaterials in blood plasma affects their biocompatibility, drug delivery, targeted organs and antitumor ability, Biomaterials 202 (2019) 12–25 with kind permission of Elsevier.)

Perspectives for the toxicological and biodegradation field

Fig. 8 Lipase-catalyzed biotransformation of carbon dots. Enzymatic biodegradation in the presence of H2O2 follows a sequential oxidative pathway where intermediates are identified by matrix-assisted laser desorption/ionization spectroscopy. (Adapted from I. Srivastava, D. Sar, P. Mukherjee, A.S. Schwartzduval, Z. Huang, C. Jaramillo, A. Civantos, I. Tripathi, J.P. Allain, R. Bhargava, D. Pan, Enzyme-catalysed biodegradation of carbon dots follows sequential oxidation in a time dependent manner, Nanoscale 11 (2019) 8226 with kind permission of the Royal Society of Chemistry.)

the action of Fenton’s reagent. Myeloperoxidase can catalyze the hypochlorous acid (HOCl) synthesis [57], and the enzyme active center includes a coordinated protoporphyrin IX iron ion, which after reaction with HOCl generates OH•, according to the following reaction, which is similar to the Fenton mechanism: HOCl + Fe2+ ! Fe3+ + OH + Cl

9. Conclusions Because of the extensive use of carbonaceous materials and their derivatives in various fields, such as adsorbents, membranes, biosensors, drug carriers, electronics, and fuel cells, their entry into the environment increases, and due to their toxicity, their degradation and elimination from the environment are desired. Research has shown that a single factor cannot describe nanomaterial-induced toxicity, and a combination of physical (physicochemical characteristics of particles) and biological (cell type and nano-bio interactions) factors determines the outcome. Functionalization, size, impurities, concentration, and exposure time are common factors between carbonaceous materials that influence their toxicities. The most important finding from this literature survey is that surface functionalization and the introduction of structural defects can increase the biocompatibility and biodegradability of carbon-based nanomaterials. It is expected that scientists will conduct research to investigate the toxicity of these nanomaterials and ways to reduce this toxicity, along with the examination of the potential applications of these materials.

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10. Important websites about the topic • https://www.google.com/search?q¼effect+of+carbonaceous+nanomaterials+in +biological+cells&rlz¼1C1GCEA_enIR758IR758& sxsrf¼ALeKk00WvgLbtpnkMmszoAf9Tdp3TydZEQ:1598516847813& source¼lnms&tbm¼isch&sa¼X&ved¼2ahUKEwiTjIan7rrAhXBsHEKHaF5BTsQ_AUoAXoECA4QAw • https://www.google.com/search?rlz¼1C1GCEA_enIR758IR758& sxsrf¼ALeKk02UWHO5S3LY8WEjCveWEqH5VYFN_A%3A1598516831362& ei¼X25HX_PhFfyK1fAP76272Ac&q¼effect+of+carboneous+nanomaterials+on +biological+cells&oq¼effect+of+carboneous+nanomaterials+on+biological +cells&gs_lcp¼CgZwc3ktYWIQAzoECCMQJzoECCEQClCwMViaamDtc WgAcAB4AIABoAKIAaAqkgEEMi0yMZgBAKABAaoBB2d3cy13aXrAAQE& sclient¼psy-ab&ved¼0ahUKEwizjZqf-7rrAhV8RRUIHe_WDnsQ4dUDCA0& uact¼5 • https://www.google.com/search?q¼Biodegradation+of+carbon+nanomaterials& rlz¼1C1GCEA_enIR758IR758& sxsrf¼ALeKk00Ck2o6y0G3OuCO7UR3nU3w47Kt8g:1598516941084& source¼lnms&tbm¼isch&sa¼X&ved¼2ahUKEwiX-cLT7rrAhUTrHEKHTkfDWMQ_AUoAXoECA8QAw • https://www.google.com/search?rlz¼1C1GCEA_enIR758IR758& sxsrf¼ALeKk01wOpXP35xgvfOPIMAQKKoiV05JdQ%3A1598516938363& ei¼ym5HX63tFdKa1fAP7Z67kA4&q¼Biodegradation+of+carbon +nanomaterials&oq¼Biodegradation+of+carbon+nanomaterials&gs_ lcp¼CgZwc3ktYWIQAzIECCMQJ1D2Clj2CmDuDWg AcAB4AIABjgKIAY4CkgEDMi0xmAEAoAEBqgEHZ3dzLXdpesABAQ& sclient¼psy-ab&ved¼0ahUKEwit-pzS-7rrAhVSTRUIHW3PDuIQ4dUDCA0& uact¼5

Acknowledgments The authors are grateful for financial support from the Research Affairs Division of Isfahan University of Technology (IUT), Isfahan. I. R. Iran, and Iran National Science Foundation (INSF), Tehran, I. R. Iran (Grant Number 98015398), and Iran Nanotechnology Initiative Council (INIC) Tehran, I. R. Iran. They are also grateful to the National Elite Foundation (NEF), Tehran, I. R. Iran, and Center of Excellence in Sensors and Green Chemistry IUT. The authors thank Miss. E. Azadi for her scientific assistance.

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Section H Functionalized carbon nanomaterials (FCNMs) —A green and sustainable vision

CHAPTER 22

Functionalized carbon nanomaterials (FCNMs): Green and sustainable vision Shikha Gulati, Shikha, and Sweta Kumari Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, India

Abbreviations ATRP BODIPY CNDs CNDs CNMs CNOs CNTs CQDs DME DNA DOX DWCNTs FCNMs f-PEG GO GQDs HIV Li-FPGNs MWCNTs NDs NIPAM P3HT PANI PCBM PEG PLLA PMMA rGO SWCNTs TA-NiFe@NCNT TEG

atom transfer radical polymerization boron-dipyrromethene carbon nanodiamonds carbon nanodots carbon nanomaterials carbon nano-onions carbon nanotubes carbon quantum dots durable medical equipment deoxyribo nucleic acid doxorubicin double-walled carbon nanotubes functionalized carbon nanomaterials functionalized polyethylene glycols graphene oxide graphene quantum dots human immunodeficiency virus Li-doped fullerened pillared graphene NC multiwalled carbon nanotubes nanodiamonds N-isopropyl acrylamide poly(3-hexylthiophene) polyaniline phenyl-C61-7 acid methyl ester polyethylene glycol poly(lactic acid) poly(methyl methacrylate) reduced graphene oxide single-walled carbon nanotubes tabular assemblies of N-doped CNTs loaded with NiFe alloy NP thermoelectric generator

Functionalized Carbon Nanomaterials for Theranostic Applications https://doi.org/10.1016/B978-0-12-824366-4.00009-1

Copyright © 2023 Elsevier Ltd. All rights reserved.

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1. Introduction The emerging global challenges that contribute to a wide range of pollution encourage researchers to develop sophisticated technologies to address such issues. Nanomaterials have drawn attention from researchers globally as they offer extraordinary characteristics that are suitable for broader applications in sensing, energy harvesting, and also in biomedical purposes. Recently, considerable work has been carried out to produce materials with controlled morphologies for their integration in designing. Among all the elements in nature, carbon accounts for the foundation of life in the atmosphere as it exhibits various orbital hybridizations which allow it to produce distinct chemical bonds with varied orientations [1]. Therefore, in this situation, carbon nanomaterials (CNMs) have emerged as one of the most dominant materials as they have the potential to manufacture various materials such as graphene sheets, carbon fibers, nanodiamonds, etc. due to their superior thermal, electrical, and mechanical qualities [2]. In a very recent work of this decade, the industrialization of CNMs has been increasing drastically via functionalizing the surface of CNMs by various guest species. This has been in the limelight for researchers as pristine or nonfunctionalized CNMs have many disadvantages, such as unstable aggregation in the presence of strong intermolecular interactions including van der Waals forces, dipole-dipole interaction, etc. In particular, the mechanical and electrical characteristics of the CNMs have been imparted by the accumulation; thus, to develop an optimum nanomaterial system, functionalization plays an essential role [3]. The timeline of the progress of CNMs is illustrated in Fig. 1. This chapter sets out the fundamental properties of carbon nanomaterials and their distinctive features over conventional materials. A section is devoted to presenting how imparting the various strategies for the functionalization of different CNMs can accelerate their commercialization as well as to demonstrate the green chemistry concept, its innovative application in sensing, energy harvesting, and biomedical has also been illuminated.

Fig. 1 Timeline of the progress of CNMs.

Functionalized carbon nanomaterials (FCNMs)

2. Fundamental characteristics of carbon nanomaterials Carbon nanomaterials have emerged as an important class of nanotechnology due to their unique structure at the nanometer scale; they also have extraordinary physical and chemical properties, such as large surface area, highly porous structure, and unique thermal, mechanical, or electronic properties [4]. Due to these characteristic structural properties of CNMs, they show exceptionally advantageous applications in numerous fields including biomedical, sensing, energy storage, etc. [5]. It must be noted that the properties of CNMs are highly dependent on their structures, and functionalized CNMs are found to have improved characteristic properties. Functional groups present on CNMs surfaces improve their adsorptive properties and increase their solubility in water and organic solvents [6]. There are different types of carbon nanomaterials, including fullerenes, carbon onions, graphene carbon nanotubes, carbon dots, and nanodiamonds [7]. These CNMs might seem different from each other but they have some similarities, especially in the case of their building units, and one carbon nanomaterial can be transformed into another under certain experimental conditions. However, it is worth noting that the discovery of fullerenes in 1985 brought a revolution in the study of nanomaterials. Many carbonbased nanoforms have been identified since fullerenes, from carbon nanotubes (CNTs) to graphene, carbon dots, and nanodiamonds [8]. Buckminsterfullerene is an allotrope of carbon that exists in spherical, tube, or ellipsoid shapes. Due to the extraordinary structural properties of CNMs, they can be used as excellent adsorbents in wastewater treatment [9]. With the advent of CNTs and graphene, their importance has diminished somewhat. Carbon nanotubes are cylindrical-shaped molecules having a radius of a few nanometers, which can be extended up to 20 cm in length. CNTs can be further divided into types as single-walled CNTs (SWCNTs), double-walled CNTs (DWCNTs), and multiwalled CNTs (MWCNTs) [10]. CNTs are highly porous, and have high thermal and mechanical stability which enhances their applications; however, they also have some limitations which hinder their commercialization. The functionalization of CNTs can overcome these limitations [11]. Functionalization of CNTs with -OH and -COOH groups increases their solubility in water and other organic solvents. Graphene is a twodimensional allotrope of carbon having a hexagonal honeycomb structure. According to various studies, it has been found that derivatives of graphene, such as graphene oxide (GO), reduced graphene oxide (rGO), and GO nanocomposites, show superior physicochemical properties compared to pristine graphene due to the presence of different functional groups on their surfaces [12]. Carbon dots (C-dots) are spherical carbon particles of sizes less than 10 nm. The C-dots can be divided into various subgroups, such as graphene dots, graphite dots, amorphous carbon dots, and polymer-like dots [13]. C-dots always contain several functional groups, such as hydroxyl, epoxy/ether, carbonyl, and

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carboxylic acid groups, on the surface [14]. Crystalline C-dots are superior to the amorphous ones based on their structure and properties. C-dots can be functionalized easily by inorganic and organic micro-molecules, which can further enhance their sensing and catalytic activity [15].

