Carbon Nanostructures in Biomedical Applications 9783031282621

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Advances in Material Research and Technology

Md Saquib Hasnain Amit Kumar Nayak Saad Alkahtani Editors

Carbon Nanostructures in Biomedical Applications

Advances in Material Research and Technology Series Editor Shadia Jamil Ikhmayies, Physics Department, Isra University, Amman, Jordan

This Series covers the advances and developments in a wide range of materials such as energy materials, optoelectronic materials, minerals, composites, alloys and compounds, polymers, green materials, semiconductors, polymers, glasses, nanomaterials, magnetic materials, superconducting materials, high temperature materials, environmental materials, Piezoelectric Materials, ceramics, and fibers.

Md Saquib Hasnain · Amit Kumar Nayak · Saad Alkahtani Editors

Carbon Nanostructures in Biomedical Applications

Editors Md Saquib Hasnain Department of Pharmacy Palamau Institute of Pharmacy Daltonganj, Jharkhand, India

Amit Kumar Nayak Department of Pharmaceutics School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University) Bhubaneswar, Odisha, India

Saad Alkahtani Department of Zoology King Saud University Riyadh, Saudi Arabia

ISSN 2662-4761 ISSN 2662-477X (electronic) Advances in Material Research and Technology ISBN 978-3-031-28262-1 ISBN 978-3-031-28263-8 (eBook) https://doi.org/10.1007/978-3-031-28263-8 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

With the innovation in the field of science and technology, advancements in nanotechnology applications have been emerged from material science to healthcare applications. Among the diverse nanomaterials available till date, the exploration of carbonbased systems has gained the considerable momentum. Unique physiochemical, mechanical, electrical, and thermal properties, along with surface tunable characteristics of carbon isotopes possess immense potential for healthcare applications. Several research reports have vouched the applicability of carbon nanostructures, which primarily include drug delivery and biomedical applications. Instances of some of the extensively investigated carbon nanocarriers include carbon nanotubes, graphenes, fullerenes, carbon nanofibres, nanorods, nanohorns, nanotorous, nanodiamonds, etc. Diversified applications of these carriers are a testimony to their multidimensional ability, thus confirming their usage in translational research for healthcare applications. In this context, despite the availability of umpteen literature reports, the present book will endeavor to provide a holistic compilation on applications of carbon nanostructures, especially in advanced healthcare applications. The current book is a collection of total 14 chapters presenting different key topics by the academicians and researchers across the world. A concise account on the contents of each chapter has been described to provide a glimpse of the book to the readers. Chapter One entitled “Fullerenes: Bucky Balls in the Therapeutic Application” describes the many biological applications of fullerenes and their derivatives. Chapter Two entitled “Nanodiamonds as Next Generation Carriers in Exploring Therapeutic Benefits” aims to inspire readers to explore new avenues for designing and developing next-generation nanodiamond-based materials with advanced functionalities and attractive properties. Chapter Three entitled “Nanographites as Multidimensional Carriers for Advanced Therapeutic Applications” highlights various nanographite composites with different synthetic approaches in various therapeutic applications, such as drug delivery and cancer treatment.

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Chapter Four entitled “Carbon Nanohorns in Drug Delivery and Medical Applications” summarizes the advancement of carbon nanohorns, including their properties, functionalization, and its possible potential in those fields. Chapter Five entitled “Carbon Nanotorous for Advanced Therapeutic Applications” deals with the advanced therapeutic applications of carbon nanotorous. Chapter Six entitled “Carbon Nanodots: A Novel Carbon Material with Multifacet Applications in Healthcare” summarizes the synthesis and diverse applications of carbon nanodots in the healthcare sector. Chapter Seven entitled “Quantum Dots in Biomedical Applications: Recent Advancements and Future Prospects” emphasizes the latest progress available in literature related to various biological and biomedical applications of quantum dots as a potential tool for sensing, biomedical imaging, and drug delivery. Chapter Eight entitled “Carbon Nanotropes: Potential Nanomaterials for Drug Delivery and Biomedical Applications” summarizes carbon nanotrophes, their unique properties, fabrication methodologies, drug delivery carrier, and other biomedical applications. Chapter Nine entitled “Carbon Nanofibres in Diversified Healthcare Applications” gives a detailed insight on the healthcare applications of carbon nanofibers. Chapter Ten entitled “Carbon Nanomaterials in Biosensor Applications for Infectious Disease Diagnostics” highlights the challenges and future considerations to expand the applicability of carbon nanomaterials for commercial point-of-care clinical diagnostic platforms. Chapter Eleven entitled “Bio-inspired Carbon Nanostructures: Advances and Challenges” is an overview of various bio-inspired carbon nanostructures, nanocomposites, and their specific properties. In addition, their applications in specific biomedical applications, advances, and challenges are also discussed in this chapter. Chapter Twelve entitled “Natural Polymer-Carbon Dot Nanocomposites for Biomedical Use” describes the preparation of natural carbon dots, composites, and their biomedical applications. Chapter Thirteen entitled “Clay-Based Composites and Nanocomposites for Drug Delivery” addresses the uses of clays in nanoarchitectonic drug delivery vehicles that are targeted and stimuli-responsive regulated. The advantages and disadvantages of using these nanomaterials along with directions for future study are also discussed in this chapter. Chapter Fourteen entitled “Biosafety and Toxicity Evaluation of Carbon Nanomaterials” presents a systematic evaluation of the safety and toxicity of various carbon nanomaterials based on recent reports. The possible strategies to minimize the unwanted toxic effects of the carbon nanomaterials in multiple applications are presented. We would like to convey our sincere thanks to all the authors of the chapters for providing timely and valuable contributions. We thank the publisher-Springer Nature. We specially thank Dr. Shadia Ikhmayies (Series Editor, Advances in Material Research and Technology, Springer Nature), Mayra Castro, and Yogesh for their invaluable support in organization of the editing process right

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through the beginning to finishing point of this book. We gratefully acknowledge the permissions to reproduce copyright materials from various sources. Finally, we would like to thank our family members, all respected teachers, friends, colleagues, and dear students for their continuous encouragements, inspirations, and moral supports during the preparation of the current book. Together with our contributing authors and the publishers, we will be extremely pleased if our endeavor fulfills the needs of academicians, researchers, students, biomedical experts, pharmaceutical students, and drug delivery formulators. In a nutshell, it will also help the health professionals in academia as well as in the industries. Daltonganj, India Bhubaneswar, India Riyadh, Saudi Arabia

Dr. Md Saquib Hasnain Dr. Amit Kumar Nayak Dr. Saad Alkahtani

Contents

Fullerenes: Bucky Balls in the Therapeutic Application . . . . . . . . . . . . . . . Dipanjan Ghosh, Gouranga Dutta, Abimanyu Sugumaran, Gopal Chakrabarti, and Biplab Debnath Nanodiamonds as Next Generation Carriers in Exploring Therapeutic Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nadia Fattahi and Ali Ramazani Nanographites as Multidimensional Carriers for Advanced Therapeutic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mahmoud H. Abu Elella, Emad S. Goda, Mariam M. Abady, Dina Mohammed, and Heba M. Abdallah Carbon Nanohorns in Drug Delivery and Medical Applications . . . . . . . . Gouranga Dutta, Nilayan Guha, Abimanyu Sugumaran, and Md. Kamaruz Zaman

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Carbon Nanotorous for Advanced Therapeutic Applications . . . . . . . . . . . 123 Sora Yasri and Viroj Wiwanitkit Carbon Nanodots: A Novel Carbon Material with Multifacet Applications in Healthcare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Anam Khan, Reena Vishvakarma, Archana Vimal, Poonam Sharma, Hassan Usman, and Awanish Kumar Quantum Dots in Biomedical Applications: Recent Advancements and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Syed Anees Ahmed, Amit Kumar Nayak, Mohammed Tahir Ansari, Abdulla Sherikar, Mohd Usman Mohd Siddique, Saad Alkahtani, Sadath Ali, Mohammad Tabish, Sidra Khatoon, Ali Qassim Darraj, and Md Saquib Hasnain

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Carbon Nanotropes: Potential Nanomaterials for Drug Delivery and Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Esha Roy, Prosenjit Mridha, Rinku Baishya, Himangsu Kousik Bora, Rituraj Konwar, and Manash R. Das Carbon Nanofibres in Diversified Healthcare Applications . . . . . . . . . . . . . 229 Nandana Sailesh, Sreelakshmi K. Warrier, Devika Manoj, Gigi George, D. S. Sheny, Laly A. Pothen, and K. R. Ajish Carbon Nanomaterials in Biosensor Applications for Infectious Disease Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Satakshi Hazra and Sanjukta Patra Bio-inspired Carbon Nanostructures: Advances and Challenges . . . . . . . 285 Zachary Ault, Sungwoo Yang, Jaison Jeevanandam, and Michael K. Danquah Natural Polymer-Carbon Dot Nanocomposites for Biomedical Use . . . . . 297 Nagarjuna Reddy Desam, Abdul Jabbar Al-Rajab, and Hari Babu Pagonda Clay-Based Composites and Nanocomposites for Drug Delivery . . . . . . . . 343 Vy Anh Tran, Thu-Thao Thi Vo, Vinh Quang Dang, and Giang N. L. Vo Biosafety and Toxicity Evaluation of Carbon Nanomaterials . . . . . . . . . . . 363 Aleena Ann Mathew, Meera Varghese, and Manoj Balachandran

Fullerenes: Bucky Balls in the Therapeutic Application Dipanjan Ghosh, Gouranga Dutta, Abimanyu Sugumaran, Gopal Chakrabarti, and Biplab Debnath

Abstract In 1985, when Kroto found the third allotropic structure of carbon after diamond and graphite. A study on fullerene C60 began, and it has shown an increasing significance in biological research. Fullerenes were determined to be innocuous at first, but their unusual cage architecture and solubility in organic solvents made them susceptible to derivatization via addition and redox reactions. These carbon spheres are currently being investigated internationally for a variety of nanomedicine applications. The extraordinary electrical characteristics of these molecules make them promising candidates for diagnostic, therapeutic, and theranostic uses. This chapter focused on the many biological applications of fullerenes and their derivatives. Keywords Carbon nano structure · Fullerene · Characteristic · Biomedical applications · Therapeutic applications

1 Introduction Carbon is a common element that occurs in nature in several forms (polymorphs), including graphite and diamond. Fullerenes are the fourth allotrope of carbon. In contrast to the stretched solid-state geometries of graphite and diamond, fullerenes are spherical molecules that are soluble in a range of organic solvents. This characteristic D. Ghosh · G. Chakrabarti Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata 700019, India G. Dutta Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur 603203, India A. Sugumaran (B) Department of Pharmaceutical Sciences, Assam University (A Central University), Silchar 788011, Assam, India e-mail: [email protected]; [email protected] B. Debnath Department of Pharmaceutical Chemistry, Bharat Technology, Uluberia, Howrah 711316, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. S. Hasnain et al. (eds.), Carbon Nanostructures in Biomedical Applications, Advances in Material Research and Technology, https://doi.org/10.1007/978-3-031-28263-8_1

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may be employed for a range of chemical processes. The empirical formula CN , where N specifies the number of carbon atoms, is used to derive the chemical formula of fullerenes with a closed mesh network. A fullerene is a carbon cage structure with a merged pentagon and hexagon ring system. In 1970, Japanese scientist Eiji Osawa suggested the term buckyball for the first time. Richard Smalley and his group created the first fullerene chemical, buckminsterfullerene, in 1985 (C60 -fullerene). The newly discovered molecule was named after the architect who constructed a geodesic dome with a similar structure, Richard Buckminster Fuller [41, 42]. Since their discovery in 1985, fullerenes have attracted a great deal of attention in a range of scientific fields. Physical, chemical, and biological examinations of the properties of fullerenes have shown positive findings. It is anticipated that their size, hydrophobicity, three-dimensionality, and electrical topologies make them fascinating subjects for biological applications [15]. Their unusual carbon cage structure and extensive derivatization potential make them an intriguing therapeutic option. Despite the low solubility of carbon spheres under physiological circumstances, there is a rising interest in studying their biological uses [7, 80]. The photochemical, electrochemical, and physical properties of the fullerene family, namely C60 fullerene, may be used in a variety of medical fields. Fullerene may fit into the hydrophobic cavity of HIV proteases, preventing substrates from accessing the active region of the enzyme. It has antioxidant and radical-scavenging properties [43]. In addition, when fullerene is exposed to light, it may produce substantial quantum yields of singlet oxygen. Additionally, it may be functionalized with a range of medications and biological molecules to treat various diseases [55, 61]. This chapter of the book focuses on the general properties of fullerene and its efficacy in various medicinal applications.

2 Overview and General Characteristics of Fullerene Fullerenes named Buckminster fullerenes or Buckyballs are one of the carbon allotropes. This is because of its symmetrical cage structure and various sizes (C60 , C76 , etc.), fullerenes have unusual chemical and physical characteristics. The C60 Fullerene is the most common in the synthesized form and can be prepared by various different methods [2, 21]. In general, C5 -C5 single covalent bond (12 pentagons), and C5 = C6 double bonds (20 hexagons) make up the structure. Each fullerene indeed contains 2n + 20 carbon atoms where ‘n’ represents the number of hexagons. These carbon structures are primarily manufactured using laser vaporization of pure carbon, electrical arc discharge heating of graphite, and resistive arc heating. Initially, it was identified via laser vaporization of carbon in an inert environment (helium). This procedure generated a minimal quantity of C60 Fullerene. Subsequently, another technique for generating fullerene included establishing an electrical arc between graphite rods in an inert environment. However, to boost the manufacturing rate, lasers were used to irritate polycyclic hydrocarbons (PAHs). This fullerene synthesis method relies on polycyclic aromatic hydrocarbons (PAHs) which

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already contain the necessary carbon scaffolds. In flash vacuum pyrolysis conditions, these PAHs molecules “wrap up” to create fullerenes when laser-irradiated at a 337 nm wavelength [54, 58]. Due to the hydrophobic character of simple fullerenes and the fact that they are exclusively soluble in organic solvents, they are not useful for different medicinal applications. However, it is readily functionalizable by covalent and non-covalent conjugation. Depending on the derivitization and exohedral and endohedral derivatization makes them more lipophilic or hydrophilic than basic fullerenes [10, 15, 58]. In this intence, the carbonic nanoparticle (buckyball) behaves differently depending on its surroundings. Because of the molecule’s dual nature among reactive oxygen species, this is the case. When exposed to light, the C60 -fullerene has the capacity to create reactive oxygen species. This effect is known as “photodynamic treatment” (PDT). Many scientists have used this phenomena to develop specific anti-cancer therapies [49, 50, 56]. On other hand, it reduces ROS, which is a neuro-protective agent [17]. This action’s mechanism remains a mystery, and additional inquiry is needed. Because this molecule lacks water solubility and many organic solvents, it is difficult to use it in biological applications. Since hydrophilicity is of higher value in biological systems than hydrophobicity, several ways have been devised to enhance the hydrophilicity and water solubility of materials. Fullerenes can be encapsulated in cyclodextrins [18, 70], polyvinylpyrrolidone micelles [11], liposomes, and other special carriers, as well as chemically modified by hydrophilic substances like amino acids [66, 91] and carboxylic acids, polyhydroxyl groups (fullerenols) [22, 72], among other things, to create two-phase colloidal solutions, as well as fullerene derivatives and fullerene polymers.

3 Fullerenes: Therapeutic Applications 3.1 Biosensor C60 -fullerene is a fundamental component that is utilized for biosensing applications. There are various scientific shreds of evidence already established on this. Here, some scientifically established reports are emphasized and enlightened. Saeedfar et al. [69] developed a potentiometric nano biosensor for the detection of urea by using C60 -fullerene [69]. An unique strategy for the quick alteration of fullerene for subsequent enzyme attachment to generate a potentiometric biosensor is provided. The novel strategy is that the urease enzyme was immobilized onto the carboxylated (-COOH) fullerene by replacing hydroxyl group (–OH) in the presence of “N, N’-dicyclohexylcarbodiimide (DCC), or N-(3-dimethylaminopropyl)N’-ethylcarbodiimide hydrochloride (EDC)” and the resultant bio-conjugate was applied to confirm the catalytic hydrolysis of urea in solution. The biomaterial was then placed on top of a pH specific screen-printed electrode consisting of a nonplasticized poly (n-butyl acrylate) (PnBA) membrane enclosed with a hydrogen

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ionophore. This pH-selective membrane is intended to function as a potentiometric urea biosensor when C60 -urease is deposited on the PnBA membrane. The optimal pH and phosphate buffer concentration for the urea biosensor were 7.0 and 0.5 mM, correspondingly. The linear response range of the biosensor was in the region of 2.31*103 M to 8.31*105 M. The cations (Na+ , K+ , Ca2+ , Mg2+ , and NH4+ ) had no discernible effect on the response of the urea biosensor. The combination of a fullerene-urease bio-conjugate with a high-adhesion acrylic membrane decreased the leaking of the urease enzyme and increased the urea biosensor’s stability for up to 140 days. In another study, Tortolini et al. [81] carboxylated gold nanoparticle conjugated fullerol as a novel electrochemical nano biosensor for the detection of polyphenolic compounds [81]. The scientists used a screen-printed electrode (SPE) as a gold substrate to make a biosensor that could find polyphenols in real wine samples. The Folin–Ciocalteau technique was used as a spectrophotometric reference method to compare their results. They suggested a biosensor called Trametes Versicolor Laccase (TvL) that uses a screen-printed electrode (SPE) as a gold substrate. For the first time, they exhibit the DET of their proposed improved biosensor in the absence of redox mediators using scanning tunneling microscopy (STM) to characterize its surface. In contrast, Uygun et al. [84] synthesized a novel chemical biosensor to detect Fetuin-A levels in blood samples [84]. Fetuin-A (Alpha-2 HS glycoprotein) is encoded by the AHSG gene [59]. It is a 64-kDa glycoprotein that is secreted from both the liver and adipose tissue, responsible for a novel link between obesity and associated problems [82]. For achieving this goal, they created an Electrochemical Impedance Spectroscopy (EIS) based antifetuin-A (Anti-HFA) modified biosensor system and tested it in actual blood samples. The detection electrode was developed by the nanostructure that comprised gold as the core and the surface was decorated by 4-amino thiophenol (4-ATP), Fullerene, and PAMAM-NH2 (G5) as different layers. Thereafter, Anti-HFA was immobilized onto the surface of the resultant particles. Herein, Gold screen-printed electrodes (AuSPE) were used as the transducer. The authors used the ELISA technique for sample detection. In a recent study, Li et al. [46] designed a photochemical biosensor by implying methylene blue-sensitized C60 fullerene for ultrasensitive DNA detection. In this work, photoactive C60 -fullerene nanoparticles were changed on the electrode surface to generate an initial photocurrent signal. A signal amplification technique was also utilized to hybridize with DNA2 to transform many DNA duplexes into immobilized methylene blues as the sensitizer, hence producing efficient sensitization toward the C60 -fullerene and enhancing the photo-current for quantitative DNA detection [51].