3. Advantages of functionalized carbon nanomaterials (FCNMs) over conventional materials Many earlier studies have identified carbon as a very crucial material for industrial application. It is worth noting that the electron orbital feature of carbon offers different properties as well as numerous morphologies. Although several studies concerning the fast growth of nanotechnology have been reported over the past few decades, the utilization of carbon nanomaterials has only recently attracted the interest of researchers [11]. As this research has progressed, it has become clear that carbon nanomaterials have an increasingly significant impact on commercialization and industrialization. The novel CNMs are constituted mainly of sp2 hybridized carbon atoms. In 1991, Iijima et al. presented the very first report for the synthesis of CNMs. Following this, several sorts of carbon nanomaterials, such as fullerene, graphene, and carbon nanotubes, have been widely studied by researchers [16]. In addition, while these materials are unstable in many solvents and have low durability, functionalized carbon nanomaterials (FCNMs) stand out as a promising type of material. FCNMs are a new class of designed carbon nanomaterials. Their topology is altered to produce an appropriate material for a specific application. FCNMs have an outstanding set of properties such as chemical versatility, thermal stability, hydrophobicity, advanced optical features, etc. They have many significant advantages over pristine carbon or other conventional materials. Due to their extraordinary features, FCNMs have been extensively studied for their wide range of applications in sensing, energy harvesting, and many other biomedical uses [11]. Various fascinating characteristics of FCNMs that distinguish them as ideal materials over other conventional materials are shown in Fig. 2.

Mechanical property

Thermal stability

Chemical versatility

Electrical conductivity

Fig. 2 The fascinating properties of FCNMs.

Functionalized carbon nanomaterials (FCNMs)

Due to various distinct combinations of characteristics and highly organized crystalline structure, it is paramount to emphasize that both the structure and degree of functionalization of CNMs are adjustable. In a study by Coyunco and coworkers, different functionalized CNMs were constructed using desirable techniques. The prepared FCNMs, after 24 h of exposure, demonstrated negligible caco-2-monolayer toxicity to living cells. This work validates the significance of FCNMs in the pharmaceutical application for drug transportation, reflecting the mechanical stability of the materials that could not be successfully replicated by traditional nanomaterials [17]. Thermal analysis, which identifies the ability of the material to resist any change in its physical and chemical properties upon heating to a relatively high temperature, is a crucial factor for studying manufacture and modification procedures [18]. In particular, the main attributes of thermal analysis of CNMs are: • rate of heating; • gas atmosphere; and • heating regime. As a result, all of these aspects contribute to the development of FCNMs other traditional catalysts in a broader range of applications for FCNMs.

4. Green and sustainable strategies for the functionalization of various carbon nanomaterials Nanomaterials and nanotechnology have become well-known topics due to nanomaterials’ extraordinary physical, chemical, and mechanical properties. With the advent of nanomaterials, it has become possible to have lighter, better, smaller, and faster products. Raw nanomaterials lack some properties in one way or another that hinders their commercial applications. For example, water is used as a solvent in many applications, such as wastewater treatment or biomedical applications. As CNMs show poor solubility in water, most of them have difficult workability in this regard, and functionalization of nanomaterials becomes necessary. Functionalization increases CNMs’ applicability by surface modification and makes it easier to explore their uses. During the synthesis of FCNMs, sometimes toxic solvents like dichloromethane, hydrazine, etc. are used which are harmful to the environment, and thus their use should be minimized. Green synthesis of functionalized carbon nanomaterials using environmentally friendly and renewable resources may be a viable alternative to toxic solvents used in conventional methods. Green synthesis of functionalized carbon nanomaterials has various benefits, such as being: • inexpensive; • environmentally friendly; • biodegradable; • more reliable;

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Chemical reaction (amidation, carboxylation, fluorination, esterification, etc.)

Covalent

More stable and powerful

Geometry disruption

CNMs , ,

Noncovalent

,

.

Less stable

Geometry is retained

Fig. 3 Various approaches to functionalize CNMs.

• stable; and • very promising in the pharmaceutical and food industries, biocatalysts, etc. On a commercial scale, green synthesis can also be performed by using renewable resources such as sunlight, water, plant extracts, etc. [19]. Functionalization is mainly done in one of two ways—covalent and noncovalent functionalization—which can in turn be achieved by different methods. Some functionalization techniques for various nanomaterials are listed in Fig. 3 and further described below.

4.1 Carbon nanotubes Carbon nanotubes are a one-dimensional form of carbon and have a hollow cylindrical shape. They can be considered as rolled-up graphene sheets. CNTs are further classified as single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs). SWCNTs are rolled-up single-layered graphene sheets while MWCNTs are rolled-up multilayered graphene sheets. Their functionalization can be done easily compared to graphene. There are two different approaches for functionalization, as follows. 4.1.1 Covalent functionalization Covalent functionalization or chemical functionalization surely strengthens the stability and improves its solubility and dispersion in solvents. During this process, the geometry of CNTs is disrupted and changes from sp2 to sp3 [20]. Covalent functionalization of CNTs is mainly done by creating functional groups such as -COOH and -OH during

Functionalized carbon nanomaterials (FCNMs)

oxidation by air, oxygen, nitric acid, sulfuric acid, or a mixture [21]. Functionalization of a fluorine group on CNTs can increase the dispersion and solubility of nanotubes in organic solvents, which provides the best solubility in alcohols and other polar solvents [22]. This occurs due to hydrogen bonding between hydroxyl protons and fluorine. Functionalization of CNTs can also be done with polymers. For this, there are two approaches: “grafting from” and “grafting to” [23]. In the grafting from method, in situ polymerized monomers are used to bond on the CNTs’ surfaces. Some successful examples of polymer grafted on CNTs’ surfaces are poly(methyl methacrylate) (PMMA) [24], poly(N-isopropyl acrylamide) (NIPAM), etc. In the grafting to method, commercially available polymers are used to bond on the CNTs surfaces. In this approach, polymers must have sufficiently reactive functional groups so that they can formulate composites [25]. 4.1.2 Noncovalent functionalization Noncovalent functionalization is a preferable method in some cases, as it does not interfere with the physical properties of CNTs and their intrinsic properties are retained [26]. This type of functionalization mostly involves surfactants, wrapping with polymers, and biomacromolecules. The method of wrapping with polymers is achieved by van der Waals interaction and π-π stacking between CNTs’ polymer chains having aromatic rings. For wrapping the copolymer around the nanotubes, Blau and coworkers made a nanotube-polymer hybrid by surrounding SWCNTs in organic solvents poly(p-phenylenevinylene-co-2,5-dioctyloxy-m-phenylenevinylene). The electrical properties of these hybrids were found to be modified compared to the previous one. Surfactants can be employed to functionalize CNTs, and include nonionic, anionic, and cationic surfactants [27]. Surfactant functionalized CNTs are found to have high dispersion stability and good pharmaceutical applications. Another approach for functionalization can be done by interaction with molecules containing aromatic molecules; this approach involves biomolecules, but it can be used beyond that too [26].

4.2 Graphene Graphene is an allotrope of carbon in which single layers of carbon are arranged in 2D honeycomb-like nanostructures. The carbon atom in graphene is sp2 hybridized. The functionalization of graphene improves its physical and chemical properties and enhances its efficiency in different fields. For example, functionalization can transform graphene into a semiconductor and makes it suitable for electrical applications. The solubility of graphene in different solvents can also be improved by functionalizing it with different groups.

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4.2.1 Covalent functionalization In graphene, the carbon atom is sp2 hybridized, and during covalent functionalization its hybridization changes from sp2 to sp3, similar to carbon nanotubes. This functionalization is considered to be more stable and powerful than noncovalent functionalization. It can be achieved by different approaches such as addition reaction, electrophilic addition, nucleophilic substitution, and condensation reaction [28]. It includes oxidation, hydrogenation, fluorination, diazotization, etc. Fluorination of graphene gives a semiconducting state with the required electron energy gap and weak disorder. Covalent functionalization of GO is easier than that of graphene as it contains many hydroxyl, epoxy, and carboxyl groups [29]. As GO contains hydroxyl and carboxyl groups, it can be functionalized by hydroxyl or carboxyl functionalization [30]. The covalent functionalization of GO can be characterized as: 1. production of amine groups by ring-opening reaction of epoxy group; 2. diazonium and other cycloaddition reactions of reduced GO; and 3. nucleophilic reaction at edges by carboxylic group (mostly hydroxyl and amine groups). Similarly, graphene sheets can also be functionalized by different methods. Fang et al. studied the polymer functionalization of nanosheets [31]. This was done by diazonium addition/atom transfer radical polymerization (ATRP) and also showed the impact of functionalized graphene sheets on nonpolar polymers such as PS. 4.2.2 Noncovalent functionalization Noncovalent functionalization is sometimes more beneficial, as in this the bulk structure and extraordinary properties of graphene and graphene-based materials are conserved. It mainly involves π-π bond interaction, hydrogen bonding, ionic bonding, and electrostatic interaction modification. (16) Functionalization of graphene and graphene-based materials with polymers can enhance their mechanical, thermal, and electrical properties [32]. Using a series of phenyl or pyrene terminated functionalized polyethylene glycols (f-PEG), Zhang et al. interacted it with rGO by π-stacking. Different biomolecules can also be combined with graphene and graphene-based materials in different ways [33]. Biomolecules having aromatic rings can combine with graphene by π-π interaction. For example, glucose oxidase immobilization on graphene. In addition, these graphene and graphene-based materials can be combined with drugs, different nanostructures, and carbon nanoallotropes, which can modify their physical properties and their applications [34].

4.3 Fullerenes Fullerenes are allotropes of carbon having a hollow caged structure of sp2 hybridized carbons. There are many types of fullerenes, but C60 is the most common and most studied one. There are two types of bond in fullerenes structure: one at the junction of one

Functionalized carbon nanomaterials (FCNMs)

pentagon and one hexagon, and the other at the junction of two hexagons. Functionalization of fullerenes enhances their strength and improves their applicability. 4.3.1 Covalent functionalization There are various strategies for the covalent functionalization of fullerene. Oxygencontaining functional groups, mostly the hydroxyl group, are bonded on the surface of fullerenes [1]. This is done mainly under strong acid conditions and at high temperatures. An example of this functionalization is fullernols C60 (OH)8-40, which are prepared by reaction of fullerene with dilute H2SO4 and KNO3 in the presence of peroxides such as H2O2 [35]. They exhibit high water stability in neutral conditions. Different amino groups such as the amino (-NH2) group, the dimethylamino (-N(CH3)2) group, and trimethylamine halide (-N+(CH3)3I
) ions can be functionalized on fullerene. A popular amination reaction is the 1,3-dipolar cycloaddition of an azomethine ylide to a fullerene molecule, which produces a stable compound bonding a pyrrolidine ring. This reaction is known as the Prato reaction [36,37]. 4.3.2 Noncovalent functionalization Most of the functionalization approaches of fullerenes are through covalent functionalization, but a few noncovalent strategies exist for functionalization. One of these involves grafting of graphene on fullerenes, and this is strengthened by van der Waals interaction between fullerenes and graphene [38]. In addition to graphene, other groups can be grafted on fullerenes such as porphyrin, which is done by π-π interaction. Another noncovalent functionalization approach is with a polymer matrix. Li et al. bonded polymer/ fullerene nanofibers through noncovalent interaction [39]. This was done by reacting a diblock copolymer derivative of poly(3-hexylthiophene) (P3HT) with phenyl-C61-7 acid methyl ester (PCBM).

4.4 Carbon onions A carbon onion, a member of the fullerenes family, has a zero-dimensional structure consisting of concentric shells. The concentric shells of carbon onions are highly disordered and have a diameter of less than 10 nm. Functionalization of these carbon onions can enhance their potential for different applications such as biomedicine, electrochemical energy storage, etc. 4.4.1 Covalent functionalization Many strategies for the covalent functionalization of carbon onions are similar to that of carbon nanotubes. The first study for covalent functionalization was done by Prato et al. in 2003, in which an addition reaction of azomethine ylide with carbon nano-onions (CNOs) was reported [40]. The functionalized compound was found to have higher stability and solubility in organic solvents. Another covalent approach is the oxidation of

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CNOs by oxidizing agents such as HNO3, H2SO4, etc. [41]. This use of strong acids has a negative impact, as CNOs can be damaged in strong acidic conditions. Well-dispersible CNOs are obtained through nucleophilic substitution. This occurs through two steps: first, the CNOs are reduced in the presence of an Na-K alloy in 1,2-durable medical equipment (DME) under vacuum, which is followed by the covalent functionalization by an electrophile precursor (1-bromohexadecane) [42]. The resulting compound exhibited high dispersion in polar solvents. 4.4.2 Noncovalent functionalization This functionalization method mainly involves surfactants and polymers grafting on CNOs’ surfaces. An example is the functionalization of CNOs with polyethylene glycol (PEG) to attach phenolic compounds and gallic acid molecules, which are known for their protective properties on mammalian cells. In another approach, pyrene-borondipyrromethene (BODIPY)-3 was used for functionalization of CNOs’ surfaces by π-π noncovalent interaction [43]. Mild conditions were used in this approach and a satisfactory result was obtained.

4.5 Nanodiamond Nanodiamonds (NDs) are single diamonds having carbon as a basic component and an average size of 4–5 nm. In NDs, carbon is sp3 hybridized. Before functionalization of NDs, it is necessary first to modify their surfaces, as these should be homogeneous [44]. It is also necessary because this will determine the quality of the final functionalized compounds and their applicability. Modification can be done by grafting carboxylated, hydroxylated, hydrogenated, carbon-containing sp2 groups or by amination of NDs’ surfaces [45]. Once the surfaces of NDs are oxidized, desirable functional groups can be grafted on to them by different approaches. 4.5.1 Covalent functionalization Different molecules can be grafted on NDs’ surfaces by this functionalization approach. Fluorinated NDs are excellent substances for grafting of more complex moieties [46]. In this case, fluorine acts as good leaving which is quite surprising. When NDs are activated with thionyl chloride, the carboxylated groups present can react with amines to give amides. On the other hand, hydroxylated NDs can be functionalized to be substituted by a wide range of compounds such as ethers, NH2, Cl2, Br2, etc. Similarly, hydrogenated NDs can also give a wide range of transformations, which is explained well by Zhong and Loh [47]. 4.5.2 Noncovalent functionalization Noncovalent functionalization is quite an easy and effective method to functionalize nanodiamonds. After acid treatment, the surfaces of nanodiamonds become hydrophilic,

Functionalized carbon nanomaterials (FCNMs)

having a lot of oxygen-based functional groups, and can interact with many polar compounds. Not one but large numbers of these interactions are equivalent in strength with covalent bonds. The greatest advantage of this approach is that the compounds retain their natural state [48]. Drug molecules, other bioactive compounds, and polymers can be functionalized on the surface of NDs. An example of noncovalent conjugation of NDs is with poly(lactic acid) (PLLA), which was developed by Zhang et al. In general their mechanical strength is found to be when functionalized with polymers [49].

4.6 Carbon dots Carbon dots are defined as zero-dimensional carbon nanomaterials. They are classified into three categories: carbon quantum dots (CQDs), graphene quantum dots (GQDs), and carbon nanodots (CDs). Pure CDs do not have much potential in practical applications so functionalization is needed to make them efficient. Functionalization of CDs is done by two methods: heteroatom doping and surface modification.

4.6.1 Heteroatom doping This is an efficient approach for adjusting the intrinsic structure of CDs. Heteroatom doping changes the electron distribution and surface structure of CDs. It is done mainly via doping of nonmetallic elements or metallic elements. General nonmetallic dopants are nitrogen, sulfur, phosphorus, boron, fluorine, silicon, chlorine, iodine, etc. [49]. Nitrogen is used as a dopant; it then acts as an N-type impurity, providing an excess electron and changing the optical properties. When phosphorus is used as a dopant, it acts as an N-type donor and modifies the electrical and optical properties of CDs. Metallic dopants which are generally used are copper, gadolinium, lanthanide, manganese, zinc, cobalt, magnesium, etc. Magnesium as a dopant improves electrical, optical, and magnetic properties while zinc as a dopant enhances photocatalytic activity [50].

4.6.2 Surface modification Surface modification is a goal-oriented functionalization technique for CDs. Due to the presence of a lot of surface groups on CDs, ligands can easily bind to them by different interactions like coordination, amidation reaction, and electrostatic interactions [51]. Ligands that are generally used for surface modification are organic molecules, proteins, ions, deoxyribonucleic acid (DNA), and polymers. For increasing their luminance efficiency, polymers are widely used for modification. PDPB-modified CDs (CDs-PDPB) were prepared by Chang et al. via a facile solid reaction. The resulting material was found to have better efficiency in photodegradation. Like this other ligands are also for modifying the structure of CDs or surface passivation [52].

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5. Applications of functionalized carbon nanomaterials (FCNMs) for a sustainable future CNMs are one of the most promising materials for a vast array of applications, due to their remarkable properties including high chemical stability, extraordinary mechanical strength, heat resistance, etc. Moreover, the features of CNMs can be enhanced further by combining/functionalizing them with other suitable materials to create FCNMs for specified applications. Some prominent applications of functionalized CNMs are listed in Fig. 4 and described below briefly.

5.1 Sensing applications Carbon nanomaterials have a high surface area, carrier mobility, flexibility, and high electrical conductivity, which make them suitable for sensing gas molecules, humidity, heavy metals, toxic substances, etc. Different sensing applications are listed in Table 1. Fullerenes, due to their unique physical and chemical properties, have also become a material of choice in sensing applications. Fullerene films and compounds combined with iodine are used to manufacture temperature and pressure sensors [56]. The sensitivity of sensors can be enhanced if the surfaces of fullerenes are oxidized. Sensors fabricated by fullerenes immobilized on alumina substrates are used for detecting moisture [57]. Fullerenes can be used in both mediators electrochemical catalysis and as redox catalysts. The fullerene-modified electrodes are used in sensing biomolecules and environmental monitoring. A stable nonenzymic electrochemical sensor was fabricated by coupling zinc porphyrin and fullerene (ZnPp-C60). This electrode showed extraordinary reproducibility with a very fast response in sensing of H2O2 in the range 0.035–3.40 mm [58]. CNObased sensors are used for detecting H2 gas which is possible due to their nonporous

Sensing

Applications of FCNMs

BioMedical Fig. 4 Some applications of FCNMs.

Energy harvesting and storage

Functionalized carbon nanomaterials (FCNMs)

Table 1 Some examples of FCNM-based nanomaterials in sensing. S. no.