3.2 Targeted Anti-cancer Therapy Fullerenes are used as anti-cancer therapy. Due to its unique characteristics, many scientists used fullerenes as the drug-conjugated carrier to deliver the drug molecules to the target site. Fullerene has excellent conjugation and loading capacity of the drug molecules as a carrier. Hence, drug-conjugated fullerene is an efficient targeted

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anti-cancer delivery system. For instance, Shi et al. [74] depicted docetaxel-loaded polyethyleneimine fullerene with a surface passivated by folic acid that was able to target the prostate cancer cells (PC3 cells) actively [74]. The size and zeta potential of the resultant nano-structure were ~140 nm and ~13.7 mV respectively. Their data reflected that after administration of the resultant nano-structured conjugate against cancer cells, early apoptosis and late apoptosis increased by 1.18–1.88 folds compared with free docetaxel. As similar, Panchuk et al. [61] synthesized doxorubicin (DOX) conjugated C60 fullerene nano-system that was used against different kinds of cell lines (HCT116: Human colon adenocarcinoma cell line, MCF7: Human Breast cancer cell line,) [61]. DOX is a well-known anti-cancer drug molecule that inhibits topoisomerase II [79]. They reported that DOX conjugation with C60 fullerene results in a 1.5–2 fold increase in DOX toxicity towards numerous human solid tumor cell lines as compared with free DOX. In contrast, this hydrophobic drug molecular moiety is encapsulated by ‘Buckysome’S’ hydrophobic interiors. Paclitaxel (PTX) is another essential anti-cancer drug molecule that acts as a microtubule de-polymerizing agent. There is scientific evidence that PTX-conjugated fullerenes may be utilized to deliver chemotherapy drugs in a targeted manner. Zakharian et al. (2004) developed a PTX-functionalized C60 -antibody combination for the targeted therapy of cancer. They also produced PTX conjugated C60 -fullerene for biological activity. In this work, they revealed that PTX directly was not conjugated with fullerene, since as stated that two–OH (hydroxyl) alteration might lose the biological activity. Hence, they employed an ester (–COOC–) or amide (–CONH2 ) linkage that may be broken by biological processes [36, 92]. In contrast, Partha et al. [64] generated PTX-loaded self-assembled C60 fullerene or buckysome (100–200 nm) amphiphilic spherical nano-structure against breast cancer (MCF-7 cell line) [64]. The buckysome was constituted of AF-1 molecules, which are C60 fullerene modified with a Newkome-like dendrimer unit with 18–COOH groups. However, the structure of AF-1 was previously established by authors in another study [63]. Herein, the authors ensure that there are six groups connected to each fullerene in an octahedral configuration with C2v symmetry in the AF-1 monomer. A dendritic moiety comprising 18 carboxylic acid groups sits atop the molecule. C12 esters are found in pairs at the other five locations (dodecyl malonates). It seems that dodecyl malonates occupy five extra sites on the fullerene, which are oriented octahedrally to the dendritic group. It is more soluble at higher pH values because of the lower electrophilicity of the carboxylic acid groups (pKa 7.5). When the pH is less than 3, the molecule precipitates out of the solution. The self-assembled complex structures were generated at 700 °C, and were morphologically observed as vesicular structures. However, they demonstrated the cellular absorption of these novel buckysomes implanted with the hydrophobic fluorescent dye Dil “(1,1' -Dioctadecyl3,3,3' ,3' -tetramethylindocarbocyanine perchlorate)”. The schematic representation of the study was also depicted in Fig. 1. In another study, Kepinska et al. [39] developed pH-responsive doxorubicin conjugated C60 -fullerenes nano- complex as targeted anti-cancer therapy against breast cancer (MCF7 cell line) [39]. They illustrated that DOX was released gradually from the synthesized DOX-fullerene nanoconjugate under a lower pH in the extracellular

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Fig. 1 Schematic depiction of Paclitaxel loaded self-assembled C60 fullerene or buckysome containing hydrophobic dye encapsulated AF-1 assembled nanostructure was administered against MCF7 breast cancer cell line. Paclitaxel is an anti-cancer drug molecule and the hydrophobic dye (Dil: 1, 1' -Dioctadecyl-3, 3, 3' ,3' -teramethylindocarbocyanine) was encapsulated for cellular tracking and bio-imaging purpose [63]

environment of the cancer cell. The authors reported that the size and zeta potential of the fullerene- DOX nano-complex was ~280 nm and −24 mV respectively. Also, they ensured that the fullerene-DOX complex leads to a threefold increase in cytotoxicity against the MCF7 cell line as compared with free DOX. Similarly, Chen et al. [13] synthesized novel metallofullerenol molecules (e.g., Gd@C82 (OH)x, where X is the number of hydroxyl group) which has a specific nanostructure that comprises several tens of molecules as magnetic cores Gadolinium (Gd) and close-caged carbon nanosheets with surface passivated hydroxyl groups (–OH) [13]. The synthesized metallofullerenol nanoparticles had anti-tumor activity against liver cancer. The hydrated particles were 22 nm (average) in size and the authors used this nanoparticles against the tumor-bearing mice at a dose level of 107 mol/kg which seems to be a very potent anti-cancer activity (~60%). Toxicant tumor inhibition is increased by 26% when the dosage is increased by one order of magnitude (107 mol/kg). The resultant particles show a great ability to boost immunity and interfere with tumor invasion in normal muscle cells, practically without harm in invivo and invitro. Aside with prioritising tailored anti-cancer treatment, the product has lower toxicity. As a result, the scientists ensured that just around 0.05% of the applied dose was found in tumour tissues. This implies the nanoparticles have high antitumor effectiveness

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without causing harm to cells. According to research results, the tumor chemotherapeutics with great effectiveness and low toxicity may be possible using fullerene derivatives with the correct surface modifications and sizes.

3.3 Photodynamic Therapy In photodynamic therapy, aberrant cells are destroyed by using light-sensitive drugs in concert with a light source. Oscar Raab, who was the first to conduct a scientific study on photosensitized reactions in 1898, who introduced the photodynamic therapy concept of employing a dye as a photosensitizer in the photodynamic process [1]. Lipson and his colleague developed hematoporphyrin derivatives by combining hematoporphyrin chloride with hydrochloric acid and sulfuric acid. The invention of hematoporphyrin derivatives as photosensitizer laid the groundwork for photodynamic treatment also know as photodynamic therapy.[37]. Many scientists develop C60 fullerene which was used as a photosensitizer [25] for the treatment of anti-cancer therapy. In addition, a radiolabelled isotope was used to conjugate with C60 fullerene for cancer treatment and as well as diagnosis. Consequently, Ji et al. (2005) developed radiolabelled fullerol [125 I-C60 (OH)] that comprises a very stable covalent Carbon-Iodine bond in-vivo system [35]. They illustrated the bio-distribution of the resultant nano-composite that was active against five different tumor-bearing mice models, such as “human lung giant-cell carcinoma PD, mouse H22 hepatocarcinoma, human colon cancer HCT-8, and human OS732 osteosarcoma and human gastric cancer MGC803”. The accumulation ratios of radiolabelled fullerol [125 I-C60 (OH)] in mouse H22 tumor to normal muscle tissue (T/N) and blood (T/B) at 1, 6, 24, and 72 h demonstrate that radiolabelled fullerol [125 IC60 (OH)] accumulates gradually in H22 tumor and persists for an extended period of time (e.g., T/N: 3.41, T/B: 3.94 at 24 h). For the other four tumor models, the T/N ratio at 24 h ranges between 1.21 and 6.26, while the T/B ratio varies between 1.23 and 4.76. Furthermore, the radiolabelled fullerol [125 I-C60 (OH)] buildup in tumors is primarily caused by the increased permeability and retention effect (EPR) and phagocytosis of mononuclear phagocytes. Consequently, radiolabelled fullerol [125 IC60 (OH)] might be used as a photosensitizer in photodynamic treatment for some types of tumors. Notably, their bio-distribution study of the radiolabelled fullerol ensured that the nano-composite was deposited into the liver, skin, kidney and bone for all types of tumor-bearing mice. The schematic representation of the study was also depicted in Fig. 2. Notably, the figure implies that the administered product with low dose was bio-available into the liver tissue as compare to the large amount. Besides, the resultant product also accumulated into the spleen, kidney & bone tissue. There was another example where fullerene used as a photosensitizer including MRI imaging that was used as an anticancer agent. Liu et al. [49] synthesized a novel photo-sensitizer (PEG-conjugated-C60 fullerene-DTPA) for MRI bioimaging that was also used as an anticancer agent by PDT (Photodynamic therapy) [49].

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Fig. 2 Schematic representation of the bio-distribution profiling of radiolabel fullerol complex [125 I-C60 (OH)X ] (X = Number of the hydroxyl groups). They used five different tumor cell line successfully implanted into the mouse. After that, 100 µL of aqueous solution of radiolabelled fullerol [125 I-C60 (OH)X ] was administered through tail vein for the bio-distribution study. The results of the distribution were denoted as % ID/g that implies percent of injected dose per gram tissue. ID: Injectable dose

The strategy of the work is depicted in Fig. 3. PEG-conjugated-C60 fullereneDTPA was prepared by adding Diethylenetriaminepentaacetic Acid (DTPA) to the terminal group of polyethylene glycol (PEG). C60 fullerene has a cage-like structure & the Gadolinium (Gd+) metal ions were coupled with the PEGylated fullerene via the metal chelation technique. In addition, they also used 59 FeCl3 solution as a precursor chemical for radiolabelled imaging. After administration of the resultant nano-composite into the tumor-bearing mice through an intravenous route, the photodynamic therapy & MRI tumor imaging were evaluated significantly. A large amount of nano-structure was entrapped & deposited into the tumor enriched site having a passive targeting phenomenon (EPR: Enhanced Permeation & Retention Effect) and showed anti-cancer activity while illuminating with light as an external environmental stimulus. Notably, reactive oxygen species (O2•–) was also generated with or without metal ion (Gd+) chelation. Also, they ensured that there was similar MRI imaging was found with the use of PEG-conjugated-C60 fullerene-DTPA and

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MAGNEVIST® , in both cases. MAGNEVIST® is a marketed product of gadopentetate dimeglumine, an injectable formulation that is the N-methylglucamine salt of the gadolinium complex of diethylenetriamine penta-acetic acid. Similarly, Morz et al. [55] synthesized six unique different kinds of functionalized fullerenes with 1, 2, or 3 hydrophilic or 1, 2, or 3 cationic groups used as a photosensitizer in photodynamic treatment of anti-cancer therapy [55]. The functionalized nano-fullerenes absorb the light which is given by an external stimulator to sensitize them that resulting to produce ROS in the specific area of the applied field in the tumor. Herein, they used three different mouse cancer cell lines, such as J774, LLC, and CT26. The apoptosis was triggered 4–6 h after illumination by the monopyrrolidinium fullerene (photosensitizer), which was the most active against all cell lines tested. Moreover, they ensured that A Type I mechanism for phototoxicity was seen when dichlorodihydrofluorescein was used as a ROS probe and caused diffuse intracellular fluorescence. The same groups of scientists develop a novel delivery system for their previous product N-methylpyrrolidinium-fullerene, a functionalized nano-fullerene that was used against colon adenocarcinoma in 2011

Fig. 3 Schematic representation of C60 -fullerene containing novel nano-composite (PEGconjugated-C60 fullerene-DTPA) which used as photodynamic therapy against cancer. The nanostructure is able to use both purposes; such as MRI (Magnetic Resonance Imaging) purpose and photodynamic therapy where NIR (Near infrared light) was used as external stimulator. Herein, the gadolinium ion (Gd+) was coupled to composite for radiolabel imaging as well as induced to produce ROS into the intracellular level. DTPA: Diethylenetriaminepentaacetic Acid [49]

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[56]. They developed micelles loaded with N- methylpyrrolidinium-fullerene that was administered via the intraperitoneal route for photodynamic therapy. Liu et al. (2010) developed a novel pullulan-functionalized C60 fullerene as photodynamic therapy against hepatoma [50]. Pullulan, a water-soluble polymer, is conjugated at the surface of C60 -fullerene with amino-spacer moiety (–NH2 ). The amine groups (–NH2 ) come from ethylene diamine which was used as a precursor chemical for amine functionalization. Pullulan is passivated with the amino group and then the resultant complex was anchored to C60 through the terminal amine group of pullulan. When illuminated with light, the C60 end-group conjugated with pullulan results to produce a superoxide anion. The pullulan functionalized C60 conjugates effectively inhibited the development of HepG2 hepatoma cells with asialoglycoprotein receptors invitro, but in HeLa cells without the receptors showed reduced suppression efficacy. In comparison to HeLa cells, this conjugate exhibits a strong affinity for HepG2 cells. In another study, Guan et al. [23] designed a novel phototheranostic agent that was used for effective tumor targeting, imaging & treatment [23]. They developed a tri-malonate derivative of fullerene shaped as nano-vesicles for effective tumor targeting & treatment. The functionalized fullerene nano-vesicles were comprised of C70 fullerene, 1,10-Diamino-4,7-dioxadecane (OEG2), and Chlorin e6 (Ce6). Herein, Ce6 was conjugated at the surface of the core composite that was made up of C70 fullerene. OEG2 was used as a space or linker molecule to conjugate Ce6 moiety as surface anchoring. The resultant developed molecular assembly was formed as a vesicle (the average size of the vesicles was 64.5 ± 6.5 nm) into the water/DMSO solution. The product had some beneficial advantages, such as high loading efficiency of Ce6 (~57wt %), effectively absorbed near-infrared light, better cellular internalization capacity & last but not least potentially biocompatible that excreted out from the body. This is because of its wide π-conjugated aromatic domains, chlorin e6 (Ce6) is a frequently applied photosensitizer because of its enhanced absorption in the near-infrared (NIR) light area and increased singlet oxygen (1 O2 ) quantum yield [45, 47, 87]. The strategy of the work was illustrated in Fig. 4.

3.4 Alzheimer Alzheimer’s disease impairs numerous brain processes, including memory retention and logical thinking, in a gradual manner. Memory and other mental processes are gradually lost when brain cell connections and cells deteriorate and die. The primary signs and symptoms are a lack of concentration and disorientation. Although there is no cure, medications and other treatment options may help alleviate symptoms for a while. The most fundamental approach for brain-related diseases is to deliver the drug molecules into the brain across the blood–brain barrier. Most of the cases the bare drug molecules can’t reach across the blood–brain barrier (BBB) into the systemic circulation of the brain. Hence, the drug delivery system is an important aspect of the treatment of brain-related diseases. Kraemer et al. [40] showed that

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Fig. 4 Depiction as a schematic representation of novel nano-vesicular structure used as photothermal therapy against cancer. The nano-composite structure was comprised of C70 -fullerenePEG- Ce6 molecule as a unit. Subsequently, the two units make together bilaterally that build up 3 layers (Hydrophobic-hydrophilic-hydrophobic) into the inner structure. The nano-bodies are biocompatible in nature and Chlorine (Ce6) was used as the photosensitizer

C60 fullerene is another hydrophobic carrier to deliver drug molecules into the brain [39]. Makraova et al. [52] illustrated the comparative study of the affectivity of the different components such as amyloid-ß25-35 (1.6 nmol/1 µL), and hydrophilic colloidal dispersion of C60 fullerene (0.46 nmol/1 µL), and colloidal dispersion of C60 fullerene before administration of amyloid via intra-hippocampal microinjections [52]. Deposition of amyloid-ß25-35 in hippocampal pyramidal neurons was avoided by administering a modest dose of C60 fullerene in an aqueous molecule of colloidal solution before the amyloid peptide. Anti-amyloid medicines that combine antioxidant and anti-aggregation capabilities might be developed using functionalized C60 . Moreover, the molecular interaction between C60 fullerene and amyloid ß was also established by computational structure biology & bioinformatics study by Xie et al. [90]. Amyloid deposits have a role in the pathogenesis of many neurodegenerative disorders, including Alzheimer ‘s disease. The inhibition of ß-sheet production has been proposed as the primary Alzheimer’s disease therapy. Nanoparticles may

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inhibit or induce the fibrillation of amyloid-ß peptides, based on their physicochemical characteristics, according to emerging research. Nevertheless, the fundamental molecular mechanism remains elusive. In this study, it has been demonstrated that replica exchange molecular dynamics (REMD) simulations indicate that fullerene (C60 ) nanoparticles (fullerene: peptide molar ratio greater than 1:8) may significantly inhibit the production of ß-sheets in amyloid-ß(16–22) peptides. Fullerene@peptide interaction indicates that the greater inhibition of ß-sheet formation by C180 is a result of the strong hydrophobic and aromatic-stacking interactions of the hexagonal fullerene rings with the Phe- rings as compared to the pentagonal rings. Strong interactions between fullerene (C60 ) nanoparticles and amyloid-ß(16–22) peptides significantly inhibit the peptide–peptide interaction required for ß-sheet production, hence retarding amyloid-ß(16–22) fibrillation. Overall, their research demonstrates the importance of hexagonal rings of C60 -fullerene in the inhibition of amyloid-ß(16–22) fibrillation and provides novel insight into the creation of Alzheimer’s disease therapy possibilities. Vorobyov et al. (2014) depicted that C60 fullerene has a neuroprotective activity that seems like a protective role for Alzheimer’s disease [86]. Similarly, Gonçalves et al. (2016) suggested five potential C60 -fullerene derivatives as new drugs against Alzheimer’s disease [77]. Herein, they suggest five potential Alzheimer’s disease treatments based on fullerene (C60 ) derivatives. Human acetylcholinesterase (HssAChE) inhibitors were developed to prevent the fasciculin II (FASII) binding site to the drugs. Herein, they emphasize computational structural biology, docking, and molecular dynamics simulations which demonstrate a stable complex formation with their proposed compounds. New human acetylcholinesterase inhibitors based on C60 -fullerene derivatives may take advantage of an area created by many residues (Asp74, Trp286, Tyr72, Asp74, Gln291, Trp286, Tyr341, and Pro344). Moreover, there are two miraculous properties of C60 -fullerene is that it may be both a potent ROS generator and a ROS scavenger due to its very delocalized double bond structure [34, 93]. Under UV or visible light, C60 -fullerene reaches a metastable triplet excitation state in order to form superoxide anion (•O2 ) and singlet oxygen (1 O2 ) by electron transfer or energy transfer [68]. C60 -fullerene can produce ROS in the biological system & acts also as a scavenger of ROS a dark state by this process. A group of scientists also illustrated the fact of the dual-state nature of C60 fullerene [17]. Du et al. [17] synthesized a novel switchable nano delivery system that was comprised of C60 -fullerene. The scheme of the study was that the nanocomposite produced ROS in the presence of NIR (Near-infrared region) that was stimulated externally and as well as decreased ROS at a dark state. C60 -fullerene and the amyloid-peptide targeting peptide KLVFF were coupled to photothermal conversion nanoparticles (UCNP@C60 -pep), which were utilized to treat Alzheimer’s disease [45, 47] Förster resonance energy transfer (FRET) from UCNPs to C60 would create ROS to target amyloid-peptide, resulting in oxygenation and inhibiting aggregation under NIR light. During the night, C60 –fullerene would scavenge excess ROS and maintain intracellular redox homeostasis at a reasonable level to prevent phototoxicity at nontarget locations. ROS-generating and ROS-quenching capabilities of the resultant nano-structure may be turned on and off using NIR light in this manner. The novel model Caenorhabditis elegans (C. elegans) strain CL 2006, a frequently used

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model for Alzheimer’s disease research, exhibited impressive neuro-protection on this platform [3, 4]. For “image-guided treatment,” their product might be employed for both up-conversion luminescence and magnetic resonance imaging (MRI). The schematic representation of the study was depicted in Fig. 5. However, disruption of the cholinergic system is also responsible for Alzheimer’s disease [24]. A recent study depicts that solution with C60 -fullerene (solvated C60 fullerene) can significantly improve memory impairment that reflects as a treatment for Alzheimer’s disease. The particle size of C60 -fullerene in the solution was ~120 nm and the zeta potential was 12.22 ± 5.98 mV. Herein, the researchers wanted to compare the efficacy of solvated C60 -fullerene with donepezil (a piperidine derivative that acts as an inhibitor of acetylcholinesterase, dose 2 mg/kg in oral route) that is conventional medicine, in enhancing spatial memory in amnesic male Wistar rats while the administered dose of solvated C60 -fullerene was 21 g/mL given in intranasal route. Moreover, Scopolamine HCL is an alkaloid, used as an anticholinergic agent, that induces memory impairments, cognition disorders, and learning problems in rodents and human beings, was administered for developing Alzheimer’s disease in

Fig. 5 Schematic depiction of the effectiveness after administration of peptide conjugated C60 fullerene for Alzheimer’s disease. Herein, the novel peptide conjugated C60 -fullerene was delivered against Alzheimer’s disease. The nano-peptide conjugate produces ROS in the intracellular environment after inducing it by NIR (Near Infrared) light. Similarly, these conjugates also scavenge the ROS at a dark state which implies they decrease the elevated ROS level. Elevation of ROS is the most responsible phenomenon which results in amyloid b fibrillation. The crystal structure of amyloid B was taken from Protein Data Bank (PDB ID: 1AAP, resolution: 1.5 Å). The crystal was characterized by XRD method

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the animals (dose: 2 mg/kg/i.p.). Some theoretical pieces of evidence also proved that C60 -fullerene binds with the P-gp protein that implying it can be effluxed from the cell [75]. For clarification of this aspect, they administered solvated C60 -fullerene with the presence and absence of P-gp inhibitor, Verapamil HCL (Dose: 25 mg/kg). In addition, they also showed the expression level of three key genes of Alzheimer’s disease, such as Sirtuin 6, SELADIN1, and Auaporins, as well as their total antioxidant capabilities (TACs), after administering solvated C60 -fullerene. Selective Alzheimer’s Disease Indicator 1 (SELADIN-1) gene expression protects neurons from various damages, such as toxicity effects of Amyloid- protein, oxidative stress, and cell death, by inhibiting caspase-3, which is involved in the apoptotic process, including being involved in Alzheimer’s disease [31, 73]. Aquaporins are especially expressed in the organs including the kidney, brain, and secretory glands that build water channels in their cell membranes [57, 85]. SIRtuins (SIRTs) play a critical role in cell proliferation, metabolism, apoptosis, DNA repair, cancer, and lifespan. SIRT6 may have a role in the regulation of neurodegenerative processes [78]. Furthermore, it has been shown to protect cells against oxidative stress-induced damage. SIRT6 is a key player in a broad variety of Alzheimer’s Disease triggers, including inflammation, aging, oxidative stress, and DNA damage, thus it lacks could exacerbate neuro-degeneration and the other way around. They ensured that C60 -fullerene successfully improves memory impairment that reflects as a treatment for Alzheimer’s disease.

3.5 Diabetes Diabetes is a condition that develops while blood glucose is increased in systemic circulation, commonly known as blood sugar or hyperglycemia. Insulin, a hormone produced by the pancreas, aids in the transport of glucose from food into cells, where it may be utilized for energy. Diabetes mellitus is another well-recognized cause of male sexual dysfunction and impairments of male fertility [26]. C60 fullerene has antioxidant properties and it could be used for type-1 diabetes or diabetes mellitus. For instance, Bal et al. (2010) developed hydrated C60 -fullerene that was used as a bio-antioxidant and could alleviate testicular dysfunction caused by streptozotocininduced diabetes in rats [8]. Streptozotocin-induced diabetic murine models develop type-1 diabetes, due to the cytotoxic glucose analogue streptozotocin (STZ) that is toxic to pancreatic β-cells and causes insulin deficiency. STZ methylates DNA, causing DNA fragmentation and killing pancreatic β-cells. Besides, type-1 diabetes is characterized by a reduction in reproductive activity due to hyperglycemia-induced oxidative stress and histological changes in the testes [20]. They ensured that after oral administration of the resultant nanocomposite, the relative weights of the right cauda epididymis, seminal vesicles, prostate, sperm motility, and epididymal sperm concentration were considerably lower in diabetic rats than in controls, but were regained in the fourth group treated with C60 HyFn (p < 0.001). Li et al. [46] developed an amino-functionalized Gadofullerene nano-composite that was used against diabetes mellitus [46]. They illustrated that the particles were

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accumulated into the pancreas and liver tissue after administration through intraperitoneal (i.p.) administration of C57BL/6 J mice. They ensured that the level of the main oxidoreductase of superoxide dismutase, catalase, and glutathione peroxidase in serum was increased significantly for the administration of gadofullerene nanoparticles. Also, the nanoparticles dramatically reduced the mRNA expression level of inflammatory markers in the pancreas, such as Nf-κb, Tnf-α, IL-1ß, and IL-6, implying that amino-functionalized Gadofullerene nano-composites reduced pancreatic inflammation in diabetic rats. Furthermore, insulin-mRNA expression in the pancreas of diabetic mice was found to be 2.8 times greater than that in normal non-diabetic mice, which was considerably reduced by amino-functionalized Gadofullerene nano-composites in diabetic animals. Demir et al. (2020) illustrated the affectivity of C60 -fullerene nanoparticles combined with curcumin against hyperglycemia with kidney failure in diabetic rats [16]. After administration of the nanocomposite into the oral route, malondialdehyde level was increased compared to bare C60 -fullerene and free curcumin (C60 : 34.141 ± 2.6, free curcumin: 34.75 ± 1.59 & C60 - fullerene-curcumin with streptozocin: 36.29 ± 4.8 nM/g) and the level of GSH was also reduced compared than bare C60 -fullerene and free curcumin (C60 : 168.93 ± 16.46, free curcumin: 166.19 ± 7.22 & C60 -fullerene-curcumin with streptozocin: 137.98 ± 8.54 µM/g) that implies oxidative stress was produced significantly into the cell.

3.6 Anti-viral Therapy There are some shreds of evidence established that implies C60 -fullerene has antiviral activity [14, 53]. Schinazi et al. [71] synthesized bis(monoscuccinamide) derivative of p,p/- bis(2-aminoethyl) diphenyl-C60 fullerene compound that is biologically active against Human Immunodeficiency Virus (HIV-1 and HIV-2) while the EC50 was ~6 and ~3 µM against 3/-azido-3/-deoxythymidine resistant HIV-1 [71]. Notably, they ensured the virucidal properties of the synthesized fullerene complex by virus inactivation assays. Similarly, they also mentioned the tolerance or non-toxic dose maximum of up to 100 µM for peripheral blood mononuclear cells and H9, Vero, and CEM cells ( It is a cell line of lymphoblastic cells that came from a child who had acute lymphoblastic leukemia). This is the 1st study report that implies fullerene derivatives may be the choice of a drug candidate against the influenza virus. Shoji et al. [76] designed 12 different types of fullerene derivatives that could be used against the influenza virus [76]. The derivatives were designed by the various specialized moiety attached to the surface of C60 -fullerene. Among all derivatives of fullerene, they identified only 8 distinct fullerene derivatives which significantly inhibited the endonuclease activity of the PA N-terminal domain or full-length PA protein in vitro. Influenza A virus is made up of three subunits: the PA, the PB1, and the PB2 subunits, and especially the Nterminal domain of the PA subunit is capable of performing endonuclease activity. Their in-silico computational biology reports reveal that C60 -fullerene can actively

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bind at the distinct active location of the PA endonuclease protein. Furthermore, in vitro, the PA endonuclease domain digested M13, mp18 circular single-stranded DNA, and they looked to see whether any of the fullerene derivatives might suppress this activity. Also, their molecular cell-biology data ensured that fullerene derivatives significantly inhibited the digestion of M13 mp18 at a dose of 10 mM. An inhibitory effect on the protease specific to the human immunodeficiency virus HIV-1 has been anticipated theoretically since 1993 and has been shown experimentally since then [19]. A dissociation constant of 10–3 to 10–6 mM was calculated while using the binding free energy of 8–12 kcal/mol. There are numerous scientific pieces of evidence were established since 1995 which imply that multiple C60 derivatives have been synthesized and tested against HIV-1 protease [10, 62].

3.7 DNA Cleavage Activity There is so much fundamental scientific evidence established that relies upon fullerene derivatives can cleave the oligonucleotide chain. This activity occurred in the presence of light and also, and this phenomenon was established on animal microbial cell lines (Salmonella) [6] and plasmids (pBR322) [65]. There are different types of C60 -functional derivatives are present that could cleave DNA molecules after exposure to light in the presence of super-coiled plasmid DNA (pBR322 DNA). While exposed to the light, the fullerene compounds were shown to split a 182-base pair fragment at guanine residues. The parts of fullerene after being excited, are sensitized production of 1 O2 , and the resultant 1 O2 react with the oligonucleotide as ROS, which are the anticipated mechanisms for oligonucleotide scission. Later, Boutorine and his colleagues breakthrough the discovery and established that the fullerene-oligonucleotide complex that could build a duplex with a hairpin from single-stranded DNA, a double-stranded DNA, and the hairpin double-stranded DNA [50]. They ensured that the fullerene-DNA complex system was cleaved at guanine residues while exposed to the light, and as a result, ROS was generated. In general, there are two different pathways of DNA photo-clevaging phenomenon that occurred at guanine sites. Scientific research findings suggest that guanosine oxidation may be caused by singlet oxygen (1 O2 ) production and energy transfer from the fullerene triplet state to bases [29, 67]. Photo-irradiation causes fullerenes to transition from a singlet state to a triplet state. DNA-intercalators and minor groove binders have been added to fullerenes to increase their affinity for nucleic acid molecules. DNA covalently bonded to a fullerene core should enhance activity and selectivity against target DNA [48]. The investigators demonstrated that another fullerene-oligonucleotide preferentially cut DNA at guanine residues positioned close to the fullerene terminal of the oligonucleotide [32]. They developed a hydrophilic group, homocalix[arene], that was actively conjugated into the surface of the C60 -fullerene, and the resultant complex was able to cleave DNA. They examined the potential intermediary of 1 O2

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by contrasting the responsiveness of the fullerene-oligonucleotide with an identically coupled eosin-oligonucleotide, which is known to increase the generation of 1 O2 which helps to treat various diseases. In this contrast, Bergamin et al. [9] synthesized new hybrid compounds consisting of an oligonucleotide chain and a trimethoxyindole (TMI) unit used as a minor groove binder to increase the efficacy, sensitivity, and integrity of the triple helix [9]. Due to steric and electrostatic interactions that hinder optimal contact with double-stranded DNA, this innovative approach needs considerable improvement, particularly the improvement of the spacer link between TMI and C60 . On the other hand, DNA may be attached to a monolayer with cationic groups at the ends capable of linking the double helix phosphates, which had previously been intercalated by C60 -fullerene. Fullerene and its derivatives may be used as photo-probes in the investigation of genic transcription [30] onward glutathione-S-transferase [73]. As well as, in the case of fullerols, towards P450-cytochrome-dependent monooxygenases, plasmatic reticulum enzymes of hepatic cells, and mitochondrial ATPase in the process of oxygenation [83]. Nitric oxide synthase (NOS) suppression by fullerene derivatives is a recent finding worth noting. A vital physiological transmitter, nitric oxide is an extremely reactive radical molecule. Even at low amounts, though, it may be harmful to humans. Trimalonic derivatives of C60 -fullerene have been shown to inhibit all three kinds of NOS, neural, epithelial, and inducible, after the revelation that fullerols may reduce bronchospasm generated by the system xanthine/xanthine oxidase [44, 88]. A particular type of derivative of C60 -fullerene “(C3-tris-malonyl-C60 -fullerene and D3-tris-malonyl-C60 -fullerene derivatives)” seems to limit electron transmission between subunits through a reversible deformation of the dimer interface, and all three nitric oxide synthase isoforms of the enzyme are inhibited in a completely reversible manner by dilution [88].

3.8 Fullerenes with Anti-bodies Fullerenes conjugated antibodies are also a developing system that achieving successfully delivers antibodies and as well as to detects a particular system precisely [12, 28]. Hendrickson et al. [27] developed anti-C60 -fullerene that can recognize free fullerene and modified water-soluble derivatives present in solution and multi-component biological samples [27]. Eight anti-fullerene antibody clones were produced when animals were immunized with a compound of fullerene C60 carboxylic derivative and thyroglobulin generated by carbodiimide activation. The antibody-fullerene binding was found to be specific. The study was performed with ELISA technique for the detection of water-soluble protein–conjugated fullerene, fullerene aminocaproic acid, fullerenol, and pure fullerene in solution. Water–organic combination suitable with immunoassay was suggested to dissolve very hydrophobic free fullerene C60 . 2 mg/L of free C60 -fullerene could not be detected in the solution. Organ homogenates from rats, intraperitoneally or intra-gastrically fed fullerene, were also identified by ELISA. Extracting fullerenes from a biological sample using

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toluene is followed by evaporation and dissolving in a water-organic medium to limit the effect of biometrics on the assay findings. The interactions between fullerene and antibodies were established by Osipov et al. [60]. X-ray analysis and molecular modelling of the Fab-fullerene complex will be used to determine the structural parameters of epitopes that particularly detect insoluble antigens, uncover the unique characteristics of immune complex formation as well as also determined the structure of the anti-C60 fullerene antibody Fab-fragment (Fab-C60 ). It has been shown by computer-assisted docking to evaluate the enthalpy and entropy value in particular the π- π stacking interactions with aromatic amino acid residues of the anti-binding pocket and therefore the Solvent Accessible Surface Area (SASA) value of the hydrophobic surface of C60 -fullerene, regulate the binding of C60 to FabC60 fullerene. By using X-ray crystallography, they were able to resolve the structure of the CDR H3 loop of FabC60 (which interferes with C60 binding at the antigen-binding site, leading to poor antibody affinity for C60 ). Antigen-binding site interactions with aromatic residues are mediated by enthalpy and entropy, particularly, by π-π stacking interactions with aromatic residues and decrease of the solvent-accessible area of the hydrophobic surface of C60 . The PDB identifier for the apo-FabC60 binding structure is 6H3H.