Material

Targeted entities

Detection limit

References

1

H2S

3.3–100 ppm

[53]

CH4 CO HCl, NH3, pH

1000–10,000 ppm – 100 ppm for HCl

[53] [1] [1]

5

SnO2-CQD/ MWCNT SnO2/graphene Cu/graphene Poly aniline + SWCNT CNT/Pt C-dots/CdS/BiOCl S-doped CDS ZnCdS QDs

50 ppm to 10% in air – 3–9 pH 1–9 pH

[54]

6 7 8

NO2, NH3, CO2, CH4, H2 Phenol pH pH

2 3 4

[15] [55] [55]

structure and hydrophobic nature. When phosphorus-doped CNOs are used, they make extremely sensitive devices for NH3 [59]. CNOs can also be used for electrochemical sensing of pH. For example, a glass electrode of carbon modified with CNOs and deposited by electropolymerization showed excellent chemical stability over a wide range of pH (2–10). The main advantages of this pH sensor device are reproducibility and the low cost of construction. CNOs can adsorb methylene blue on their surface by hydrophilic interaction and charge transfer [60]. Due to the hardness and high thermal stability of NDs, they can be used in harsh environmental conditions and can be employed in high power electronic devices [61]. Diamond nitrogen-vacancy (NV
) was used to detect substances in a solution having unprecedented sensitivity. Fluorescent NDs in high-resolution microscopy have high photostability. Sensors based on NDs also show great potential in the detection of monophenol and bisphenols [62]. CQDs show a typical absorption spectrum having two main bands at around 230 and 350 nm. The feature at 230 nm is assigned to Π-π* transition as CdC bonds in aromatic rings, while the shoulder at 300 nm is assigned to n-π* transition in n C]O bonds or other functional groups containing N and O [63]. The above properties increase their potential in sensing. Different sensors based on CQDs can detect Fe3+, Hg2+, Pb2+, Cr6+, Au3+, and K+. In electrochemical sensors based on CNTs, sensing is based on charge transfer induced by the analyte which changes the conductivity of CNTs. CNTs can be used to detect a wide range of gases. Pure CNT is not very efficient, but functionalized CNTs show extremely high potential in sensing. Sensors made by coupling of CNTs with metal oxides are used for the detection of NH3 and NO2. For example, SWCNTs coupled with SnO2 show greater potential in the detection of NH3 gas [64]. When CNTs are functionalized by different metals (Co, Cu, Pb, Pd, Ni, Pt, Ru, Ag), they can efficiently detect CO, CO2, NH3, CH4, and NO2. Volatile organic compounds such as benzene, toluene,

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and ethanol can also be detected by CNTs. The electrical properties of CNTs are influenced by the change of pH; thus, they can also be used for pH sensing purposes. For example, poly(1-amino anthracene) SWCNTs are sensitive to protonation, making the complex useful for pH sensing, having high stability and better responses up to a wide range of pH 2–12 [65]. Graphene has a high surface area, excellent optical and thermal properties, and extraordinary flexibility. An important characteristic of graphene is that it can be adapted to its structure and conditions of working according to the application. If considering strain, graphene shows the best reversible tensile elastic strain (>20%) among twodimensional materials [8]. The area of research for the detection of different molecules or substances by graphene-based sensors is quite wide. Graphene possesses a large electrochemical window, has a peculiar electronic structure, and thus a good electron transfer rate. All these are required qualities for a good electrochemical sensor, making graphene a suitable substance for this application [1]. Detection of biomolecules is an important application among the many sensing applications of graphene. There are different methods for sensing different molecules or substances such as glucose, DNA, H2O2, etc. Graphene-based sensors can be used in the food industry for the detection of toxic pesticides residues in food [66]. Other toxic substances that can be detected by graphene are sulfides, hydrazine, hydroquinone, etc., and hazardous gases including CO, CO2, NO, SO2, NO2, etc. [67]. It can also be used for fluorescence detection of substances like toxins in food, metal ions, pathogens, etc.

5.2 Energy harvesting and storage applications Electrochemical energy storage devices like lithium-ion batteries and supercapacitors produce high energy and power. Functionalized carbon nanomaterials show the conversion efficiency of stored energy and cycling performance due to their unique morphological, electrical, optical, and mechanical properties. Some examples of these materials are listed in Table 2 [11]. Table 2 Examples of FCNMs for energy harvesting and storage applications. S. no.

Material

Application

References

1. 2. 3.

B-doped graphene +K Li-FPGNs TA-NiFe@NCNT

[68] [68] [68]

4.

Graphene/PANI/DWCNT/ PANI SWCNTs/PANI

H2 storage (22.0 wt%) H2 storage (9.1 wt%) Catalyst for rechargeable Zn-air battery TEG TEG

[68]

5.

[68]

Functionalized carbon nanomaterials (FCNMs)

5.2.1 Lithium-ion batteries Surface modified and structured CNMs are used as reversible sinks inserting Li-io and offering a conductive path for fast transfer of electrons. For lithium-ion batteries, CNTs and graphene are considered the best material for electrodes because they have high energy and power density. Pure CNMs do not show much efficiency but surface doping of CNMs with F, N, and P can enhance their potential [69]. Replacement of traditional acetylene black with the same loading of MWCNTs in Li/CFx batteries showed higher specific energy storage capability [70]. A lightweight and porous N, S-codoped 3D graphene foam was made as a freestanding electrode in lithium batteries. The foam can collect a higher amount of hazardous lithium polysulfide dissolved. CNMs are used as anode material in lithium batteries; however, they have low capacity which hinders their commercial applications. Other anode materials for lithium batteries are Sn, metal oxides, alloys, red phosphorus, etc., and among these Sn is considered the most efficient. However, there is a high volume variation when Sn is used as the anode [71]. This limitation can be overcome by using structured CNMs, which can form soft matrices and accommodate this high volume variation. For example, a 3D porous graphene/Sn framework was made, and the resulting material showed higher electrical conductivity [72]. This complex not only retained the conductivity of graphene but also stabilized Sn particles and accommodated their high volume variations, thus improving the overall cycling performance of the electrode. 5.2.2 Supercapacitors Supercapacitors store energy by the formation of an electrolyte ion double layer on a noninsulating electrode material surface. Carbon nanomaterials have high electrical conductivity and are thus considered ideal candidates for making electrodes with higher efficiency. Surface-functionalized graphene exhibits relatively high pseudocapacitance, excellent wettability, and electrical conductivity in supercapacitor electrodes [73]. Surface-functionalized doped graphene with heteroatoms, like F or P, or the bonding of graphene with polar hydrophilic groups, such as carbonyl, carboxyl, and hydroxyl groups, improve pseudocapacitance compared to pure graphene [74]. The assembling of CNMs into macroscopic 3D hybrid structures is an efficient strategy for integrating the unique properties of CNMs like fullerene, CNTs, and graphene in practical applications of supercapacitors. Using solid polymeric hydrogel and the electrolyte, a selfsupporting supercapacitor was made by using MnO2-coated fibers as the anode and doped CNMs as the cathode [75]. The mechanical flexibility of the resultant material was found to be enhanced with higher charge transport and excellent volumetric power density, even under a high voltage.

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5.3 Biomedical applications Due to the unique physical and chemical properties of CNMs, they show great potential in diagnosis and curing diseases. Functionalization of CNMs can enhance their performance in their delivery efficiency and other ways, but it has been found that the cationic and anionic methods of functionalization of CNMs can increase their toxicity and thus can have certain side effects on the body. The use of CNMs in drug delivery is highly favorable as not only reduces the overall dosage but also reduces the side effects of drugs on the body [5]. CNMs have a small size, a relatively high surface area to volume ratio, and their binding capacity with drugs enhances their uptake toward the plasma membrane. A delivery system based on fullerene (C60) has been found to be excellent for antiviral drugs such as in the treatment of HIV [76]. Functionalized fullerenes also show great performance in delivering many anticancer drugs. For example, dendrofullerene shows the highest antiprotease capacity and fullerenol due to its high solubility, and can deliver many drugs. FCNMs are preferred for use in various biomedical applications as shown in Tables 3 and 4. Surface-functionalized CNMs offer better binding and enable the controlled release of preferred molecules. CNTs loaded with doxorubicin (DOX) offer great capability in delivering anticancer drugs to the targeted site [84]. The problem of this approach is the side effects of the DOX solution; this was solved by Sahoo et al. by Table 3 Examples of FCNMs for biomedical applications. S. no.

CNMs

Application

Reference

1

SWCNT

[55]

2 3 4

GQD PEG functionalized MWCNT PMMA microspheres and polyacrylonitrile-based MWCNT Fullerene modified with ammine group CNT

Chemo-photothermal therapy Radiotherapy Brain tumor therapy Bone regeneration Heal wound infection Detect arginase

[78] [79]

5 6

[55] [55] [77]

Table 4 Examples of FCNMs based drug delivery systems. S. no.

Carbon nanomaterial

Drug

Target disease

Reference

1.

Diltiazem hydrochloride Doxorubicin

Angina pectoris

[80]

2.

Multiwalled carbon nanotubes Carbon nanotubes

[81]

3. 4.

Carbon nanodiamonds Graphene oxide

Doxorubicin Paclitaxel

Cervical carcinoma Breast cancer Lung cancer

[82] [83]

Functionalized carbon nanomaterials (FCNMs)

modifying the surface of CNTs with folic acid. This modification not only reduced the side effects but also decreased tumor growth. GO and nanodiamonds also show great potential in drug delivery systems [85]. CNMs are also used as biosensors for sensing biorecognition changes in a disease condition. For biosensing, two methods are used: optical and electrical medical. In optical sensing, CNMs are used as fluorescence quenchers and emitters, while in another one, due to their electrochemically active surface they enhance the performance [86]. Fullerene-based biosensors can be used in the detection of DNA. Functionalized fullerenes have shown great potential in detecting glucose, H2O2 organic vapors, etc. [87]. Similarly, other CNMs such as NDs, CDs, CNTs, and graphene also show great potential in biosensing applications. CNT-based glucose sensors have been designed which can sense the glucose level in samples, and CNT-based electrochemical sensors show great potential in detecting nitric oxide and many other compounds. Bioimaging is another biomedical field where the applications of CNMs can be explored. They have extraordinary aqueous solubility, biocompatibility, less toxicity, and good photobleaching tolerance [88]. All these excellent features of CNMs enhance their fluorescence activity and bioimaging of tissues and cells. For example, for imaging and photothermal therapy in cancer, a protein-based GO was designed for ultrasonic dual-modality. Quantum dots tagged with reduced GO can show better performance in tumor imaging and tumor treatment monitoring [89]. Vaccination is the most popular method and considered the most effective way to treat infectious and noninfectious diseases. Functionalized CNMs can play a vital role in the delivery of vaccines throughout the body. In the vaccine delivery system, CNTs can be used against bacterial, protozoal, and viral diseases. For dual DNA vaccine delivery in HIV treatment, a self-assembled fullernol has been developed and showed good results. GO has been used as a delivering agent of biomolecules like antigens, and has also been found to enhance immunity [90]. Due to the extraordinary absorbing properties of GO, it can be used in protein delivery and shows greater efficiency in vaccination [91]. CNMs show great potential in many other biomedical applications, such as in the healing of wounds, tissues engineering, biomedical scaffolds, and photodynamic therapy. Thus, we can see that CNMs have enormous applications in the biomedical field. However, the toxicity of some CNMs is a hindrance in their applications. If their toxicity is reduced and their solubility improved, CNMs will be able to show better potential in this field.