4 Current Clinical Studies, Marketed Formulations and Patents A small market exists for C60 -fullerene as an antioxidant in cosmetics, but there are no fullerene-based commercial products that have made a substantial effect. Radical sponge® (BioResearch Corporation) and LipoFullerene® were made from C60 /PVP and squalane-dissolved C60 respectively [38, 89]. These preparations were deemed safe due to their lack of cytotoxicity and pro-oxidant activity when exposed to light under a microscope [5]. When LipoFullerene® enters the skin’s cells, it functions as a radical scavenger, preventing mitochondrial damage and DNA breakage. Photocytotoxicity, reverse mutagenicity of bacteriophage, and skin penetration into the human skin are also not important biological harmful consequences [38, 89]. For the treatment of inflammatory acne vulgaris, which has been linked to oxidative stress in recent clinical investigations, fullerene gel (Zelens® ) is effective [33]. There are some patented formulations regarding C60 -fullerene are enlisted in the Table 1.

5 Conclusion and Future Aspect After its discovery, C60 -fullerene has become an emergent carbon molecule with several chemical and biological uses. Effective functionalization characteristics make them more reactive and capable of conjugating diverse biological and chemical

Sl. No

Patent No

Inventor names

Product description

Current assignee

1

CN104127872B

Wang Chunru, Zhen Mingming, Shu Chunying, Wang Taishan, Li Jie, Zhang Guoqiang

Metal fullerene nanometer monocrystalline particle is in the application of preparing in the agent of specific tumor blood vessel blocking

Beijing Fullcan Biotechnology Co., Ltd. & Chifeng Funakang Biotechnology Co., Ltd.

2

CN111514306A

Wang Chunru, Li Lei, Zhen Mingming

Fullerene nanoparticles for enhancing anti-tumor immunotherapy

Beijing Fullcan Biotechnology Co ltd & Institute of Chemistry of CAS

3

JP2017521454A

Chunru Wang, Mingming Zhen, Chunying Shu, Taishan Wang, Taishan Wang, Jie Li Jie Li, Guoqiang Zhang, Guoqiang Zhang

Tumor treatment method with metal fullerene single-crystal nanoparticles selectively destroying tumor blood vessels

–

4

CN108478598B

Wang Chunru, Zhou Yue, Zhen Ming

Water-soluble fullerene nano material and preparation method and application

Beijing Fullcan Biotechnology Co ltd & Institute of Chemistry of CAS

5

US9233166B2

Hongjie Dai, Zhuang Liu, Xiaolin Li and Xiaoming Sun

Supramolecular functionalization of graphitic nanoparticles for drug delivery

Leland Stanford Junior University

6

KR101725613B1

Eunsung Lee, Sol Kim

Photosensitizer for photodynamic diagnosis or therapy and photodynamic therapy using the same

–

7

CN108853142A

Wang Chunru, Zhen Mingming, Zhou Yue, Bai Chunli

Water-soluble fullerene nanoparticle inhibits the application in tumor growth drug in preparation

Beijing Fullcan Biotechnology Co ltd. & Institute of Chemistry of CAS

8

US20090214101A1

Lon J. Wilson Jared M. Ashcroft Michael G. Rosenblum

Targeted nanostructures for cellular imaging

William Marsh Rice University

9

KR101503573B1

Lee Eun-seong, Kwak Dong-seop

Hyalronated fullerene, preparing method of the same, and biological use of the same

–

Fullerenes: Bucky Balls in the Therapeutic Application

Table 1 Patents list belonging to C60 -fullerene formulations as a therapeutic products

19

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components as therapeutic possibilities. This conjugation makes the compounds more soluble in water and less poisonous. Multiple studies have been presented to illustrate the many therapeutic uses. Although further study needs to be conducted on the use of functionalized fullerenes in the biosensor, anticancer, drug delivery, and photodynamic treatment.

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81. Tortolini, C., Sanzò, G., Antiochia, R., Mazzei, F., Favero, G.: Application of a nanostructured enzymatic biosensor based on fullerene and gold nanoparticles to polyphenol detection. In: Methods in Molecular Biology, pp. 41–53. Humana Press, New York, NY (2017). https://doi. org/10.1007/978-1-4939-6911-1_4 82. Trepanowski, J.F., Mey, J., Varady, K.A.: Fetuin-A: a novel link between obesity and related complications. Int. J. Obes. 734–741. Nature Publishing Group. https://doi.org/10.1038/ijo. 2014.203 83. Ueng, T.H., Kang, J.J., Wang, H.W., Cheng, Y.W., Chiang, L.Y.: Suppression of microsomal cytochrome P450-dependent monooxygenases and mitochondrial oxidative phosphorylation by fullerenol, a polyhydroxylated fullerene C60. Toxicol. Lett. 93(1), 29–37 (1997). https:// doi.org/10.1016/S0378-4274(97)00071-4 84. Uygun, Z.O., Sahin, ¸ Ç., Yılmaz, M., Akçay, Y., Akdemir, A., Sa˘gın, F.: Fullerene-PAMAM(G5) composite modified impedimetric biosensor to detect Fetuin-A in real blood samples. Anal. Biochem. 542, 11–15 (2018). https://doi.org/10.1016/j.ab.2017.11.007 85. Verkman, A.S.: Aquaporins. Curr. Biol. R52–R55 (2013). https://doi.org/10.1016/j.cub.2012. 11.025 86. Vorobyov, V., Kaptsov, V., Gordon, R., Makarova, E., Podolski, I., Sengpiel, F.: Neuroprotective effects of hydrated fullerene C60: cortical and hippocampal EEG interplay in an amyloidinfused rat model of alzheimer’s disease. J. Alzheimer’s Dis. 45(1), 217–233 (2015). https:// doi.org/10.3233/JAD-142469 87. Wang, C., Cheng, L., Liu, Y., Wang, X., Ma, X., Deng, Z., Li, Y., Liu, Z.: Imaging-guided pH-sensitive photodynamic therapy using charge reversible upconversion nanoparticles under near-infrared light. Adv. Funct. Mater. 23(24), 3077–3086 (2013). https://doi.org/10.1002/ adfm.201202992 88. Wolff, D.J., Papoiu, A.D.P., Mialkowski, K., Richardson, C.F., Schuster, D.I., Wilson, S.R.: Inhibition of nitric oxide synthase isoforms by tris-malonyl-C60- fullerene adducts. Arch. Biochem. Biophys. 378(2), 216–223 (2000). https://doi.org/10.1006/abbi.2000.1843 89. Xiao, L., Takada, H., Gan, X.H., Miwa, N.: The water-soluble fullerene derivative “Radical Sponge®” exerts cytoprotective action against UVA irradiation but not visible-light-catalyzed cytotoxicity in human skin keratinocytes. Bioorganic Med. Chem. Lett. 16(6), 1590–1595 (2006). https://doi.org/10.1016/j.bmcl.2005.12.011 90. Xie, L., Luo, Y., Lin, D., Xi, W., Yang, X., Wei, G.: The molecular mechanism of fullereneinhibited aggregation of Alzheimer’s β-amyloid peptide fragment. Nanoscale 6(16), 9752–9762 (2014). https://doi.org/10.1039/c4nr01005a 91. Yang, X., Ebrahimi, A., Li, J., Cui, Q.: Fullerene-biomolecule conjugates and their biomedicinal applications. Int. J. Nanomedicine 77–92. Dove Press (2013). https://doi.org/10.2147/IJN. S52829 92. Zakharian, T.Y., Seryshev, A., Sitharaman, B., Gilbert, B.E., Knight, V., Wilson, L.J.: A fullerene-paclitaxel chemotherapeutic: synthesis, characterization, and study of biological activity in tissue culture. J. Am. Chem. Soc. 127(36), 12508–12509 (2005). https://doi.org/ 10.1021/ja0546525 93. Zhu, X., Sollogoub, M., Zhang, Y.: Biological applications of hydrophilic C60 derivatives (hC60s)ˆg’ a structural perspective. Eur. J. Med. Chem. 438–452. Elsevier Masson (2016). https://doi.org/10.1016/j.ejmech.2016.03.024

Nanodiamonds as Next Generation Carriers in Exploring Therapeutic Benefits Nadia Fattahi and Ali Ramazani

Abstract Recent advances in nanotechnology have gained remarkable attention to nanodiamonds (NDs) in both research and industrial areas thanks to their promising intrinsic properties such as large specific area, poor cytotoxicity, high biocompatibility, facile surface functionalization, chemical resistance, optical and biological properties, inexpensive large-scale synthesis, and surface reactivity. Owing to their unique physicochemical features, NDs are regarded as promising candidates in biomedicine. This chapter presents the fabrication, surface modification, and significant applications of NDs in biomedical field. The present chapter aims to inspire readers to explore new avenues for designing and developing next-generation nanodiamond (ND)-based materials with advanced functionalities and attractive properties. Keywords Nanodiamonds · Surface functionalization · Drug delivery · Biosensing · Gene delivery · Bioimaging · Tissue engineering

1 Introduction Considering the significance of human life, researchers have always sought to develop new therapeutic strategies and diagnosis techniques for diverse diseases. Despite the progress in medicine during the last decades, unresolved challenges are remained for hard-to-treat diseases such as heart diseases, antibiotic-resistant bacterial infections, cancer, and organ dysfunction diseases, resulting in a high annual mortality rate [1–3]. As a solution, NDs have attracted enormous interest as a research breakthrough for various biomedical purposes due to their unique features. NDs, also known as diamond nanoparticles, are a novel class of carbon nanoparticles with remarkable chemical and physical characteristics. The core–shell structural architecture of NDs is based on the existence of an inner diamond core (sp3 carbon N. Fattahi · A. Ramazani (B) Department of Chemistry, Faculty of Science, University of Zanjan, 45371-38791 Zanjan, Iran e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. S. Hasnain et al. (eds.), Carbon Nanostructures in Biomedical Applications, Advances in Material Research and Technology, https://doi.org/10.1007/978-3-031-28263-8_2

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atoms) and a graphitic outer shell (sp2 carbon atoms) with hanging bonds terminating in functional moieties [4]. The specific properties of NDs are attributed to the individual features of nanoparticles and diamonds (Fig. 1). These properties include excellent hardness and Young’s modulus, good biocompatibility, high adsorption capacity, superior chemical and physical properties of versatile functionalization, optical properties and fluorescence, electrical resistivity and high thermal conductivity, large surface area, and the resistance of ND to harsh environments [5, 6]. NDs were first discovered as a byproduct of detonation in 1963 in the USSR [7]. Following several innovations in synthesis, isolation, and purification procedures in the late 1990s, NDs have subsequently gradually attracted more attention from all over the world. The NDs are divided into nanocrystalline particles (1–150 nm), ultra nanocrystalline particles (2–4 nm), and diamondoids (1–2 nm) based on their particle size. The composition of the reactants and the method of synthesis have a significant impact on the distribution of the sp2 sites in the outer shell, the size of the diamond core, and the range of reactive functional moieties on the surface of ND. In recent years, many studies have focused on developing NDs for biomedical applications [8–11]. The nitrogen-vacancy (NV) center in ND has been used as a biological sensor to monitor physiological parameters such as pH and temperature in a very narrow specific area [12–14]. In addition, NDs are promising carriers for drug delivery and next-generation therapeutics owing to their particular physical and chemical properties [15–17]. Considering the significant importance of NDs, this chapter describes their synthesis and their modification methods. Furthermore, the remarkable potential of NDs in various biomedical applications, including tissue engineering, gene/drug delivery, imaging and diagnostic, and biosensing, are also highlighted. The approaches reported here serve as a guide for constructing novel ND-based materials for future biomedical and pharmaceutical applications.

Fig. 1 Schematic representation of properties of diamonds and nanoparticles

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2 Modification of NDs Surface modification of NDs is necessary to meet requirements for their biomedical applications, such as improved stability and solubility in various biological pH environments, high colloidal dispersibility, and the presence of particular functional groups to interact with targeted biomolecules [18]. There are mainly two approaches to modify NDs: (1) surface functionalization and (2) doping of NDs.

2.1 Surface Functionalization The versatile surface properties of NDs provide an ideal platform for a wide range of functionalization schemes (Fig. 2) [19–21]. Many techniques for developing a surface modification of NDs have been developed in recent years [22]. These methods include mechanical disruption of the bundles, and covalent and non-covalent procedures, such as conventional chemical approaches (refluxing, milling, and sonication). In an interesting study, the investigations on surface modification of NDs were carried out by Krueger and Lang [24] using lithium and borane. The obtained findings showed enhancement in the surface C=O and –OH groups which can be utilized for the immobilization of various biomolecules [24]. Using the carboxylate NDs

Fig. 2 Surface modification of NDs with various functional moieties. Reprinted with permission from Ref. [23], Copyright (2019) Elsevier

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produced by ozone or air purification, followed by their functionalization, is another practical strategy. The reduction of carboxylate NDs at above ~700 °C made NDs containing hydroxyl moieties using hydrogen microwave-assisted chemical vapor deposition (CVD) plasma. Acyl chlorides were used to esterify NDs, leading to the production of long alkyl chains. The carboxylated NDs have also been used to create halogenated NDs using halogen annealing and photochemical chlorination [25–28]. Interestingly, ND surfaces can also be functionalized with biomolecules, including nucleic acids, peptides, biotin, and many more, for use in biomedical fields. For instance, Hens et al. [29] prepared ND-NH2 by reducing ND using lithium aluminum hydride. The modified aminated NDs were then utilized to synthesize conjugates of tetramethylrhodamine and biotin that can be employed in biomedical applications [29]. Other studies showed strong interaction bonding between the positively charged amine moieties of molecules such as bovine serum albumin, lysozyme myoglobin, cytochrome C, and poly-lysine with negatively charged carboxylates onto NDs. This interaction resulted in these proteins’ strong saturated absorption [30–32]. In another interesting study by Xu et al. [33], ring-opening polymerization was used to synthesize poly(amino acid)s functionalized ND conjugate with ethylene glycol and glutamic acid. The synthesized conjugate showed low toxicity and improved water dispersibility, making it suitable for biomedical applications [33]. To improve the colloidal stability and suitability of NDs in physiological environments, they can also be coated with biocompatible polymers with a negative or neutral charge and optimal hydrophilicity. In this regard, several biocompatible polymers have been utilized, such as polyethyleneimine (PEI) [34], polyethylene glycol (PEG) [35, 36], poly(vinylidene fluoride) [37], polylactide [38], Poly(N-isopropyl acrylamide) [39], poly(sodium 4-styrene sulfonate) [40], 2-methacryloyloxyethyl phosphorylcholine [41], and polycaprolactone [42].

2.2 Doping NDs could be carefully and precisely doped with foreign atoms like silicon, nitrogen, and transition metals to produce optically active centres with various uses [43]. Shenderova et al. [44] investigated nitrogen content in ND particles prepared using various procedures and found that when nitrogen is not entirely consumed during detonation, it is engulfed in the ND core, creating optically active centres known as NV centres [44]. The silicon vacancy (SiV), created by doping ND with Si, is another notable vacancy and can be used in bioimaging applications. These SiV centres can be produced by adding Si to a pristine diamond or incorporating Si during CVD [45– 47]. The microelectronic industry currently has a high demand for boron-doped NDs, but the main obstacle is the incredibly low boron level (as low as 800 ppm), which is inadequate for electrical conductivity. To solve this problem, Ekimov et al. [48] showed that boron-doped ND particles were directly synthesized using organoboron compounds as the starting material by the high-pressure, high-temperature (HPHT) method yielding NDs with a high boron concentration [48]. Moreover, Kondo et al.

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[49] used an alternate technique of solid-state boron in diffusion into the ND to synthesize heavily boron-doped ND [49]. Although numerous methods, such as thermal diffusion [50], and electric field enhanced diffusion [51, 52], have been developed for the synthesis of NDs that are commercially available, the industry still faces difficulties in producing NDs with a sufficient amount of doped atoms and a significant number of optically active centers [53].

3 Production of NDs Although NDs have been present in nature in the form of meteorites, interstellar dust, protoplanetary nebulae, crude oil, and various layers of the earth’s sediment for billions of years, they were synthesized for the first time in 1963 when carbon-based explosives were used to create diamond nanoparticles [7]. A remarkable effort has been made to fabricate NDs with uniform surface features and controllable size in order to decrease the level of variability related to their synthesis. NDs may have different properties, depending on the technique used. NDs can be produced using special techniques like HPHT, detonation technique, light hydro-dynamic pulse (LHDP) synthesis, and CVD technique [54]. The benefits and drawbacks of each synthesis technique are shown in Table 1. As shown in Table 1, the surface and size characteristics of the produced NDs are significantly impacted by each approach. The degree of aggregation and purity of the nanoparticles can also be affected by the technique chosen, which both require careful examination before further utilization of NDs in biomedical applications.

4 Biomedical Applications of NDs Nowadays, the application of NDs in various medical and biotechnological fields has remarkably increased. The wettability, hardness, biocompatibility, versatile surface chemistry, stability, and optical properties of NDs are all desirable features that enable them to be utilized as multifunctional materials in a broad range of biomedical applications (Fig. 3). The following sections provide a brief overview of the various biomedical applications of NDs, such as gene/drug delivery, bioimaging, tissue engineering, biosensing, and antibacterial activities.

4.1 Drug Delivery Gradual advances in modern medicine have been made by using drug delivery systems (DDSs) for the controlled release of drugs improving their therapeutic

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Table 1 Summary of the significant techniques for producing NDs Synthetic method

Average size (nm)

Surface chemistry

Detonation

4–5

CVD

Morphology

Benefits

Drawbacks

Heterogeneous, Truncated containing sp2 octahedral polarized carbon morphology as well as other metal impurities Oxygen functional moieties (carboxyl, carbonyl, hydroxyl, epoxy)

Large-scale production

Aggregate formation (200 nm or larger) Hazardous and polluting technology Various purification process High costs

5–100

Hydrogenated surface

NDs films

Beneficial for producing films Absence of metal impurities

High production costs It is only used for making films

HPHT

>20

Absence of sp2 defects on the surface

NDs with sharply faceted external surfaces

Uniform size Nitrogen content is high, which is beneficial for imaging applications

Costly production

LHDP

4–5 or 250–300

Controlled surface chemistry

NDs with similar morphology to DNDs

Control over the size Remarkably pure production of NDs with excellent homogeneity Environmentally friendly

The restricted transition from early technologies to mass production

and pharmacological properties. DDSs must overcome many barriers before clinical applications, such as biocompatibility, the requirement for specific targeting, and intracellular transport while completing the foundations of responsive behavior to the physiological environments [55–57]. The unique properties of NDs, such as surface modifiability, chemical stability, and considerable biocompatibility, give them an excellent opportunity to be versatile drug delivery platforms. Utilizing NDs enables researchers to address three of the main problems associated with drug or diagnostic molecule release: (1) inefficient uptake at target sites that leads to low imaging agent or low drug efficacy in cells, (2) unfavorable biodistribution and pharmacokinetics, which lead to unwanted side effects and, (3) early drug degradation in the bloodstream by the reticuloendothelial system [58]. As mentioned

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Fig. 3 Schematic presentation of NDs-based materials in the biomedical field

before, ND is a promising material due to its surface characteristics, providing conjugation and modification of various biofunctional entities for targeted controlled drug delivery. These surface properties also improve the interaction with the target cell and enhance the penetration of the drug complex inside cells. In various studies, therapeutic agents have been loaded onto ND surfaces and introduced into biological systems, and then their biocompatibility and availability at the site of action have been investigated. Due to their lack of cellular resistance and low toxicity, NDs make excellent nanocarriers for the delivery of anticancer agents with improved therapeutic potential and minimal adverse effects [9, 21, 59–61]. A list of the important research on the use of NDs for drug delivery has been summarized in Table 2. Paclitaxel (PTX) is a tricyclic diterpenoid first isolated from the bark of Taxus brevifolia [97]. PTX has good therapeutic effects against breast, ovarian, and numerous other malignancies; however, its poor water solubility restricts its oral bioavailability. In this regard, using NDs is one of the important strategies for improving its clinical efficacy. In a study reported by Lim et al. [69], the hydroxylated NDs (ND-OH), which have superior colloidal dispersibility, were created by converting the carboxylated NDs (ND-COOH). PTX was loaded onto ND-OH clusters and entrapped between ND interparticle nanocages. The well-distributed

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Table 2 Some important reports regarding the potential of ND in drug delivery applications Composition

Drug

Study model

Significant outcomes

Refs.

NDs containing carboxylic groups

Purvalanol A, 4-hydroxytamoxifen, dexamethasone

In vitro

NDs maintained drug cytotoxicity and improved drug dispersion in water

[62]

ND-embedded polymeric microfilms

DOX

In vitro

Showed continuous and stable release of drug

[63]

ND-PTX conjugate

PTX

In vitro and in vivo

Decreased the cell [64] viability in the A549 human lung cancer cell line, induced apoptosis and mitotic arrest in A549 cells, blocked the formation of lung cancer cells and tumor growth in xenograft mice model

TAT-DOX-ND conjugate

DOX

In vitro

Increased the intracellular delivery of DOX, enhanced translocation across C6 glioma cells membrane, showed superior cytotoxicity than free DOX

[65] N. Fattahi and A. Ramazani

(continued)

Composition

Drug

Study model

Significant outcomes

ND-PEG conjugate

DOX

In vitro

DOX delivery into [66] HepG2 cells via clathrin-dependent endocytosis, increased the uptake half-life of ND-PEG-DOX compared to free DOX, showed sustained and slow drug release capability

Three ND-cisplatin systems (incorporation of cisplatin via 1. Directly attached to the Cisplatin ND surface, 2. Physical adsorption within a POEGMEMA surface coating, 3. Complexation to MAETC groups of a POEGMEMA-st-PMAETC surface layer)

In vitro

Showed lower IC50 [67] values than free cisplatin in A2870 and A2870cis ovarian cancer cells

DSPE-PEG coating NDX

In vitro and in vivo

Significant capability for DOX delivery to the nucleus, inhibited the lung metastasis of breast cancer, high drug loading, induced cell apoptosis, improved drug accumulation in the lung, good tissue compatibility

DOX

Refs.

[68]

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Table 2 (continued)

(continued) 35

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Table 2 (continued) Drug

Study model

Significant outcomes

Refs.

ND-PTX

PTX

In vitro

Well-dispersed cellular [69] uptake, sustained drug release up to 97.32% within 70 h

ND-Epirubicin conjugate

Epirubicin

In vitro and in vivo

Promoted endocytic uptake and enhanced tumor cell retention, reduction in dose, making it safer and more efficient to treat cancer cells with resistance

[70]

ND-Ciproten+Quercetin conjugate

Ciproten Quercetin

In vitro

Improved anti-proliferative activity of the drug on murine B16F10 melanoma and human HeLa cells

[71]

ND-DOX conjugate

DOX

In vitro

Increased cytotoxicity, [72] high ablation efficiency, and cell killing (continued)

N. Fattahi and A. Ramazani

Composition

Composition

Drug

Study model

Significant outcomes

Refs.

β- and γ-CD modified NDs-DOX

DOX

In vitro

Showed 18 ng ml−1 [73] limit of detection, precision (RSDs of 4.7 and 5.9%), and recoveries (94.0 and 93.2%) at 400 and 100 ng mL−1 DOX values in urine Although DOX can accommodate both γCD and βCD, DOX prefers the bigger γCD cavities

ND-DOX conjugate

DOX

In vitro and in vivo

Showed the safety evaluation of ND in large animal models, the DOX toxicity for the Naïve Beagle dog model was significantly reduced by the ND drug delivery technology

[74]

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Table 2 (continued)

(continued)

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Table 2 (continued) Composition

Drug

Study model

Significant outcomes

Refs.

ND-PEG-glycidol-DOX

DOX

In vitro and in vivo

Showed high therapeutic efficacy, theranostic capabilities, higher rate of tumor growth inhibition with minimal cardiotoxicity, hepatotoxicity, and nephrotoxicity

[75]

Red FNDs- DOX conjugate

DOX

In vitro

Efficient DOX delivery [76] into living HeLa cells via a clathrin-dependent endocytosis pathway, sustained and slow drug release profile

PolyPEGylated ND-DOX complex

DOX

In vitro

Facilitated the transport of DOX into A549 cells

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(continued)

Composition

Drug

Study model

Significant outcomes

Refs.

PEG-DOX/sodium acetate conjugate

DOX

In vitro

Enhanced drug loading [78] with ultra-low drug leakage, time-dependent, sustained, and slow drug release from the lysosomes with a low pH, selective accumulation of conjugate in tumor cells, Inhibited the proliferation and migration of tumor cells and changed the cell cycle in comparison with free DOX

ND-silk fibroin-DOX conjugate

DOX

In vitro

Stable and controlled release of drug

[79] (continued)

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Table 2 (continued)

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Table 2 (continued) Drug

Study model

Significant outcomes

Refs.

ND-PTX-cetuximab conjugate

PTX

In vitro and in vivo

Increased apoptosis and catastrophic mitotic effects both in vivo and in vitro, Remarkably reduced tumor size in the xenograft EGFR-expressed human colorectal tumors

[80]

DOX-ATRA-ND conjugate

DOX ATRA

In vitro and in vivo

Increased tumor cell [81] apoptosis and inhibited tumor growth in both breast and liver cancer cells

ND-β-CD-HPG conjugate

DOX

In vitro

Low toxicity, excellent [82] water dispersibility, controlled drug-release behavior, and high drug-loading capacity (continued)

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Composition

Composition

Drug

Study model

Significant outcomes

Refs.

ND modified with mitochondrial localizing sequence peptide and FA

DOX

In vitro

Targeted DOX delivery [83] to mitochondria with sufficient cytotoxicity, Increased cellular uptake in DOX-Resistant MCF-7 breast cancer cells

FA-ND-DOX conjugate

DOX

In vitro and in vivo

Considerable decrease [84] in tumor volume and selective accumulation in the tumor site

Poly(1-O-methacryloyl-2,3:4,5-di-Oisopropylidene-β-D-fructopyranose)-ND-DOX conjugate

DOX

In vitro

Massive cell death after 8 days of incubation, PH-dependent drug delivery system

[85]

ND-DOX complex

DOX

In vitro

Showed an increase in DOX efficacy of approximately 50%, optimal release (80%, pH = 4), Excellent loading efficiency (95.7%)

[86]

Nanodiamonds as Next Generation Carriers in Exploring Therapeutic …

Table 2 (continued)

(continued)

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Table 2 (continued) Composition

Drug

Study model

Significant outcomes

Refs.

ND-DGEA+DOX conjugate

DOX

in vitro

Increased the efficacy [87] of 2 and 1 µg/ml DOX doses from 11 to 34% cell death and 2.5% to 12% cell death, respectively

ND-PG-RGD-DOX conjugate

DOX

In vitro

Increased selective toxicity and cellular uptake to A549 cells, good aqueous solubility, and cytocompatibility

ND-DOX conjugate

DOX

In vitro and in vivo

Prolonged the lifespan [89] of tumor-bearing mice, non-toxic to the liver, kidney, or spleen, slow and sustained drug release, suppressed tumor growth

ND-DOX conjugate

DOX

In vitro and in vivo

Improved DOX uptake [90] and retention in glioma cells

[88]

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(continued)

Composition

Drug

Study model

Significant outcomes

Refs.

Dendritic cell-mediated delivery of DOX-PG-NDs composites

DOX

In vitro and in vivo

Demonstrated the [91] efficacy of synthesized composites to stimulate glioblastoma cells immunogenicity and elicit an anti-cancer immune response in the glioblastoma

ND-HCPT complex

HCPT

In vitro

Improved drug loading [92] and solubility

Cisplatin-ND conjugate

Cisplatin

In vitro

pH-dependent drug [93] delivery, the same cytotoxicity as free cisplatin against human cervical cancer cells

ND-PEG-GEM complex

GEM

In vitro

Efficient drug delivery [94, 95] to AsPC-1 cells, but no noticeable increase in GEM performance

ND-5,7- Dimethoxy coumarin conjugate

5,7- Dimethoxy coumarin

In vitro

Decreased the growth [96] of B16F10 tumor cells

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Abbreviations: DOX: Doxorubicin; POEGMEMA: Poly(oligo(ethylene glycol) methyl ether methacrylate); MAETC: 1,1-Di-tert-butyl 3-(2 methacryloyloxy)ethyl)butane-1,1,3-tricarboxylate; PTX: Paclitaxel; NDX: NDs-DOX complex; FNDs: Fluorescent nanodiamonds; PG: Polyglycerol; βCD: Beta cyclodextrin; γCD: Gamma cyclodextrin; ATRA: All-trans retinoic acid; HCPT: 10-Hydroxycamptothecin; FA: Folic acid; HPG: Hyperbranched polyglycerol; DGEA: Asp–Gly–Glu–Ala peptide; GEM: Gemcitabine; EGFR: Epidermal growth factor receptor

Nanodiamonds as Next Generation Carriers in Exploring Therapeutic …

Table 2 (continued)

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N. Fattahi and A. Ramazani

cellular absorption of PTX from the ND-OH was confirmed by TEM images. Moreover, the modified NDs showed sustained drug release throughout 70 h (Fig. 4) [69]. In another study [98], PTX and ND were conjugated using the microwave irradiation approach. Comparative studies of cell viability were performed between conventionally produced ND-PTX and microwaves-assisted produced ND-PTX against A549 lung cancer cells. The findings showed that synthesized ND-PTX conjugate using microwave technology significantly reduced cell viability compared to synthesized ND-PTX conjugate using conventional methods. Additionally, microwavesynthesized ND-PTX was more cytotoxic than conventionally synthesized conjugate against HCT116 colorectal cancer cells [98]. Zhang et al. [99] demonstrated that the target specificity and therapeutic effect of PTX could be improved using the multi-component ND drug delivery system. This was achieved by surface functionalization of ND and transforming it into FND, followed by labeling with PTX and finally conjugation with human epidermal growth factor receptor monoclonal antibodies [99]. Another significant chemotherapeutic drug, doxorubicin (DOX), was investigated using NDs as a carrier in various research investigations. In an interesting study reported by Xiao et al. [68], DOX was conjugated successfully to NDs. Following in vitro treatment for 16 h, the synthesized complex demonstrated slow and sustained drug dissociation with maximal release. This shows that the dose frequency could be decreased by developing controlled drug delivery ND devices. After systemic delivery, ND–DOX complexes accumulated in the tumor tissue, and finally, the efficacy of DOX increased to 4 times [68]. In another interesting work, DOX was covalently bonded to the surface of carboxylated NDs and then conjugated with the cell-penetrating peptide TAT to create a TAT-DOX-ND nanocomposite. It was concluded that the developed delivery system provided a valuable strategy that could not only avoid premature release before targeting sites, but also enhance the pharmaceutical toxicity of drug against cancer cells [65]. Moreover, in another study, DOX was physically adsorbed on the red FND (size: 140 nm). It was found that FND incorporating DOX could significantly deliver the DOX inside living HeLa cells via a clathrin-dependent endocytosis pathway. Moreover, the results of the MTT assay and confocal fluorescence microscopy revealed that the FND-DOX system had a sustained and slow drug release capability [76]. The anticancer drug 10-hydroxycamptothecin (10-HCPT), which has very poor water solubility, has also been delivered using NDs. In another interesting study reported by Li et al. [92], the surface of ND was coated with 10-HCPT, and it was found that adding NaOH improved the drug’s solubility in alkaline media. As a result, in comparison to plain aqueous media, more drug was loaded onto the surface of ND. Additionally, tests of cell viability and TEM imaging demonstrated that the HCPT-ND complex was significantly more efficient than free HCPT [92]. Cisplatin is one of the most broadly utilized drugs for the treatment of various malignancies, such as ovarian cancer, lymphoma, glioma, and testicular cancer. However, its usage is restricted owing to the toxicity associated with its use. In a study reported by Guan et al. [93], cisplatin was incorporated into oxidized and carboxylated ND by complexation and physical adsorption. The in vitro release experiments

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⏴Fig. 4 a Schematic representation of reduction process of ND-OH from ND-COOH. b Schematic pictures of production of crystalline PTX and ND-OH/PTX nanocomplex. Green drops show concentrated PTX in ethanol solution. c Dispersion stability of ND-COOH, nanocrystalline PTX, ND-OH, and ND-OH/PTX complex in DMEM buffer and distilled water. d–f Cellular uptake of nanocrystalline PTX and ND-OH/PTX complexes. d TEM images of ND-OH/PTX complex in HeLa cells with 6,000×, e 100,000×, and f 200,000×. g–i TEM images of PTX nanoparticle in HeLa cell with g 6,000×, h 100,000×, and i 200,000× (ND-OH around PTX nanoparticles indicated with dark blue arrows, nanocrystalline PTX indicated with red arrows). ER: endoplasmic reticulum, MVB: multivesicular body and, N: nucleus. Reprinted with permission from Ref. [69], Copyright (2016) American Chemical Society

showed pH-dependent release of the drug from the cisplatin-ND complex, facilitating release under an acidic tumor environment. This pH-dependent release of the cisplatin-ND complex showed that it would release the low amount of the drug in the blood throughout circulation and would increase the release amount of the drug in the acidic cytoplasm. In addition, against human cervical cancer cells, the drug released from the composite retained the same cytotoxicity as free cisplatin [93]. Gemcitabine (GEM) is a pyrimidine nucleoside analog with antitumor activity against various types of solid tumors; however, its clinical use is limited by its inefficient penetration, thanks to its hydrophilic properties. Moreover, free GEM accumulates in both healthy and tumor cells, exhibiting adverse side effects. In order to overcome this issue, RAFT polymerization was used to load GEM onto an aminated ND-PEG conjugate. Confocal microscopy was utilized to determine the cellular uptake of the conjugate, and AsPC1 cells were used to test for cytotoxicity. The fluorescent properties of the GEM allow monitoring of its delivery in the specified cell line, although the results did not demonstrate a noticeably increased GEM activity [94, 95]. In addition to anticancer drug delivery, NDs also have great potential as carriers for protein delivery. In this regard, a variety of protein-based therapeutic substances such as transforming growth factor-β antibody [100], enzyme glucose oxidase [101], Transferrin [102], egg white lysozyme [103], bovine insulin [104], glycoproteins amino phenyl boronic acid [105], bone morphogenetic proteins [106], alphabungarotoxin [107], yeast cytochrome C [30], fluorescent thiolated peptide [108], mussel adhesive protein [109], immunoglobulin G [110], chlorotoxin- like peptide from the venom of Buthus martensii Karsch [111] have been investigated using NDs for pH mediated delivery, targeted delivery, and improved cellular uptake. Taken together, it can be concluded that due to the attractive properties of NDs, such as their biocompatibility, unique physicochemical features, narrow particle size distribution, near-spherical shape, water dispersibility, ease of surface functionalization, and high specific area, these molecules play a significant role in the drug release process in vivo, and they provide a promising approach for the treatment of various cancers.