6. Conclusion and future prospects Carbon nanomaterials have great potential for bringing breakthroughs in nanotechnology due to their remarkable chemical and physical properties. Progressing interest and development in the domain of functionalization of carbon nanomaterials like CNTs, graphene and its derivatives, carbon dots, nanodiamonds, fullerenes, etc. have been

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discovered. Although numerous studies have been carried out on FCNMs, they are still expanding as an area of interest for various applications. The potential of CNMs can be enhanced through surface modification techniques for functionalizing CNMs with varying materials like polymers, metal ions, surfactants, different acids, etc. Many studies have showcased the excellent efficiency of FCNMs in various fields such as biomedical, electrochemical energy storage, wastewater treatment, and sensing of various toxic materials. The main obstacle with CNMs is the limitation of various functionalized materials available for commercial purposes. There are many obstacles to the commercialization of carbon nanomaterials including high production costs. However, for the synthesis of highquality nanomaterials, cost-effective techniques and harsh conditions are required. Most of the available functionalizing elements are only available in limited quantities, and this is the main obstacle for their commercialization. For example, the availability of lithium is now at a critical level, so it cannot be used for a longer duration in batteries. Many other problems also need to be resolved for the commercialization and best use of these very promising FCNMs.

Important websites 1. https://www.nanowerk.com/nanotechnology/introduction/introduction_to_ nanotechnology_22.php 2. https://www.nanowerk.com/nanotechnology-in-green-industries.php 3. https://www.nanowerk.com/searchresults100.php?search¼graphene% 20nanotechnology%20in%20energy#gsc.tab¼0&gsc.q¼graphene% 20nanotechnology%20in%20energy&gsc.page¼1 4. https://www.nanowerk.com/searchresults100.php?search¼graphene%20dots#gsc. tab¼0&gsc.q¼graphene%20dots&gsc.page¼1 5. https://www.nanowerk.com/nanotechnology-news2/newsid¼59817.php 6. https://www.nanowerk.com/nanotechnology-news2/newsid¼52495.php 7. https://www.nanowerk.com/searchresults100.php?search¼functionalization% 20carbon%20nanomaterial#gsc.tab¼0&gsc.q¼functionalization%20carbon% 20nanomaterial&gsc.page¼1 8. https://www.nanowerk.com/spotlight/spotid¼7288.php 9. https://www.nano.gov/nanotech-101/what/definition

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Index Note: Page numbers followed by f indicate figures and t indicate tables.

A Acquired immunodeficiency syndrome (AIDS), 396 Acute myocardial infarction (AMI), 210 Adenylate kinase (ADK) activity, 209–210 Aging population diseases, 3 Animal imaging system, 373–376 Antibody-mediated drug delivery, 338–339 Antimicrobial applications, 150 Arc discharge method, 23, 95, 108 Ascorbic acid (AA), 212, 463–465 Assisted Model Building with Energy Refinement (AMBER), 162–163 Atomic force microscopy (AFM), 360

B Biocompatibility, 57 Biocompatible graphene oxide, 274–275 Biodegradation CNT biodegradation, 495–497 fullerene (C60) biodegradation, 497–498 graphene biodegradation, 497 Bioimaging technology, 200, 208, 431–433, 432t Biomedical imaging carbon nanomaterial-based bioimaging, 373–376 animal imaging system, 373–376 biopharmaceutical analysis imaging models, 376 hepatic bioimaging models, 376 nanoplatform-based cardiovascular imaging, 375 neurological disorders bioimaging models, 375 oncological bioimaging and radiopharmacy, 374 pulmonary bioimaging models, 375–376 carbon nanomaterials, 353 atomic force microscopy (AFM), 360 Boehm titration, 366 capillary electrophoresis (CE), 365 carbon nanotubes (CNT), 355 characterization of, 357–366, 358t chemical derivatization (CD), 366 diffraction techniques, 359, 361

electron microscopy, 359 energy dispersive spectroscopy (EDS), 363 field flow fractionization (FFF), 365 fluorescence spectroscopy, 363 Fourier transform-IR (FT-IR) spectroscopy, 362 fullerence, 356–357 graphene, 354 grazing incidence single angle X-ray scattering (GISAXS), 365 Infrared (IR) spectroscopy, 362 microscopy techniques, 359 neutral diffraction (ND), 361 quantum carbon dots (QCDs), 355–356 Raman spectroscopy, 362 scanning electron microscopy (SEM), 359 scanning tunneling microscopy (STM), 360 separation techniques, 364 size exclusion chromatography (SEC), 364–365 spectroscopic methods, 361 thermal techniques, 364 thermogravimetric analysis, 364 transmission electron microscopy (TEM), 359–360 types of, 354 ultracentrifugation (UC), 364 ultraviolet-visible (UV-vis) spectroscopy, 363 X-ray absorption near-edge structure (XANES), 365 x-ray diffraction (XRD) technique, 361 X-ray photoelectron spectroscopy (XPS), 363 drug-loaded carbon nanomaterials applications, 366–373 biosensors, 366–367 carbon nanotube biosensors, 367 carbon quantum dots as biosensors, 369 fluorescence imaging and therapy, 369–370, 371f fullerenes, 367–368 graphene oxide as biosensor, 367 magnetic resonance imaging and therapy, 370, 371f

549

550

Index

Biomedical imaging (Continued) multimodel imaging and therapy, 373 photoacoustic imaging and therapy (PA), 372 radionuclide imaging and therapy, 372–373 Raman imaging and therapy, 371 Biomedical therapy, functionalized carbon nanomaterials for bone tissue engineering, 384 carbon dots, 392–393, 392f carbon nanofibers (CNF), 388–389, 388–389f carbon nanotubes, 384–388, 385–386f chemical functionalization, 384 classification of, 383f drug delivery systems, 384 effectiveness of, 383–384 fullerenes, 395–396, 395f graphene, 393–395, 394f nanodiamonds (NDs), 390–392, 390–391f nanomaterials, 381–382 nanotechnology, 381–382 novel drug delivery systems, functionalized CNTs for, 384–388, 385–387f Biomolecules, 113 Biopharmaceutical analysis imaging models, 376 Biosensing technology, 430–431, 432t Biosensors, 152–153, 320–322 Boehm titration, 366 Bone tissue engineering, 384 Bone tissue regeneration, functionalized CNTs in, 387 Bottom-up approaches chemical synthesis, 24 chemical vapor deposition (CVD), 23–24 epitaxial growth, 23 plasma synthesis, 24 pyrolysis, 23

C Cancer, 13 nanotechnology, 4 theranostics applications, 251–252 therapy, 319–320, 428–429, 429f, 429t Capillary electrophoresis (CE), 365 Carbonaceous nanomaterials biodegradation of, 513–517, 514–517f biological cells carbon-based QDs on, 512 carbon black on, 512–513 CNTs on, 507–508, 509–510f graphene on, 510–512, 511f

carbon-based quantum dots (CQDs), 507 carbon black, 507 carbon nanotubes (CNTs), 505–506 fullerene, 507 graphene, 507 Carbon-based nanomaterials (CNMs), 5–8, 10 carbon dots (CDs), 7 carbon nanofibers, 7 carbon nanohorns (CNHs), 7 carbon nanotubes (CNTs), 6, 264–266 carboxy fullerenes (CFs), 269 carboxylated and polyhydroxylated fullerenes, 267–268 drug carriers, 270–276 drug delivery cancer therapy, graphene quantum dots (GQDs) for, 273 carbon nanohorns, 276 carbon nanotubes for, 270–271 graphene oxide, 273–276 graphene quantum dots (GQDs), 271–273 quantum dots, 271–273 fullerenes, 6–7, 266–269 future prospectives, 279–280 graphene, 266 nanodiamonds (NDs), 8 nanomaterials made of, 269–270 nanoporous carbon, 8 photodynamic therapy (PDT), 269 polyhydroxy fullerenes (PHFs), 269 toxicological assessment, 276–279 types of, 263–270, 264f Carbon-based quantum dots (CQDs), 507 Carbon black (CB), 207–208, 507, 512–513 Carbon dot-functionalized carboxymethyl cellulose hydroxyapatite nanocomposite (CDs-CMC-HA), 58–59 Carbon dots (CDs), 7, 210–212, 392–393, 392f bioimaging probes, 57–59, 59f delivery of drugs, 393 drug delivery agents, 59–60 fluorescence imaging, 393 limitations, 393 Carbon/graphene quantum dots, 25–28 bottom-up approaches, 27–28 hydrothermal/solvothermal synthesis, 27–28 microwave synthesis, 27 plasma synthesis, 26 thermal decomposition, 27 top-down approaches, 26