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4.2 Gene Delivery Gene therapy is a research approach to study gene control, gene regulation, and even treatment of various acquired or inherited disorders using transferred genes. It presents controlled, precise delivery of nucleic acids (RNA and DNA) to target cells, leading to treatments that are more useful, less invasive, and cheaper than existing modalities. However, the uptake of nucleic acids is limited due to their negative surface charge density and large size. Thus, the main challenge for gene therapy is to design vectors capable of protecting and delivering genes to target cells with sufficient efficacy, safety, and specificity [112]. The significant potential of NDs as drugdelivery vehicle has been leading researchers to evaluate their efficiency for gene delivery [113]. Small interfering RNA (siRNA) or plasmid DNA (pDNA) delivery via an ND vector requires the functionalization of NDs to produce a cationic surface to which negatively charged siRNA or DNA can desorb and adsorb. For instance, on the surfaces of carboxylated NDs, polymers such as poly(allylamine hydrochloride) (PAH) or polyethyleneimine (PEI) were adsorbed to create ND-polycation complexes known as ND-PAH and ND-PEI, respectively [114]. Highly effective vectors can be created by combining these polymers with NDs. It was found that when siRNA was delivered to Ewing sarcoma cells, both NDPAH and ND-PEI demonstrated significant siRNA loading capacities, but ND-PEI had greater transfection activity than ND-PAH for the knockdown of an oncogenic marker. Moreover, compared to Lipofectamine, a well-known lipid-based non-viral vector, both ND-PAH and ND-PEI showed significantly improved transfection efficiency and much lower cytotoxicity [114]. The same complexes were also made by Alhaddad et al. [114] using FNDs, enabling confocal microscopy to monitor the delivery of the vectors in real time. Using fluorescence imaging of siRNA delivery, polycation complexes created with FNDs demonstrated that cells internalized the ND vectors through endocytosis [114]. Similar research on the application of ND-PEI complexes for siRNA delivery was performed by Chen et al. [115]. ND-PEI vectors were created by adsorbing PEI (MW = 800 Da) to carboxylated NDs, showing high loading capacity and prolonged siRNA release. It was found that, in contrast to Lipofectamine, which reduced cell viability by 26.4% to achieve similar knockdown levels, ND-PEI vectors, when administered in vitro to GFP-expressing M4A4 cells, induced a 62.2% knockdown of GFP expression at 48 h with no cytotoxicity to the cells [115]. Although physically self-assembling ND-polycation complexes have demonstrated impressive outcomes as biocompatible and effective vectors, the long-term stability of these materials in ND aggregation and suspension are two major difficulties that limit their therapeutic use. Therefore, chemically created ND vectors may be used to fabricate well-dispersed and stable siRNA and DNA carriers. One approach is to provide a cationic surface charge to NDs via covalent modification with lysine, which makes siRNA more easily adsorbable and prevents particle aggregation [116]. Interestingly, when siRNA was physically adsorbed onto lysine-modified

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NDs, the developed complexes showed a high transfection efficacy with low cytotoxicity in HeLa cells [116]. In an interesting work, Zhao et al. [117] studied the covalent bonding of polyglycerol (PG) to polypeptides to fabricate positively charged and highly-dispersed conjugates. In this work, well-distributed DNA vectors were produced by chemically coupling positively charged polypeptides with PG-NDs using click chemistry [117]. The ability to produce targeted gene delivery by attaching NDs to cell-targeting ligands is another advantage of chemical conjugation in the development of NDbased vectors. Covalently attaching functionalized NDs to RGD peptide, which was then employed as vectors to deliver VEGF siRNA and silence the expression of VEGF protein in cells, is one approach for making tumor-targeted NDs for siRNA delivery [118]. RGD-ND vectors demonstrated a considerably superior efficiency with a 63% reduction of VEGF expression compared to Lipofectamine, which silenced VEGF expression by 34%. It was also found that RGD-ND vectors inhibited tumor growth by silencing the VEGF gene in vivo [118]. Using peptide-targeted NDs, Bi et al. [119] successfully silenced the survivin gene, an apoptosis inhibitor that can be utilized as a therapeutic target for cancer therapy. Similar to a therapeutic dose of DOX, the RGD-linked NDs containing survivin siRNA inhibited tumor growth in a mouse model in vivo [119]. In a study reported by Lim et al. [120], to treat cervical cancer caused by the human papillomavirus, NDs modified with polyamidoamine (PAMAM) were created and loaded with the E7/E6 oncoprotein-suppressing siRNA gene. According to studies, the siRNA:PAMAMND complex can be utilized for gene delivery because it inhibits the activity of the E7 and E6 oncogenic genes [120]. In addition to the above-mentioned studies, Zhang et al. [121] conjugated luciferase pDNA with NDs coated with PEI (MW = 800 Da). In HeLa cells, this compound increased transfection efficiency by about 70 times [121]. It is clear from all of the mentioned studies that NDs play a critical role in gene delivery.

4.3 Bioimaging Today, bioimaging is an effective and powerful technique in biological and life science research because it facilitates the diagnosis process and provides a unique way to visualize the morphological details of tissues and cells [122]. The stable fluorescence, high biocompatibility, and small size of NDs enable them to be appropriate for bioimaging applications. NDs have developed as valuable candidates for contrast agents in comparison to other nanomaterials [123, 124]. In recent years, many studies have been conducted on fluorescence imaging based on NDs. For instance, Mohan et al. [125] investigated the nano-bio interactions between the model organism and NDs and showed in vivo long-term imaging of fluorescence NDs in Caenorhabditis elegans [125]. Hsiao et al. reported the super-resolution imaging and homogeneous labeling of albumin-conjugated FNDs in cells [126]. Chang et al. [127] created FNDs with stable fluorescence and enough brightness to enable three-dimensional tracking

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of individual particles in cells using two- or single-photon excitation fluorescence microscopes [127]. In another study, for simultaneous cell transfection and spatiotemporal fluorescence imaging of DNA payload release, Petrakova et al. [34] created a promising NDs vehicle based on FNDs non-covalently coated with PEI [34]. This study showed that NDs have the potential to function not only as labels but also as fluorescent biosensors that report complex molecular events and are non-toxic and resistant to photobleaching [34]. Nawa et al. [128] reported multi-color imaging of FNDs using direct electron-beam excitation in living HeLa cells [128]. In another study, Su et al. [129] showed the feasibility of using albumin-conjugated FNDs for background-free imaging and quantitative tracking of human placenta choriodecidual membranederived mesenchymal stem cells in animal models beyond rodents [129]. In another interesting study, Faklaris et al. [130] used FNDs (size = 50 nm) for intracellular labeling and studied the mechanism of their uptake by living cells [130]. In a study reported by Liu et al. [131], gold (Au) nanoparticles were attached to FND to create FND-Au hybrid particles for multimodal optical and electron microscopy cellular imaging [131]. In another study, Yoshino et al. [132], fabricated PG-functionalized ND (ND-PG) conjugated with cyanine dye (Cy7) and demonstrated that the resulting ND- PGCy7 conjugate was preferentially accumulated in the tumor, giving clear ex vivo and in vivo fluorescence images (Fig. 5). Although NDs are broadly utilized in cell imaging owing to their remarkable fluorescence, they have considerable penetration limits in histology applications. Magnetic resonance imaging (MRI) is a well-established imaging technique broadly utilized for anatomical organ and vascular evaluation. Recently, numerous studies have been carried out on using NDs in MRI. Waddington et al. [133] showed the versatility of the ND material system for hyperpolarized 13 C MRI. They demonstrated that synthetic HPHT NDs could have sufficient dangling bonds and impurities to cause hyperpolarization. In addition, the hyperpolarized NDs’ nuclear relaxation times were long enough for 13 C MRI to resolve structures at the millimeter scale. As shown in Fig. 6a–d, using NDs (diameter ≈ 210 nm) that had been hyperpolarized for 2 h, they obtained 13 C images of them in water at various detection times and concentrations. Figure 6e shows the image after injecting 150 mg of the hyperpolarized micro diamonds into the thoracic cavity of a mouse [133].

4.4 Tissue Engineering Tissue engineering is a revolutionary and promising approach treating patients who suffer the failure or loss of tissue or organ, with the aim of repairing the dysfunctional tissues and improve life expectancy [134]. Given the particular chemical and physical characteristics of NDs, tissue engineers have proposed the development of NDs-based materials as cell substrates to control cell adherence and proliferation. In particular,

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Fig. 5 a Schematic structure of ND-PG-Cy7 conjugate. b GFP/HeLa tumor-bearing mouse fluorescent (right) and optical (left) images before injection (fluorescence image in GFP mode, λem ≥ 561 nm, λex = 490 nm). c Optical and in vivo fluorescence images of a tumor-bearing mouse before and following injection of ND-PG-Cy7, respectively (fluorescence images in Cy7 mode, λem = 810 ± 45 nm, λex = 690 nm). d Ex vivo and in vivo fluorescence images of GFP/HeLa bearing mice at 72 h following injection of saline or ND-PG-Cy7. Images were achieved in GFP mode (λem ≥ 561 nm, λex = 490 nm) and Cy7 mode (λem = 810 ± 45 nm, λex = 690 nm). Reprinted with permission from Ref. [132], Copyright (2019) Wiley

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Fig. 6 Hyperpolarized ND imaging. a Phantom schematic. One side of the “half-moon” phantom is filled with water, and the other half of the phantom is filled with a mixture of hyperpolarized NDs and water. b Images of the phantoms described in (a) using hyperpolarized 2-µm diamonds dispersed in water (120 mg/ml) as the sample after 0 and 30 min in an MRI scanner. c Hyperpolarized 210 nm NDs in a Teflon tube at 200 mg/mL concentration have imaged after transfer from the polarizer after 0 min and 5 min in the MRI scanner. d Images of hyperpolarized 2 µm micro diamonds in a Teflon tube immediately after transfer from the polarizer. e Co-registered 1 H:13 C MRI of a mouse thorax following intrathoracic injection of hyperpolarized 2 µm diamond particles. The 1 H component (gray) of the co-registered image indicates the structure of the phantom and the location of water, with the 13 C component (red–orange) showing the location of the hyperpolarized diamonds, scale bars: 3 mm. This figure is reused from a published article [133], under the article’s Creative Commons license. The Creative Commons CC BY license permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit: http://creativecommons.org/licenses/by/4.0/

the surface charge distribution of NDs makes them more accessible for cell adhesive serum proteins to bind to the surface of the nanoparticle physically. This cellular interface has been mainly studied in neural tissue engineering and bone regeneration. In order to investigate the impact of surface chemistry on cell interactions, in a study published by Keremidarska et al. [135], DNDs of varying hydrophilicity were deposited to substrates by CVD. It was found that the more hydrophilic DND films improved alkaline phosphatase expression in rat mesenchymal stem cells (rMSCs) and promoted osteoblast adhesion [135]. In another study reported by Xing et al. [136], 24 weeks after implantation of carboxylated ND-coated poly (L-lactide)-co(-caprolactone) (PLCL) bone scaffolds into defects in sheep calvaria, the developed scaffolds demonstrated complete regeneration of the defects, but unmodified PLCL scaffolds displayed minimal bone restoration [136]. The in vitro studies demonstrated that on PLCL scaffolds, the use of NDs as a surface coating plays a critical role in the upregulation of osteogenic markers in human BMSCs [136]. Additionally, NDs

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have found a promising substrate for neural cells that could be utilized to create biocompatible, implantable neural prosthetics [137, 138]. For example, it has been demonstrated through additional research that ND substrates can facilitate the culture of various neural cells. Hopper et al. [139] showed that amino-functionalized NDs could support neural cell adhesion for Schwann, neuroblastoma-glioma, and dorsal root ganglion cells. On the aminated ND substrates, it was found that over long periods of culture, all three cell lines produced neurite extensions and dense neural networks [139]. Due to the remarkable tribological characteristics of NDs, they can be utilized to increase the wear resistance of joint prosthesis in addition to their application as celladhesive substrates [140–147]. It is worth noting that NDs can act as nanofillers to improve the mechanical features of polymers and produce multifunctional nanocomposites that can be used in both hard tissue and soft tissue regeneration because of their abundance of reactive functional groups on their surfaces and high surface area to volume ratio [148]. Zhang et al. [149] developed a multifunctional fluorescent composite bone scaffold with identical mechanical qualities to the human cortical bone using poly octadecylamine-functionalized ND (ND-ODA) and (L-lactic acid) (PLLA) (Fig. 7). At concentrations up to 10% by weight of ND-ODA complexes, octadecylamine (ODA) and NDs were chemically attached to produce ND-ODA complexes that purportedly improved the mechanical characteristics of PLLA. The increase in hardness and Young’s modulus of the composites were found due to the uniform dispersion of nanoparticles in the polymer [149]. Salaam and Dean [150] showed that the mechanical features of electrospun poly(εcaprolactone) (PCL) scaffolds were reinforced with DNDs at varying loading concentrations. A tensile modulus of 108.5 MPa was found in PCL that contained 0.1 wt% DNDs, which is comparable to the tensile modulus of human cancellous bone [150]. In a study reported by Wang et al. [151], it was found that the addition of 2 wt% NDs to polyvinyl alcohol nanofibers resulted in 89% increase in tensile strength, 155% increase in Young’s modulus, as well as a 336% elevation in energy to break

Fig. 7 a Schematic manufacturing and use of ND-OD/PLLA composites. b Molecular model of an ND-ODA particle. Reprinted with permission from Ref. [149], Copyright (2011) Elsevier

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compared with unmodified PVA [151]. In another study, Brady et al. [152] demonstrated that electrospun poly (lactide-co-glycolide) (PLGA) nanocomposite bone scaffolds could be reinforced by the addition of DNDs. Elastic modulus and hardness were increased twofold in PLGA nanocomposites containing 2.3 wt% DNDs [152]. The potential of NDs as nanofillers in polymeric scaffolds has also been investigated for wound healing applications. For instance, in a study published by Mahdavi et al. [153], NDs were added to bacterial cellulose and chitosan polymers to improve the tensile strength of electrospun membranes in order to produce biopolymer films with features similar to skin. The uniaxial tensile strength was shown to increase from 13 to 25 MPa with the addition of 1 wt% of NDs, and the NDs’ subsequent increase in hydrophilicity improved cellular adherence to the scaffolds [153].

4.5 Antibacterial Agents The development of bactericidal nanoparticles requires an efficient synthetic approach, a rational design of the particle, and an understanding of their toxicity and biocompatibility [154, 155]. Antibacterial or antimicrobial agents terminate/hinder the reproduction and growth of bacteria. The surface functionalization of NDs allows the possibility of producing an active biological and chemical surface. The presence of functional moieties on the ND surface determines its non-cytotoxic effects and antibacterial properties. Similar to other carbon materials, it is likely that ND’s antibacterial properties are associated with: (i) direct attachment to the bacterial wall via the surface groups (e.g., charge interaction and hydrogen bonding), (ii) membrane stress (physical damage of the membrane) and (iii) suppression of metabolic activities (i.e., inability to produce antioxidants in response to oxidative stress) [156–161]. Antimicrobial therapeutics have been grafted onto the ND surface using various modification techniques [162– 165]. NDs have been demonstrated to kill both gram-negative and gram-positive bacteria. NDs have been investigated in combination with proteins [103, 166–168], antibiotics [154, 169], and carbohydrates [170–172]. It is essential to mention that 90% of urinary tract infections are caused by the Gram-negative bacterium uropathogenic E. coli (UPEC). Some bacteria survive despite numerous innate immune system defenses and antibiotic treatment [173] by hiding in intercellular reservoirs of bladder epithelial cells (BECs) [174, 175]. ND provides an interesting potential to break BEC membranes followed by their exfoliation owing to its exceptional hardness and numerous sharp edges, which was reported to facilitate its transport through the cell membrane with subsequent quick endosomal escape [176]. FimH, a type I pili virulence factor that binds to uroplakin mannosylated proteins on the surface of BECs, is crucial for UPEC establishment in the bladder [172, 177]. Thus, preventing UPEC adherence to the bladder cells is a possible line of defense [178]. FimH lectin has an extremely strong binding to mannose molecules. Monosaccharides have a low affinity for FimH, whereas multivalent mannose ligands have a

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high affinity for lectin. However, at certain times the synthesis methods for multivalent mannose ligands are overly complex [162, 171, 179]. The photoactivation of ND-tetrafluoroazide, which produces an ND-nitrene radical that combines with sugar molecules through C-H insertion, has recently been reported [165] as a promising method of integrating polymannose ligands onto the ND surface. The successful binding of ND-glycans to plant fluorescent lectins presented evidence of the preserved activity of sugar units following the reaction with nitrenes. ND-glycans have been investigated as biofilm inhibitors for Gram-negative and Gram-positive bacteria [171, 180], E. coli antiadhesives [163, 170, 179], and promoters of agglutination [162, 165]. Wehling et al. [181] demonstrated that NDs are effective antibacterial agents based on their surface chemistry. Their findings showed that the NDs possessing negatively charged and partially oxidized surfaces would have antibacterial effects, viz. acid anhydride group on the surface. Furthermore, the surface functionalization of NDs with proteins improved their bactericidal ability [181]. It was also found that NDs showed a bactericidal effect specifically for type 1 fimbriae-mediated E. coli adherence after their surface functionalization with glycan (sugar coating). These may be effective in preventing the growth of E. coli biofilms. Inhibiting crucial enzymes and proteins, which NDs do by forming covalent bonds with molecules on cell walls or attaching to internal components, causes a rapid collapse of the bacterial metabolism and, finally cell death [182].