Index

ultrasonication, 26 Carbon, nano-carbon materials, 439 Carbon nanodiamonds, 250, 251t Carbon nanofibers (CNFs), 7, 81, 388–389, 388–389f characteristic structure, 389f functionalization of, 84–85 neural applications, 388–389 neuronal interface, 389f synthesis of, 83 Carbon nanohorns (CNHs), 7, 60–63, 249, 333 bioimaging probes, 62 drug delivery agents, 62–63, 63f Carbon nanolights, 94 Carbon nanomaterial-based bioimaging, 373–376 animal imaging system, 373–376 biopharmaceutical analysis imaging models, 376 hepatic bioimaging models, 376 nanoplatform-based cardiovascular imaging, 375 neurological disorders bioimaging models, 375 oncological bioimaging and radiopharmacy, 374 pulmonary bioimaging models, 375–376 Carbon nanomaterials (CNMs), 92 biodegradation of, 495–498 CNT biodegradation, 495–497 fullerene (C60) biodegradation, 497–498 graphene biodegradation, 497 biomedical imaging, 353 atomic force microscopy (AFM), 360 Boehm titration, 366 capillary electrophoresis (CE), 365 carbon nanotubes (CNT), 355 characterization of, 357–366, 358t chemical derivatization (CD), 366 diffraction techniques, 359, 361 electron microscopy, 359 energy dispersive spectroscopy (EDS), 363 field flow fractionization (FFF), 365 fluorescence spectroscopy, 363 Fourier transform-IR (FT-IR) spectroscopy, 362 fullerence, 356–357 graphene, 354 grazing incidence single angle X-ray scattering (GISAXS), 365 Infrared (IR) spectroscopy, 362 microscopy techniques, 359 neutral diffraction (ND), 361 quantum carbon dots (QCDs), 355–356 Raman spectroscopy, 362

scanning electron microscopy (SEM), 359 scanning tunneling microscopy (STM), 360 separation techniques, 364 size exclusion chromatography (SEC), 364–365 spectroscopic methods, 361 thermal techniques, 364 thermogravimetric analysis, 364 transmission electron microscopy (TEM), 359–360 types of, 354 ultracentrifugation (UC), 364 ultraviolet-visible (UV-vis) spectroscopy, 363 X-ray absorption near-edge structure (XANES), 365 X-ray diffraction (XRD) technique, 361 X-ray photoelectron spectroscopy (XPS), 363 carbon nanotubes (CNTs), 91, 92f, 93, 486–487 carbon quantum dots (CQDs), 94 classification of, 484–487, 485f ecotoxicity, 492–494, 492t, 494f fullerenes, 93–94, 486 functionalized carbon nanomaterials, applications of, 100–101 general characteristics of, 92–95 graphene, 94–95 graphene (GRA), 487 molecular docking (MD) technology, 484 nonbiodegradation, 484 strategies for functionalization, 98–100, 98t alternative routes for functionalization, 100, 101t covalent functionalization (chemical method), 98–99 noncovalent functionalization (physical method), 99–100 synthesis of, 82–83, 95–98, 488–489 carbon nanotubes, 95, 488 carbon quantum dots (CQDs), 96–97 fullerenes, 96, 489 graphene, 97–98, 489 toxicity investigations for, 489–492 carbon nanotubes, 489–490 fullerenes, 491 graphene, 491–492 toxicology, issues and research needs in, 494–495 detailed material characterization, necessity for, 495 track nanomaterials in biomaterials investigations, 495

551

552

Index

Carbon nanostructures, 77–78 Carbon nanotube-dependent field-effect transistor (CNTFET), 78–79 Carbon nanotubes (CNTs), 6, 24–25, 64–67, 77–79, 79f, 165–167, 204–205, 220–221, 222f, 248–249, 264–266, 355, 383–388, 385–386f, 486–490, 505–506 advancements in functionalization, 84 biocompatibility of, 333–334 bioimaging probes, 65–66 biomedical applications, 387–388 biosensors, 387 bone development, 252–253 bone tissue regeneration, 387 carbon nano fullerene (C60), 165–167, 165f characterization of, 333–334 chemical vapor deposition (CVD), 82, 421 companies, 85–86 covalent functionalization, 83, 184–186, 185f, 385f, 424–425 direct side-wall functionalization, 84 drug delivery, 66–67, 67f, 244–247, 245t, 337–339, 338f, 386f antibody-mediated drug delivery, 338–339 targeted drug delivery, 338, 339f drug likeliness, 167–168, 168t electric arc discharge method, 422 electronic properties of, 190 endohedral functionalization, 84 exohedral functionalization, 84 functionalization, 109–117 covalent functionalization (see Covalent functionalization, carbon nanotubes (CNTs)) noncovalent functionalization (see Noncovalent functionalization, carbon nanotubes (CNTs)) functionalization of, 83–85, 183–187, 189–190t functionalization techniques, 424–427 functionalized carbon nanomaterials (FCNMs), 331–332, 332f, 334–337 biosensors, 335–336, 336f magnetic resonance imaging (MRI), 334–335, 335f radiography, 337 ultrasound, 336 functionalized carbon nanomaterials as, 173 fundamental bases on, 107 future perspectives, 173–174, 187–191 graphene-based materials (GBMs), 121–128

CNT hybrid nanofiller-reinforced polymer composites, 130–131 graphene, 121–122 graphene nanohybrids, 128–129 graphene nanoplatelets (GNPs), 122–125 graphene oxide (GO), 125–128 graphite, 121 metal nanoparticles (NPs), 128–129 reduced graphene oxide (rGO), 128 hybrid nanofiller-reinforced polymer composites, 130–131 laser ablation, 25 laser ablation method/physical vapor deposition, 422 mechanical properties of, 190 modification of, 33–35, 34f multiwalled carbon nanotubes (MWCNTs), 420 need for functionalization of, 423 noble metal nanoparticles (NPs)/CNTs nanohybrids, 118–121 synthesis of, 118–121 noncovalent functionalization, 83, 186–187, 386f organizations, 85–86 pharmacokinetics, 167–168, 168t research groups, 85–86 SARS-CoV-2, 165–167, 165f, 170–173, 171–172f scaffolds in, 345–346 single-walled carbon nanotubes (SWCNTs), 420 stem cell differentiation, 253–255 stem cell growth, 252–253 stem cell therapy, 252–256, 341–346, 342–343f, 345f graphene-based nanomaterials, 344 nanodiamonds (NDs), 343–344 research, 253 structures, 385f, 420, 421f surface modification of antimicrobial applications, 150 biosensors, 152–153 diagnosis, 152 drug delivery and therapy, 150–151 gene delivery, 152 imaging, 152 neural regeneration, 151–152 tissue engineering, 151–152 synthesis of, 82, 108–109 arc discharge method, 108 chemical vapor deposition (CVD), 108–109 green methods, 109

Index

laser ablation (LA), 108 synthesis techniques for, 420–422 toxicity, 255 features, 167–168, 168t types, 332, 333f, 420, 421f vaccines, carbon-based nanomaterials for use, 339–341 carbon-based nano delivery systems, 340, 340f single-walled carbon nanotubes, 341, 341f viral infection application, 169–170 Carbon quantum dots (CQDs), 91–92, 250 Carboxy fullerenes (CFs), 269 Carboxylated/polyhydroxylated fullerenes, 267–268 Carboxyl-rich poly acrylic acid, 150 Carboxymethyl cellulose and hydroxyapatite (CMC-HA), 58–59 Cerium nanocubes, 207–208 Chemical ablation, 96 Chemical derivatization (CD), 366 Chemical exfoliation, 21–22, 97 Chemical fabrication, 22–23 Chemical functionalization, 384 Chemical reagents, 85 Chemical synthesis, 24 Chemical vapor deposition (CVD), 23–24, 64, 82, 95, 108–109, 421 Chemistry at HARvard Macromolecular Mechanics (CHARMM), 162–163 Chemotherapy, 14 drugs, 394 Coating, 42–43 Cobalt-based nanocrystals (CoNCs), 315 Conjugation, 215 Conservative therapeutic alternatives, 14 Conventional materials, 528–529 Copper nanocrystals (CuNCs), 313 Copper sulfide (CuS), 320 Covalent bond modification, 11 Covalent functionalization, 10–11, 83, 424–425 approach, 110–111 carbon nanotubes (CNTs), 109–113 biomolecules, 113 covalent functionalization approach, 110–111 oxidation functionalization, 110 plasma treatment, 110 polymer grafting of, 111–112 end-defect covalent functionalization, 428–429 free radical grafting, 425 sidewall covalent functionalization, 427

COVID-19 pandemic carbon nano fullerene (C60), 165–167, 165f computational biology, 160 computer-aided drug discovery (CADD), 160–163, 161f current therapies, 159–160 drug targets of, 163, 164f limitations, 159–160 overview of, 158 potential lead molecules, functionalized carbon nanomaterials as, 164–165 SARS-CoV-2, 158–159, 159f vaccines, 159–160

D Dengue virus (DENV), 203 Dental/bone healing, 325–326, 326f Dentifrices, 301–302 Dextran, 509–510 Dielectrophoresis (DEP), 202–203 Diels–Alder reaction, 150 Diffraction techniques, 359, 361 Digital tomosynthesis (DT), 152 2,4-dinitrofluorobenzene (DNFB), 508 Direct side-wall functionalization, 84 DNA labeling, 322–323 Double junction capacitive (DIDC), 203 Double-walled carbon nanotubes (DWCNTs), 420 Double-walled CNTs (DWCNTs), 150 Doxorubicin (DOX), 273–274 Drug carriers clearance pathways of, 219 stimuli-responsive as, 216–218, 217f toxicity of, 218–219 Drug delivery, 427, 428f carbon-based nanomaterials cancer therapy, graphene quantum dots (GQDs) for, 273 carbon nanohorns, 276 carbon nanotubes for, 270–271 graphene oxide, 273–276 graphene quantum dots (GQDs), 271–273 quantum dots, 271–273 metallic nanocrystals (MNCs) modern healthcare systems, 316–319 Drug-loaded carbon nanomaterials applications biomedical imaging, 366–373 biosensors, 366–367 carbon nanotube biosensors, 367 carbon quantum dots as biosensors, 369

553

554

Index

Drug-loaded carbon nanomaterials applications (Continued) fluorescence imaging and therapy, 369–370, 371f fullerenes, 367–368 graphene oxide as biosensor, 367 magnetic resonance imaging and therapy, 370, 371f multimodel imaging and therapy, 373 photoacoustic imaging and therapy (PA), 372 radionuclide imaging and therapy, 372–373 Raman imaging and therapy, 371 Drug-loading capacity, 214–215 cell uptake, 215–216 penetration, 215–216 targeting, 215–216 Dynamic light scattering infrared spectroscopy, 333

E Ebola virus, 3 Ecotoxicity, 492–494, 492t, 494f Electric arc discharge method, 422 Electric Arc method, 96 Electrocardiogram (ECG), 207–208 Electrochemical carbonization, 96 Electrochemical exfoliation, 22 Electrochemical impedance spectroscopy (EIS), 206 Electrochemiluminescence (ECL), 208 Electron microscopy, 359 Embryonic stem cells (ESCs), 222–223 End-defect covalent functionalization, 428–429 Endodontics, 292–295 Endohedral functionalization, 84 Energy conversion, 39–40, 41f Energy dispersive spectroscopy (EDS), 363 Energy storage, 39–40, 41f Enhanced permeability and retention (EPR) effects, 55–56 Eosinophil peroxidase (EPO), 513–514 Epitaxial growth, 23 Ethylene-diamine triacetic acid (EDTA), 31 Excellent electrical conductivity, 79 Exhaled breath (EB) biomarkers, 203–204 Exohedral functionalization, 84

F Field flow fractionization (FFF), 365 Filtration, 43–44 Fluorescence imaging (FI), 210–211 Fluorescence spectroscopy, 363

Folic acid (FA), 267–268, 447 Foot-and-mouth disease virus (FMDV), 203 Fourier transform-IR (FT-IR) spectroscopy, 362 Free radical grafting, 425 Fullerence, 356–357 Fullerenes, 6–7, 80–81, 91–92, 205–207, 225, 249, 266–269, 395–396, 395f, 486, 489, 491, 507 antimicrobial activity, 396 antiviral agents, 396 degradation, 515–517 derivatives, 395f limitations, 396 neuroprotective therapeutics, 396 synthesis of, 82–83 Functionalized carbon nanomaterials (FCNMs), 331–332, 332f, 334–337 advantages of, 528–529 antibacterial utilization of, 452–460 applications, 212–219, 213–214t approaches to, 530f ascorbic acid, 463–465 bioactivity utilization of, 469–472, 470f biomedical applications, 248f biomedical imaging (see Biomedical imaging) biomedical utilization of, 441–452 biosensors, 335–336, 336f biosensor utilization of, 461–469, 462f cancer theranostics applications, 251–252 cancer treatment, 247–252 carbon nanodiamonds, 250, 251t carbon nanohorns (CNHs), 249 carbon nanotubes (CNTs), 248–249 carbon quantum dots (CDs), 250 fullerenes (C60), 249 graphene nanosheets (GR), 249 carbon/graphene quantum dots, 25–28 bottom-up approaches, 27–28 hydrothermal/solvothermal synthesis, 27–28 microwave synthesis, 27 plasma synthesis, 26 thermal decomposition, 27 top-down approaches, 26 ultrasonication, 26 carbon nanotubes (CNTs), 24–25, 220–221, 222f laser ablation, 25 conventional materials, 528–529 diagnostic purposes, 200–212 carbon black (CBs), 207–208 carbon dots (CDs), 210–212 carbon nanotubes (CNTs), 204–205

Index

fullerenes, 205–207 graphene and graphene oxides (GOs), 200–204, 201–202f graphitic carbon nitride (g-C3N4), 208–210 drug carriers clearance pathways of, 219 stimuli-responsive as, 216–218, 217f toxicity of, 218–219 drug delivery, 198–199t drug-loading capacity, 214–215 cell uptake, 215–216 penetration, 215–216 targeting, 215–216 drug loading/release analyses, 448–450 fabrication of, 19–28 fascinating properties of, 528f folic acid, 447 functionalization of, 19–21, 30–31 fundamental characteristics of, 527–528 future research, 473 gold nanostructures, 459–460 graphene, 443–444, 462–463 bottom-up approaches (see Bottom-up approaches) top-down approaches (see Top-down approaches) graphene oxide, 444–446, 458 graphitic carbon nitride (g-C3N4), 28 green and sustainable strategies (see Green and sustainable strategies) magnetic resonance imaging (MRI), 334–335, 335f microscopic examination, 444–446 mitochondria-mediated apoptosis, 448 modified graphene oxide, 456–457 neurosurgery, 452 pathogenic microorganisms, 457 phenolic compounds, 465–466 phosphorus, 466–468 poly(diallyldimethylammonium chloride) (PDDA), 466–468 polyethylenimine, 452–453 properties of, 28–36 CDs, functionalization of, 35–36 CNTs, modification of, 33–35, 34f ethylene-diamine triacetic acid (EDTA), 31 graphene modification, 30–31 graphene oxide (GO), 31–33 radiography, 337 silk fibroin, 444–446

spectrophotometry, 466–468 stem cells therapy, 219–225 carbon nanoparticles (CNTs), 224–225 graphene oxide (GO), 222–224, 223f sustainable release, 214–215 tannic acid, 457 theragnostic and biomedical applications, 36–44, 37f coating, 42–43 energy conversion, 39–40, 41f energy storage, 39–40, 41f filtration, 43–44 gas storage, 40–42 thermogravimetric analysis, 447 ultrasound, 336 Functionalized carbon nanotubes (FCNTs) biomedical applications of cancer therapy, 428–429, 429f, 429t drug delivery, 427, 428f drug delivery, 246–247 functionalized CNTs in diagnostics, diverse applications of, 430–433 bioimaging technology, 431–433, 432t biosensing technology, 430–431, 432t need for, 245–246 pyrazinamide (PZA), 246 Functionalized graphene nanomaterials aging population diseases, 3 application of, 12–14 cancer nanotechnology, 4 carbon-based nanomaterials (CNMs), 5–8 carbon dots (CDs), 7 carbon nanofibers, 7 carbon nanohorns (CNHs), 7 carbon nanotubes, 6 fullerene, 6–7 nanodiamonds (NDs), 8 nanoporous carbon, 8 Ebola virus, 3 future prospect, 14–15 graphene, 8–10 covalent functionalization, 10–11 derivatives, 8–10 functionalization of, 10–11 graphene oxide (GO), 9 graphene quantum dots (GQDs), 10 noncovalent functionalization, 11 reduced graphene oxide (rGO), 9–10 nanomedicine, 4 nanotechnology, 3–4

555

556

Index

Functionalized graphene nanomaterials (Continued) near-infrared (NIR) absorption, 3–4 polyethylene glycol (PEG) polymer, 3–4 properties of, 12 therapy, 4–5 Zika virus, 3

G Gadolinium entrapped graphene nanoparticles (Gd@GCN), 266 Gamma scintigraphy, 337 Gas storage, 40–42 Gene delivery, 152 Gold nanocrystals (AuNCs), 312, 324 Gold nanostructures, 459–460 Grafting from approach, 112 Grafting to approach, 111–112 Graphene, 8–10, 79–80, 80f, 91–92, 121–122, 266, 354, 393–395, 394f, 443–444, 489, 491–492, 507 covalent functionalization, 10–11 derivatives, 8–10 functionalization of, 10–11, 84 graphene oxide (GO), 9 graphene quantum dots (GQDs), 10 noncovalent functionalization, 11 reduced graphene oxide (rGO), 9–10 synthesis of, 82 Graphene (GRA), 487 Graphene and graphene oxides (GOs), 200–204, 201–202f Graphene-based materials (GBMs), 121–128 CNT hybrid nanofiller-reinforced polymer composites, 130–131 graphene, 121–122 graphene nanohybrids, 128–129 graphene nanoplatelets (GNPs), 122–125 graphene oxide (GO), 125–128 graphite, 121 metal nanoparticles (NPs), 128–129 reduced graphene oxide (rGO), 128 Graphene-based nanomaterials, 344 Graphene-derived nanomaterials, 13 Graphene family nanomaterials (GFNs), 510 Graphene modification, 30–31 Graphene nanohybrids, 128–129 Graphene nanoplatelets (GNPs), 122–125 covalent functionalization approach, 122–123 polymer grafting covenant functionalization, 123

noncovalent functionalization approach, 123–125 Graphene nanosheets (GR), 249 Graphene oxide (GO), 9, 31–33, 125–128, 393–394, 444–446, 458 covalent functionalization, 125–126 noncovalent functionalization, 126–128 Graphene oxide field-effect transistor (GOFET), 202–203 Graphene oxide-iron oxide nanohybrid (GO-IONP), 274–275 Graphene quantum dots (GQDs), 10, 224–225, 272 Graphite, 121 Graphitic carbon nitride (g-C3N4), 208–210 Grazing incidence single angle X-ray scattering (GISAXS), 365 Green and sustainable strategies applications of, 536–541, 536f biomedical applications, 540–541, 540t carbon dots, 535 heteroatom doping, 535 surface modification, 535 carbon nanotubes, 530–531 covalent functionalization, 530–531 noncovalent functionalization, 531 carbon onions, 533–534 covalent functionalization, 533–534 noncovalent functionalization, 534 energy harvesting, 538–539 fullerenes, 532–533 covalent functionalization, 533 noncovalent functionalization, 533 future prospects, 541–542 graphene, 531–532 covalent functionalization, 532 noncovalent functionalization, 532 nanodiamonds (NDs), 534–535 covalent functionalization, 534 noncovalent functionalization, 534–535 sensing applications, 536–538 storage applications, 538–539 lithium-ion batteries, 539 supercapacitors, 539 Green methods, 109 GROningen MAchine for Chemical Simulations (GROMACS), 162–163

H Hepatic bioimaging models, 376 Hepatocellular carcinoma (HCC), 204–205 Hippocampal neurons, 151

Index

Human immunodeficiency virus (HIV), 396 Hyaluronic acid (HA), 216 Hyaluronidase (HAase), 209–210 Hydroquinone (HQ), 206 Hydrothermal/solvothermal carbonization, 97 Hypochlorous acid (HOCl) synthesis, 515–517

I Ibuprofen, 395 Idiopathic pulmonary fibrosis (IPF), 206–207 Infrared (IR) spectroscopy, 362 Iron-based nanocrystals (FeNCs), 315 Iron oxide nanoparticles (IONPs), 319–320