4.6 Biosensing Biosensors are analytical tools incorporating a biological sensing element to convert the bio-signal into a measurable response [183]. NDs have attracted a lot of attention in the biosensor field owing to their versatile physical and chemical properties [184–186]. In an interesting study reported by Zhao et al. [187], the application of NDs-modified Au electrodes was investigated for glucose biosensing. In this work, Glucose oxidase-modified NDs were attached to the surface of Au electrodes. The reduction of dissolved oxygen was greatly improved thanks to NDs pre-modification of the electrode’s anode, which also enhanced the electron transfer rate inside the NDs chip. The negative potential of glucose can be detected by monitoring the current change in oxygen reduction. The glucose sensor can selectively perform electrochemical measurements of glucose in the presence of usual interference compounds, including acetaminophen, uric acid, and ascorbic acid [187]. Liu and Sun [188] developed a method for immobilizing lysozyme-coupled NDs on a silicon template as a biosensing chip using e-beam lithography and self-assembled monolayer techniques. The experimental results showed that synthesized ND-lysozyme complex arrays retained their antibacterial activity and interacted with E. coli bacterial cells [188]. In Another study, a stimuli-responsive NDs-based biosensor for improved metastatic tumor site detection was developed by Wang et al. [189]. Matrix metalloproteinase 9 (MMP9)-specific fluorescently labeled substrate peptides were utilized to functionalize NDs in the biosensor complex. This approach enables the precise

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measurement of the MMP9 protease activity and the correlation with MMP9 expression. The NDs–MMP9 biosensor also showed an increased ability to protect the base sensor peptide from nonspecific serum protease cleavage [189]. In another study published by Kaçar and Erden [190], an amperometric L-ascorbic acid biosensor utilizing ascorbate oxidase immobilized onto poly(L-aspartic acid) film was created on carbon nanofiber and ND particle-modified glassy carbon electrode (GCE) for the detection of L-ascorbic acid. The developed biosensing method showed good selectivity and reproducibility. Under optimized experimental conditions, the synthesized biosensor demonstrated a linear response to L-ascorbic acid with a sensitivity of 105.0 µAmM−1 cm−2 and a detection limit of 1.0 × 10−7 M in the range of 2.0 × 10–7 –1.8 × 10–3 M [190]. Camargo et al. [191] demonstrated that NDs and potato starch (PS) could be mixed and deposited on a glassy carbon electrode (GCE) as a homogenous, rough film, with the electroanalytical performance-tuned by varying the relative NDs-PS concentration (Fig. 8). Tyrosinase (Tyr) was immobilized on the NDs/PS film, which served as a matrix. With a detection limit of 3.9 × 10–7 mol L−1 in the range of 5.0 10–6 and 7.4 × 10–4 mol L−1 , the resulting Tyr-NDs-PS/GCE biosensor showed suitable to detect catechol using differential pulse voltammetry [191].

Fig. 8 Scheme presentation of Tyr-ND-PS/GCE and ND-PS/GCE preparation. Reprinted with permission from Ref. [191], Copyright (2018) Elsevier

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In another study reported by Purdey et al. [192], a promising hybrid nanomaterial capable of extended imaging and detection of hydrogen peroxide was developed by attaching an organic fluorescent probe to an NV-ND without the photobleaching commonly associated with imaging the separate organic fluorophore alone [192]. In a study reported by Fernandes-Junior et al. [193], a promising nanostructured biocomposite electrode, ND-manioc starch/GCE, was developed as an electrochemical sensor for the determination and analysis of tetracycline. The fabricated sensor demonstrated superior electrochemical performance in the presence of tetracycline compared to the unmodified electrode, which was related to the increase in the electroactive surface area owing to the presence of ND [193]. Zhang et al. also reported a technique for immobilizing antibodies on impedance biosensors via NDs seeding, which increased overall detection sensitivity than that obtained with indium tin oxide or Au electrodes [194]. Taken together, it is concluded that NDs are excellent materials for the entrapment of several molecules in sensors and biosensors and play a critical and specific role in the construction of various sensors and biosensors.

5 Conclusions Recently, NDs have attracted remarkable interest owing to their outstanding properties, such as stable and unique fluorescence, chemical inertness, good biocompatibility, and versatile surface chemistry. NDs combine the dual characteristics of nanoparticles and diamonds. Various functional moieties adsorbed on the surface facilitate the functionalization of NDs. In this chapter, we have compiled the synthesis of NDs along with their surface modifications. Moreover, we mainly focused on the recent advances of NDs in biomedical fields, including tissue engineering, gene/drug delivery, bioimaging, biosensing, and antibacterial applications. The multifunctional properties of NDs can be used to enhance drug delivery to tumors in conjunction with imaging their fate in biological systems, which can revolutionize studies in the medical field. ND-containing materials can be utilized as potential antimicrobial materials for various biomedical applications. Moreover, a gene delivery vehicle and a label to identify the biomolecular targets of drugs could be developed using NDs. Undoubtedly, this class of carbon nanomaterials will be more investigated by numerous research groups, and more developments will be achieved. Overall, we believe that NDs-based materials will open a novel and very promising path toward materials science and biomedical applications. However, further studies are needed to completely elucidate the toxic principle of these materials before they can progress to clinical trials.

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Nanographites as Multidimensional Carriers for Advanced Therapeutic Applications Mahmoud H. Abu Elella, Emad S. Goda, Mariam M. Abady, Dina Mohammed, and Heba M. Abdallah

Abstract Multidimensional nanographite’s structures have attracted great attention in various therapeutic applications. Due to their fabulous properties such as large surface area, high electron density, good mechanical and thermal stability, and excellent electrical conductivity, they are widely utilized in advanced therapeutic applications including targeted drug delivery and controlled drug delivery application through various drug route administration, and cancer treatment via different approaches such as drug delivery, targeted therapy, gene delivery, phototherapy, and photothermal therapy. This book chapter highlights the employed various nanographite composites with different synthetic approaches in various therapeutic applications such as drug delivery and cancer treatment. Keywords Nanographites · Therapeutic applications · Drug delivery · Cancer treatment

M. H. A. Elella (B) Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt e-mail: [email protected]; [email protected] E. S. Goda Organic Nanomaterials Lab, Department of Chemistry, Hannam University, Daejeon 34054, Republic of Korea Fire Protection Laboratory, National Institute of Standards, 136, Giza 12211, Egypt M. M. Abady Division of Chemical and Biological Metrology, Biometrology Group, Korea Research Institute of Standards and Science, Yuseong-gu, Daejeon 34113, Republic of Korea Department of Bio-Analytical Science, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea M. M. Abady · D. Mohammed Department of Nutrition and Food Science, National Research Centre, Dokki, Cairo 12622, Egypt H. M. Abdallah Polymers and Pigments Department, National Research Centre, Chemical Industries Research Institute, Dokki, Giza 12622, Egypt © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. S. Hasnain et al. (eds.), Carbon Nanostructures in Biomedical Applications, Advances in Material Research and Technology, https://doi.org/10.1007/978-3-031-28263-8_3

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1 Introduction The advancement of nano-biomedicine and current drug delivery platforms has come from the following flaws in conventional therapies and the limited effectiveness of medications for in vivo administration. These shortcomings include rapid drug metabolization and exhaustion from the body before operation on their intended site(s), the limited solubility of certain medications concerning water, non-targeted exploitation, the limited persistence efficiency on dead parts, plus detrimental effects on normal cells. With the aid of newly suggested drug delivery methods, nevertheless, recent advances in nanotechnology, as well as nanomaterials presented a vibrant potential in the biomedicine field, including improved medication bio-distribution, less detrimental consequences on cells that are healthy, particular specificity, and more localized therapeutic uptake [1–3]. A wide range of materials, including polymers, micelles, liposomal membranes, as well as a wide range of inorganic nanoparticles such as metal oxides, noble materials, and carbon nanotubes, are all included in this category. Additionally, other nanomaterials have all been investigated by researchers in the nano-biomedicine sector throughout the past several decades [4–6]. Aside from the previously stated nanomaterials, many researchers were interested in the recently suggested two-dimensional (2D) nanographite carbon layered nanomaterials have different chemical shapes such as graphene, graphene oxide (GO), and reduced graphene oxide (rGO) nanosheets (Fig. 1) and intensively employed in biomedicine field because of their unique characteristics, including such their large aspect ratio, biocompatibility, and ease of alteration. Graphene seems to be a carbon atom monolayer that is consistently flat and compacted firmly via a honeycomb hexagon shape, making it a so-called twodimensional substance [7]. Graphene’s immensely intriguing features, including extremely high mechanical strength, intense electric, heated as well as magnetised capabilities, as well as distinctive visual characteristics, had accomplished it a viable contender for usage in a variety of technical sectors [1–3, 8]. Up to now, graphene nanosheets can be commonly prepared using different techniques such as layer by layer (exfoliation), chemical vapor deposition, chemical and electrochemical methods, and ice-crystal-template [9–12]. Reasonable biocompatibility, relatively vast surface areas, excellent optical characteristics, and simple biofunctionalization of graphene, graphene oxide (GO), and graphene oxide reduction (rGO) have piqued the interest of various researchers in biomedical engineering sectors such as drug delivery [13, 14]. Graphene oxide (GO) and reduced graphene oxide (rGO) constitute functional graphene derivatives with appealing qualities such as assimilation by liquid, producing apparent and IR fluorescence, and certain other graphene qualities crucial in drug delivery [15]. GO is the oxidized form of graphene and is considered one of the most popular carbons nanofillers that has been employed to design hierarchical nano-architectures owing to the presence of the abundant highly reactive groups such as alkenyl, hydroxyl, epoxide, carbonyl, and carboxyl groups onto its surface (Fig. 1)

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Graphene

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Graphene Oxide

Reduced Graphene Oxide

Fig. 1 Chemically illustration of the chemical structure of 2D graphite structures layered nanosheets: graphene, graphene oxide and reduced graphene oxide [22]

[16, 17]. GO contains SP3 hybridization carbon atom which boosts its interlayer spacing and enhances its ability to maintain compounds. The attached functional groups modify the electronic structure of graphene and serve as massive scattering centers which affect its electrical transport. Therefore, GO shows insulating properties, low carbon mobility (0.1 cm2 /V s) and sheet resistance around 1012 W/sq [18]. GO demonstrates sustainable features including aqueous processability, versatility, surface functionalization capability, and amphiphilicity. Additionally, GO has good hydrophilic nature and can fabricate stable aqueous colloids to boost the macroscopic structure assembly which is very important for large-scale applications [19]. GO can be prepared according to “bottom-up” and “top-down” techniques. The former includes simple carbon molecules like graphene but has disadvantages, for instance, time-consuming and scalable problemes. As a result, another technique “top-down” is widely applied and includes four approaches: Hummers’, Hofmann’s, Staudenmaier’s, and Brodie’s method [18]. Hummers’ method is the most employed technique for the preparation GO nanosheets. It contains the addition of potassium permanganate (KMnO4 ) to graphite solution and also both NaNO3 , and H2 SO4 are added. Many factors are changed in this method to improve its preparation and to achieve a low-cost process [20]. In another route, GO can also be prepared from graphite oxide using sonication and stirring as well. The sonication factor completely exfoliated graphite oxide through a short time and declines the size of GO from a few microns to nanometer sheets. While mechanical stirring is another approach but it consumes a long time and is less heavy-handed [21]. Conversely, the reduced GO

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is prepared through a reduction process for GO to create some extra double bonds and hydroxyl groups on the GO structure according to Fig. 1. A review of the most recent innovations and advancements in nanographene and its derivatives for drug administration is presented in this chapter.

2 Nanographite Nanostructures as Drug Carriers A variety of innovative drug-delivery systems have been developed as a result of nanotechnological and nano-science advancements that have enabled the creation of novel nanomaterials [1, 2]. Therapeutic drugs may be delivered in nanocarriers constituted of a broad variety of materials that were investigated [1, 2, 23]. The internalisation of nanocarriers with cells is dependent on numerous important characteristics according to earlier studies on nanoparticles and carbon nanotubes. Graphene and GO have a unique 2D structure that does not even present in biological systems, hence shape plays a big impact. Because this form differs from the round (nanoparticles) and tubular (carbon nanotubes, asbestos fibres) forms investigated in prior research, a such concern will need to be considered and handled later. Rigidity seems to be a crucial structural feature in preserving the structural stability of drug carriers, yet overly stiff graphene and GO structures might cause cell injury [24]. To diminish this effect, it is crucial to lessen the stiffness of graphene and GO sheets, which might be a stumbling block for drug delivery applications. The new revelation of graphene has sparked a surge in a study into the potential of this novel material for drug delivery applications. Graphene and its derivatives had arisen as novel biomaterials in the field of nanomedicine, affording intriguing possibilities for the progress of a diverse set of possibilities [7, 8, 13, 14]. Throughout the last Five years, graphene, and graphene oxide (GO), as well as other graphene derivatives were extensively investigated for drug delivery applications due to their beneficial features besides the prospective being used for systemic, selective, and local drug delivery systems. Many different research groups’ involved external stimuli, internal stimuli or delivery systems that respond to a variety of inputs and deliver therapeutic compounds at lower doses while yet increasing bioactivity, temporal precision, and spatial precision while reducing toxicity and other negative effects [25–27]. Targeted drug delivery to particular tissues, organs, or cells, as well as controlled drug release, are two of the most common uses for drug nanocarriers. Biocompatible nanoparticles or nanocapsules, as well as targeting compounds are the cornerstone of drug delivery. To strengthen hydrophobic carrier systems’ hydrophilicity or pharmaceuticals, biocompatible materials are chosen and integrated. Antibodies or avidin/biotins are examples of targeting molecules, which specifically target tissue, organs, or cells. The environmentally sensitive composition of nanocarrier systems provides drug release properties. Managing drug release provides the most effective therapeutic impact by delivering the drug to the appropriate location with high efficiency plus limiting potential healthy tissue injury that certain medicines, which including chemotherapy treatments, might cause [5]. Solid

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colloidal particles between 10 and 500 nm in diameter have been used to create polymer based nanocarriers [7]. Drug delivery might be improved by using graphene nanomaterials (GNMs) since their loading ratio (the weight of drug to carriers) is up to 200% greater than that of nanoparticles and certain many more existing drug delivery technologies [5]. Surface area, layer number, lateral dimension, surface chemistry, and purity are all features of graphene nanomaterials (GNMs) that are crucial for drug delivery and biological techniques. Graphene has a surface area of about 2600 m2 /g, which is four times more than any other nanomaterials investigated for drug delivery [8]. Through covalent π–π cooperative interaction [28], graphene may be loaded with the drug [28–32], and electrical management may indeed be used to modulate drug distribution [33]. The surface modification guarantees that the drug is released in large quantities. Additional nanoparticles, which include magnetic nanoparticles for photothermal therapy, may well be incorporated into graphene. Multifunctionality is a feature of grapheme based nanomaterials [15, 34, 35]. Due to the obvious polar groups, the material is very hydrophilic. Therefore, anticancer medicines including DOX, quercetin and gefitinib, sumatriptan succinate (SS), in addition to cytarabine (CYT) were distributed through them. Consequently, grapheme based materials that have been functionalized are intriguing prospects for creating intelligent drug delivery systems, specifically for cancer treatment [36–38].

2.1 Various Drug Administration Routes A drug’s propensity to approach its target site of action in the body is characterized by two critical criteria, the first one is drug’s bioavailability and the other is the way that the drug is administered (route of administration).

2.1.1

Bioavailability

Administered drug’s bioavailability assesses how much makes it into the systemic circulation and therefore may be delivered to the intended action location. Relative medicines’ bioavailability administered via direct IV injection is 100%. Certain drugs, including the antibiotic ciprofloxacin, which are exceptionally efficiently ingested into the digestive tract, may well have bioavailability equivalent to that of an IV dosage. As the oral route is not available for the majority of medications, the dosage oral administered is often more than the total administered intravenously. When taken orally, the beta-blocker propranolol, for instance, is proffered at dosages of 40 mg and more. 1 mg is the corresponding IV dosage. A drug’s bioavailability may be greatly affected by the method of administration as well as formulation (tablet, capsule, liquid).

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Fig. 2 Different drug administration routes

2.1.2

Routes of Administration

Numerous plenty administrative pathways are presented to choose from each with its benefit to cost ratio. Diverse routes of drug administration must be recognised for their ramifications for drug therapy efficacy and patient outcomes with drug treatment (Fig. 2).

3 Drug Delivery Applications for Multidimensional Nanographite Carriers The efficient drug delivery system (DDS) is aimed at providing therapeutic drugs to the affected site in a controlled way while minimizing the impact on healthy tissue. Chemotherapy medications sometimes have severe adverse effects on non-targeted organs attributable to their low solubility in water plus omission of selectivity in drug recompilation inside a tumour. Nanotechnology advancements over the last several decades have avoided certain challenges in this field by creating nanoscaled drug carriers with effective uses in DDS [38]. Because of their adequate enlarged surface area, biocompatibility, and ease of surface functionalization [35, 37], graphene and certain derivatives, notably GO have been intensively explored as well as in the realm of nanomedicine including bacterial inhibitors [3], imaging contrast agents [33], and drug delivery systems [29, 31]. New drug nanocarriers based on graphene and GO, fascinated by CNTs’ success, have indeed been actively studied in recent years to load a range of medicines, notably anti-cancer medications and poorly soluble

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medications; antibiotics; antibodies; peptides; DNA; RNA; as well as gene therapies [14, 25]. Graphene and GO may be used for targeted, regulated, and boosted drug delivery, particularly specialized applications for anticancer and gene treatments.

3.1 Targeting Drug Delivery Chen et al. [34] created a targeted drug delivery system employing GO with the addition of sulfonic acid groups; thereby making it resilient in physiological conditions. MCF-7 cells, human breast cancer cells having folic acid (FA) receptors, are therefore covalently bound by FA molecules. FA-conjugated GO (FA–GO) was loaded with doxorubicin (DOX) and camptothecin (CPT) by π–π stacking and hydrophobic reactions, and the outcomes revealed that the loaded FA-GO demonstrates selective targeting to MCF-7 cells and remarkable high cellular toxicity comparable to GO supplied with simply DOX or CPT. Several teams have incorporated FA to create drug carriers that target certain organs. New graphene oxides with minimal cytotoxicity and high solubility have been developed to target photodynamic treatment in cancer patients. Using hydrophobic reactions besides π–π stacking, the second generation photosensitizer (PS) Chlorin e6 (Ce6) was successfully integrated into the system. When irradiating MGC803 cells with GO nanocarriers, the concentration of Ce6 in tumour cells is considerably increased, culminating in remarkable photodynamic effectiveness. Multi-functional GO was developed by conjugating GO-Fe3 O4 nanohybrid with FA by various studies [15] that could provide dual-targeted administration by way of electromagnetism and particular interactions between the drug carriers and the excessively folate receptors on select tumour cells. At high concentrations, a gold nanocluster and graphene nanocomposite may suppress HepG2 cells and transport DOX into the cells, resulting in some synergy in karyopyknosis producing cells.