L Laser ablation (LA), 95, 97, 108 Laser ablation method/physical vapor deposition, 422 Laser vaporization of carbon, 96 Limit of detection (LOD), 210 Lipase enzyme degradation, 514–515 Low immunogenicity, 339–340 Lycurgus Cup of Rome, 417

M Magnetic graphene oxide-iron oxide nanoparticles, 334–335 Magnetic nanocrystals, 314–316 cobalt-based nanocrystals (CoNCs), 315 iron-based nanocrystals (FeNCs), 315 nickel-based nanocrystals, 315–316 MDL Drug Data Report (MDDR), 162 Mechanical exfoliation, 97 Mesenchymal stem cell (MSC), 220 Mesoporous silica nanocarriers (MSNs), 320 Metallic nanocrystals (MNCs) advantages of, 311–312 disadvantages, 311–312 future perspectives, 327 magnetic nanocrystals, 314–316 cobalt-based nanocrystals (CoNCs), 315 iron-based nanocrystals (FeNCs), 315 nickel-based nanocrystals, 315–316 modern healthcare systems, 316–326 biosensors, 320–322 cancer therapy, 319–320 dental and bone healing, 325–326, 326f DNA labeling, 322–323 drug delivery, 316–319 nanomedicine, 317t

nanoshells, 318 quantum dots (QDs), 318–319 wound healing, 323–324 nonmagnetic nanocrystals, 312–314 copper nanocrystals (CuNCs), 313 gold nanocrystals (AuNCs), 312 platinum nanocrystals (PtNCs), 314 silver nanocrystals (AgNCs), 312–313 zinc oxide nanocrystals (ZnONCs), 313–314 synthesis of, 310–311 types of, 312–316 Metal nanoparticles (NPs), 128–129 Microscopy techniques, 359 Microwave pyrolysis, 97 Middle East respiratory syndrome (MERS), 159–160 Midkine (MDK) indicators, 204–205 Mitochondria-mediated apoptosis, 448 Modern healthcare systems, 316–326 biosensors, 320–322 cancer therapy, 319–320 dental and bone healing, 325–326, 326f DNA labeling, 322–323 drug delivery, 316–319 nanomedicine, 317t nanoshells, 318 quantum dots (QDs), 318–319 wound healing, 323–324 Modified graphene oxide, 456–457 Molecular docking (MD) technology, 484 Molecular Operating Environment (MOE), 162–163 Multiwalled carbon nanotubes (MWCNTs), 77–78, 150, 197, 418, 420

N Nanobelt, 290 Nanocarriers, 339–340 Nanoclusters, 290 Nanocomposite film, 153 Nanocrystals, 289 applications, 292–302, 292f dentifrices, 301–302 endodontics, 292–295 future trends, 302–303 nanodentistry, 288–291, 288f nanobelt, 290 nanoclusters, 290 nanocrystals, 289 nanofibers, 289

557

558

Index

Nanocrystals (Continued) nanopores, 289 nanoring, 290 nanorod, 289–290 nanoshells, 290 nanospheres, 290–291 nanowires, 289 nanotechnology approaches, 291–292, 291f biomimetic approach, 292 bottom-up approach, 291–292 functional approach, 292 top-down approach, 291 orthodontics, 295–296 periodontics, 296–298 prosthodontics, 298–301 Nanodiamonds (NDs), 8, 270, 343–344, 390–392, 390–391f antibacterial applications of, 391–392 limitations, 392 optical bioimaging, 391 structure of, 390f synthesis of, 390f Nanoelectromechanical systems (NEMS)-based signal processing, 79–80 Nanofibers, 289 Nanomaterials, 381–382 Nanomedicine, 4, 55, 317t Nanoplatform-based cardiovascular imaging, 375 Nanopores, 289 Nanoporous carbon, 8 Nanoring, 290 Nanorod, 289–290 Nanoscale Molecular Dynamics (NAMD), 162–163 Nanoshells, 290, 318 Nanospheres, 290–291 Nanotechnology, 3–4, 381–382 Nanotechnology approaches, 291–292, 291f biomimetic approach, 292 bottom-up approach, 291–292 functional approach, 292 top-down approach, 291 Nanotheragnostics, 12–13 Nanotubes, 418 Nanowires, 289 Near-infrared (NIR) absorption, 3–4 Near-infrared (NIR) photo-luminescence, 343–344 Negative temperature coefficient (NTC), 207–208 Neural regeneration, 151–152

Neural stem cells (NSCs), 222–223 Neurological disorders bioimaging models, 375 Neurosurgery, 452 Neutral diffraction (ND), 361 Nickel-based nanocrystals, 315–316 Noble metal nanoparticles (NPs)/CNTs nanohybrids, 118–121 synthesis of, 118–121 Nonbiodegradation, 484 Noncovalent functionalization, 11, 83 carbon nanotubes (CNTs) biomolecules, 117 conjugated aromatic polymers, 114–115 polyaromatic molecules, 115 surfactants, 116–117 water soluble polymers, 115–116 physical method aromatic compounds, 99–100 polymers, 100 Nonmagnetic nanocrystals, 312–314 copper nanocrystals (CuNCs), 313 gold nanocrystals (AuNCs), 312 platinum nanocrystals (PtNCs), 314 silver nanocrystals (AgNCs), 312–313 zinc oxide nanocrystals (ZnONCs), 313–314 Nonsteroidal antiinflammatory drug (NSAID), 395 Novel coronavirus – 2019 (nCoV-19), 158 Novel drug delivery systems, 386–387 functionalized CNTs for, 384–388, 385–387f Nuclear magnetic resonance (NMR), 163, 333 Nucleic acids (NAs), 335–336

O Oncological bioimaging and radiopharmacy, 374 One-dimensional (1D) nanotubes, 342–343 Orthodontics, 295–296 Oxidation functionalization, 110 Oxidized nano-diamonds (O-NDs), 343–344

P Pathogenic microorganisms, 457 Periodontics, 296–298 Phenolic compounds, 465–466 Phosphorus, 466–468 Photodynamic therapy (PDT), 269 Plasma synthesis, 24 Plasma treatment, 110 Platinum nanocrystals (PtNCs), 314

Index

Pluripotent stem cells, 220 Poly(diallyldimethylammonium chloride) (PDDA), 466–468 Poly(lactic-co-glycolic acid) (PLGA), 220–221 Polycaprolactone (PCL), 222–223 Polydimethylsiloxane (PDMS), 207–208 Polyethylene glycol (PEG), 3–4, 150, 215–216 Polyethyleneimine (PEI), 270 Polyethylenimine, 65, 452–453 Polyhydroxy fullerenes (PHFs), 269 Polymer grafting, 111–112 Poly methyl methacrylate (PMMA), 211–212 Procalcitonin (PCT), 210 Prostate-specific antigen (PSA), 202–203 Prosthodontics, 298–301 Pulmonary bioimaging models, 375–376 Pyrazinamide (PZA), 246 Pyrolysis, 23

Q Quantum carbon dots (QCDs), 355–356 Quantum dots (QDs), 318–319 Quantum yield (QY), 57, 209

R Radionuclide imaging, 337 Raman spectroscopy, 333, 362 Raw nanodiamonds (R-NDs), 343–344 Reactive oxygen species (ROS), 383, 508 Reduced graphene oxide (rGO), 9–10, 128, 393–394 Regenerative medicine, 343 Resistive Arc heating of graphite, 96 r-GO field-effect transistor (rGOFET), 203

S Scaffold promoted neural cell growth, 220–221 Scanning electron microscopy (SEM), 359 Scanning transmission electron microscopy, 273 Scanning tunneling microscopy (STM), 360 Scotch tape method, 393–394 Separation techniques, 364 Severe acute respiratory syndrome (SARS), 159–160 Sidewall covalent functionalization, 427 Silk fibroin, 444–446 Silver nanocrystals (AgNCs), 312–313 Single-atom layer configuration, 14

Single-layered graphene (SLG), 79–80 Single-stranded DNA (ssDNA), 270 Single-walled carbon nanotubes (SWCNTs), 77–78, 197, 418, 420 Single-walled nanohorns (SWNHs), 276 Size exclusion chromatography (SEC), 364–365 Spectrophotometry, 466–468 Spectroscopic methods, 361 Spherical/ellipsoid particles, 77–78 Stem cells differentiation, 253–255 growth, 252–253 Stem cell therapy, 219–225, 252–256, 341–346, 342–343f, 345f carbon nanoparticles (CNTs), 224–225 graphene-based nanomaterials, 344 graphene oxide (GO), 222–224, 223f nanodiamonds (NDs), 343–344 research, 253 Stimuli-responsive carriers, 216 Superparamagnetic IONPs (SPIONs), 319–320 Surface-functionalized graphene-based materials, 202–203 Surface plasmon resonance (SPR), 203 Sustainable release, 214–215 SWISS-MODEL, 161–162

T Tannic acid, 457 Targeted drug delivery, 338, 339f Thermal chemical vapor deposition (CVD), 98 Thermal techniques, 364 Thermogravimetric analysis, 333, 364, 447 Timely detection, 334 Tissue engineering, 151–152 Top-down approaches, 21–23 arc discharge, 23 chemical exfoliation, 21–22 chemical fabrication, 22–23 electrochemical exfoliation, 22 Toxicity, 57, 255 Toxicological assessment, 276–279 Transmission electron microscopy (TEM), 333, 359–360, 509–510 Triple-walled carbon nanotubes (TWCNTs), 420 Tuberculin, 341 Tuberculosis (TB), 202–203

559

560

Index

U

X

Ultracentrifugation (UC), 364 Ultraviolet-visible (UV-vis) spectroscopy, 363

X-ray absorption near-edge structure (XANES), 365 X-ray diffraction (XRD) technique, 361 X-ray photoelectron spectroscopy (XPS), 363

V Vaccines, carbon-based nanomaterials for use, 339–341 carbon-based nano delivery systems, 340, 340f single-walled carbon nanotubes, 341, 341f Vertically aligned multiwalled carbon nanotubes (VA-MWCNTs), 205 VitalCore, 208

W Wound healing, 150, 323–324

Z Zeolite imidazolate framework (ZIF-8), 272–273 Zero-dimensional (0D) nanotubes, 342–343 Zika virus, 3 Zinc oxide nanocrystals (ZnONCs), 313–314