3.2 Controlled Drug Delivery Diffusion techniques are used to manage the release kinetics of drug carriers, which signifies that their release behaviour and the quantity of released drug cannot be adjusted after their delivery. It is indeed critical to creating more sophisticated methods capable of delivering medications precisely at the ideal dose and timing to supersede such passive drug delivery methods. To that purpose, numerous innovative responsive “smart” drug carrier techniques have been developed that can adapt to internal (body temperature, pH, specific chemical reaction) or exterior (administered ultrasonic, magnetic, electric field) stimuli [39, 40]. Graphene and GO nanocarriers have already been used effectively to implement such ideas. Advantages and limitations of using nanographene and its nano derivatives as drug nanocarriers on different drug administration routes (Table 1) [2, 14, 41–49]

Nanographite composite

Gold nanoparticle (AuNP)—Folic Acid—GONS

Folic acid (FA)-Graphene Oxide Nanosheet (GONS)

Carboxymethylcellulose (CMC)-Zn-based metal-organic framework (MOF-5)-GO

Carboxymethylcellulose (CMC)-Zn-based metal-organic framework (MOF-5)-GONS

Drug routes

Intravenous

Intravenous

Oral

Intravenous

Doxorubicin (DOX)

Tetracycline (TC)

Doxorubicin (DOX) and Camptothecin (CPT)

Doxorubicin (DOX)

Drug model

Advantages: – Chemotherapy human blood cancer cell lines are delivered with precision and released in a controlled manner Limitation: – Needs for in vivo study

Advantages: – Effective oral drug administration – Effective stomach pH protection Limitation: – In vivo studies are required – Complex synthetic techniques

Advantages: – GONS that seem to be FA-linked have a high affinity for folate receptors – Multi-drug co-administration – Incredible increase in cancer-causing toxicity Limitation: – Needs for in vivo study – Possible immunogenicity

Advantages: – Photo-thermal ablation and targeted chemotherapy Limitation: – Needs for in vivo study – Low stability

Main results (advantages and limitations)

Table 1 Advantages and limitations of various nanographite’s formulations on different drug administration routes

(continued)

[33]

[32]

[31]

[30]

References

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Nanographite composite

Maghemiteγ-Fe2 O3 -GO

Polyvinylpyrrolidone (PVP)-GO

Polyethylene Glycol bis Amin (PEGA)-GO Magnetic NS (GOMNS)

NGO–PEG–SN38

Drug routes

Intravenous

Oral

Intravenous

Intravenous

Table 1 (continued)

SN38 (CPT analog)

Methotrexate (MTX)

Quercetin (QSR) and Gefitinib (GEF)

Cisdiamminedichloroplatinum (II) (CisPt)

Drug model

[34]

[35]

References

Advantages: [37] – Water insoluble anti-cancer drugs delivery Limitation: – In vivo studies are required – Inappropriate protein corona formation – Higher concentrations of cell damage and tissue injury (continued)

Advantages: [36] – Magnetic Iron NPs – Enhanced chemotherapeutic effectiveness by pH-dependent drug release and bio—compatibility Limitation: – Needs for in vivo study

Advantages: – High biocompatibility – Contribute to the anticancer advancement activity in a dose range Limitation: – Needs for in vivo study

Advantages: – A successful malignant glioma chemotherapy Limitation: – Needs for in vivo study

Main results (advantages and limitations)

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Nanographite composite

β-Carrageenan (β-Car)-GONS-biotin

NGO–PEG–RB

GN–CNT–Fe3O4

Drug routes

Intravenous

Intravenous

Intravenous

Table 1 (continued)

5FU

DOX

Doxorubicin (DOX)

Drug model

Advantages: – pH dependent drug release – Super paramagnetic – HepG2 cells efficiently uptake Limitation: – In heptacyte, GN-CNT-Fe3 O4 might accumulate – In vivo studies are required – Potential imunogencity

Advantages: – Appropriate for cancer therapy – High precision Limitation: – Complex synthetic methods – Lung tissue inflammation – Needs for in vivo study

Advantages: – Cervical cancer targeted treatment – pH-sensitive drug release Limitation: – Needs for in vivo study

Main results (advantages and limitations)

[39]

[2]

[38]

References

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4 Nanographite Carriers for Cancer Treatment Cancer is one of the big issues of worldwide health problemes [50]. The statistics of the American Cancer Society’s global burden supposed the elevation of cancer global burden till 2030 (estimated 21.7 million cancer novel cases) [51]. Current cancer treatments encompass surgery, chemotherapy, radiation therapy, photodynamic therapy, immunotherapy as well as stem cell transplantations, cancer vaccinations, or a synergistic combination of them. Nonetheless, many side effects and limitations are raised for most of these conventional therapy strategies [51]. Consequently, the improvement of an economically suitable alternative method for cancer treatment specifically targeting the tumour site devoid of impairing the healthy tissue is immediately needed. Nanobiotechnology has a substantial role in overwhelming the several limits of conventional therapy approaches. Nanobiotechnology is one of the branches of nanotechnology and nanoscience which treats the application of nanoparticles (recommendable 1–100 nm) in biology as well as medicine owing to their distinctive properties such as (small size, high surface energy and high surface to volume ratio) [52]. Recently, several reports applied nanotechnology in biology and medicine for diagnostic strategies (bioimaging, MRI-imaging, biosensing) in addition to therapeutic one (drug delivery, photodynamic therapy, antibacterial) [51, 53, 54]. Lately, Carbon is attracted much attention in nanobiotechnology because it is the second most abundant element in human in addition to, its unique physical and chemical properties such as (optical, electrical, thermal and mechanical). Carbon based nanomaterials such as (nanodiamonds, carbon nanotubes, carbon nanodots, fullerenes, graphene, carbon nanocone disks, carbon nanofibers and nanohorns) are recently considered vital materials for possible biomedical applications [55] in cancer therapy due to efficient absorption ability for NIR light, which is resulted from their unique biological and physicochemical characteristics. Carbon quantum dots are characterized by availability for functionalizing with several groups for targeting drug delivery. As well, sp2-hybridized carbon in the lattice of carbon quantum dots could bind with aromatic therapeutics (on basal planes to increase the drug loading capacity and efficient treatment. For instance, the conjugation between multi-walled carbon nanotubes (MWCNT) and candesartan has been assembled with plasmid AT-2 for targeting αvβ3-integrin, AT1R of tumor endothelium [56]. Additionally, carbon nanotubes provide effective drug stability by surrounding the drug inside the internal hollow cavity and protection from the external environment [57]. Moreover, the synergistic efficacy of temperature and NIR for hydrogel of MWCT-carrageenan was studied in vitro on cancer cells by controlling the release of methylene blue from this conjugate [58]. On the other hand, the conjugates of MWCNT—anticancer drug complex showed distinct properties in the efficacy of in vitro and in vivo treatment compared to the effect of anticancer drug alone [59]. It has been reported the conjugation of doxorubicin-magneto fluorescent-MWCNT carbon quantum dot [60]. This could be explained by the interaction between the

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positively charged doxorubicin and the surface of negatively charged magnetoMWCNT carbon quantum dot provided a strong ability for NIR light absorption resulting in temperature elevation up to 51.8 °C inside the target tumour [61]. In the case of targeting mitochondria for apoptosis induction, the combination of polyethyleneglycol-carbon nanotubes and ABT737 drug showed higher efficacy compared to the free drug [62]. Nanographite is also considered a promising anticancer drug delivery (Fig. 3) owing to its unique architecture such as DMA-C60-NGR with 2-methoxyestradiol, which induced photodynamic treatment by target penetration of tumour cell membrane and elevated the intracellular reactive oxygen species leading to dramatic damage of DNA[63]. Furthermore, another modified one (C60-PEI) was conjugated with doxorubicin for dual chemo and thermal therapy and complexed with CdSe/ZnS for more targeting efficacy. Such complexation showed 2.4-fold higher doxorubicin release in cancer sites compared to normal cell sites [63, 64]. Several published reports compared the efficiency of photo thermal treatment between GO and single-walled nanotubes (SWNTs). In the NIR region, the optical density of the beneficial GO for photothermal treatment as well as photoacoustic imaging is highly lower than that of SWNTs [65, 66]. Remarkably, Markovic et al. testified that while graphene nanomaterials show lower NIR absorbing ability, the in vitro photothermal efficacy for cancer cell killing is highly improved as compared to carbon nanotubes [67]. As well, the 2D nano-graphene showed better passive targeting for tumor cells compared to 1D SWNTs [68, 69], due to the unique size and shape of 2D nanographene, which stimulates the retention effect and permeability. Furthermore, the 2D graphene nanosheets might be complexed easily with Fig. 3 Possible application of nanographite formulations for cancer treatment

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numerous functional nanoparticles for possible multimodality therapy in addition to imaging uses, whereas the individual alteration of carbon nanotubes is fairly more problematical. Functionalized graphene nanosheets have been applied for drug delivery of in vitro intracellular antitumor chemotherapy drugs [70, 71]. The nanographene coating with biocompatible polyethylene glycol (PEG) showed great passive uptake of in vivo tumour trials besides effective photothermal removal of tumour tissues from a mouse model [72–74]. The presence of large p-electrons in graphene enhances energy transmission from the near molecules, leading to effective fluorescence quenching [65, 75, 76]. Additionally, the functionalization of the graphene’s surfaces (covalently and non-covalently) is required for the improvement of water solubility as well as biocompatibility [77, 78]. For instance, the complexation with hydrophilic polymers could increase the GO stability in biological solutions plus salts [65]. π–π interactions or hydrophobic bindings could be used for non-covalent functionalization of graphene with several molecules and polymers [65, 79] such as adsorption of many aromatic anticancer drugs such as (doxorubicin and SN38) on the surface of polyaromatic graphene via π–π stacking [80]. Due to the high surface area of graphene, ultra-high efficiency of drug loading was accomplished [71, 80].

4.1 Targeting of Cancer Drugs Nanographene is characterized by a wide surface area-to-volume ratio enhancing the loading capacity for various therapeutics (drug, DNA, antibodies and enzymes) as well as easy delivery through the cells by diffusion, endocytosis or insertion [81–83]. This facilitates improvement of higher synergistic production of multipurpose therapeutics such as targeting, stability, and drug delivery. The choice antibody is the first choice for targeting the tumour cells by conjugation to nanographenedrug complex, which is present on the tumour cell surface. Another strategy, is the coating of carbon nanotubes with magnetite nanoparticles such as Fe3 O4 [84]. The usage of an outside magnet facilitates the delivery to target cells. Additionally, folic acid is another approach for cancer cell targeting [85]. The addition of folic acid to doxorubicin-PEG-nanographene revealed higher targeting and uptake into breast cancer [85]. Also, hyaluronic acid could be loaded on nanographene to enhance its targeting efficacy [86]. Blood–brain barrier (BBB) penetration is one of a major issue for efficient drug delivery to the target sites because BBB is a highly specific endothelial tight junction, which is hard for the passage of big therapeutic drugs. To date, several invasive techniques are used for drug delivery to the brain such as surgery, injection or intracranial delivery, which could result in infection and edema [87]. Modified and targeting carbon nanotubes may provide a helpful solution for such a problem. Many examples of nanographene applications have been reported such as PEG-carbon nanotubes complexed with C225 for the treatment of brain tumour by stimulating the release of pro-inflammatory cytokines [36]. Another example is the fabrication of nanohybrids between graphene oxide nanosheets with magnetic poly (lactic-co-glycolic acid)

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for targeting drug delivery of radiosensitizing (5-iodo-2-deoxyuridine) in glioma tumours [88]. The modifications of graphene based nanomaterials for targeting the effect of cancer sites [89–97] are summarized in Table 2.

4.2 Gene Delivery Gene therapy is considered a favourable treatment for replacing mutated genes; expressing new genes yields or knocking out a functionally defective gene [98–100] by delivery of RNA or DNA. The challenges are finding effective and nontoxic carriers for nucleic acids in addition to the ability to passage any biological barriers to confirm the delivery of nucleic acids to cytoplasm and nuclei. Although the viral vectors are efficient because of their natural capability for invasion and delivery of nucleic acids, the induced immunogenicity is one of the big issues for their clinical application [101]. Nanographite based gene nanocarriers could be used as a non-viral vectors for gene therapy. The complex of graphite quantum dots-chimeric peptides-plasmid DNA was developed. The positively charged motif of MPG-2H1 chimeric peptide complexed non-covalently with plasmid DNA forming fusion peptide for endosomal membrane disruption stimulating endosomal escape and nuclear localization. This complex of graphite quantum dots-chimeric peptide–plasmid DNA revealed higher transfection efficacy (eightfold) compared to chimeric peptide–plasmid DNA proving that graphite quantum dots are considered a promising transfection vector for gene therapy applications [102]. Moreover, the π-stacking and sp2-hybridized structure of nanographite quantum dots facilitate greater drug loading capability compared to further non-viral drug delivery systems. On the other side, the conjugation sites of other signalling molecules besides cationic polymer for loading of DNA are restricted to functionally edge groups via covalent binding. The basal planes of graphene quantum dots, which were highly used for drug delivery, have not provided any advantage for gene therapy [102].

4.3 Photo-Chemotherapy and Photothermal Therapy Photo-chemotherapy is a branch of nanotechnology for cancer therapy and it utilizes heat and has strong absorption efficiency in NIR (near infrared) region [103]. For example, high doses of laser radiation result in dramatic damage to neighbouring healthy cells. Also, metal nanoparticles (silver and gold)-coated carbon nanomaterials (theragnostic agent) have some toxic effects and low biodegradability. Photothermal therapy is one of the highly promising strategies for cancer treatment but it has a big challenge for the production of photothermally safe agents. For breast cancer treatment, fluorescent cyanines showed low toxicity and higher stability

Target

Active targeting

Active targeting

Active targeting

Active targeting

Active targeting

Passive targeting

Tumor microenvironment (TME) targeting

Modifications of GBNs

Folic acid (FA)

Transferrin (Tf)

MUC1 ligand

Anti-human epidermal growth factor receptor 2 (HER2) antibody

TRC105

GBNs size

High glutathione (GSH) levels

GBNs can be designed to target the TME

Diffusion or endocytosis

CD105 (endoglin)

HER2 receptor

MUC1-binding aptamer (AptMUC1) and mucin 1 receptor immunoglobulin G antibody

Tf receptors

Folate receptors

Receptors

(NGO) conjugated with Tf to carry a Pt complex into MCF-7 breast cancer cells

GO loaded with doxorubicin (DOX)-FA

Examples

[47]

[46]

References

Improved perfusion, extravasation and penetration

Greater tumor accumulation due to their improved retention

Targeting the tumor vasculature

Selectivity

GBN conjugate with M75 (monoclonal antibody)

Graphene based targeted nanoprobe

rGO to TRC105

Trastuzumab on 111In-labeled GO for single-photon emission computerized tomography (SPECT) imaging

(continued)

[14]

[50]

[14]

[49]

Nonimmunogenicity, rapid AptMUC1 conjugated with [48] tissue infiltration, low cost GO and simple synthetic process

Biodegradable, nontoxic, and nonimmunogenic

Nontoxicity, low cost, dispersion stability, and target specificity

Advantages

Table 2 Possible modification of nanographene for targeting effects in cancer treatment

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Target

pH-sensitive targeting

Redox-responsive targeting

Hypoxia-mediated targeting

Modifications of GBNs

Acid-liable ester Amide Ketal/acetal groups

GSH concentration

Hypoxia-mediated effect

Table 2 (continued) Advantages

Tumor hypoxia

Redox Suppressed HIF-1α and increased the anticancer effect, and reverse drug resistance

Targeting strategies

The pH in breast tumors is Specifically release 5.4–7.1 chemotherapeutic drugs, reduced systemic toxicity and of-target effects

Receptors

References

GO as a carrier to deliver HIF-1α-siRNA into 4T1 breast cancer cells

GO microcapsules with disulfide bonds

[53]

[52]

Curcumin was loaded into a [51] sericin-modified GO carrier

Examples

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in addition to successful localization for NIR imaging. Additionally, the employment of PEG improved the life span of blood circulation and therapeutic efficacy [104]. Recently, gold nanoparticles showed photothermal ability. The conjugation of graphene with gold nanoparticles increased the photothermal and photoacoustic characteristics [105]. Moreover, the conjugation of folic acid to nanographene could be very helpful for the delivery and targeting of photosensitizers which have difficulty in tumour site delivery because of their hydrophobicity [106]. Zinc oxide was used as a photosensitizer and its conjugation with folic acid-graphene improves its dual function of bio-imaging and photodynamic therapy [107]. Another report about the synthesis of graphene oxide complexed with Ru (II) and PEG for synergistic photothermal and photodynamic treatment as well as lysosomal targeting imaging [108]. Lately, nanoparticles (with functionalized carbon networks) have revealed great potential for targeting and drug delivery in chemotherapy treatments such as (carbon nanotubes, carbon dots, graphene materials and fullerenes) [15, 109–111]. Graphene sheets have flexible structure and can produce heat by changing the magnetic field or via noble metal lasers [112]. For instance, nanographene-PEG have been labeled via a NIR fluorescence dye for in vivo imaging because of the week in vivo imaging of nanographene and high passive uptake in different models of xenograft tumor mouse [74]. Additionally, photothermal therapy for tumour killing due to robust optical absorbance of PEG-nanographene in the NIR range via intravenous administration of PEG-nanographene and NIR laser irradiation (low power) on the cancer tissue. Interestingly, nanographene showed better photothermal therapy and in vitro tumor cell killing of U251 human glioma cells, compared to carbon nanotubes [67]. One wide example is reduced graphene oxide (rGO). GO nanosheets are loaded with Indocyanine green (theranostic naoplatform) with a synergistic combination between PTT treatments and photoacoustic imaging in addition to conjugation with folic acid for targeting tumour sites. Nevertheless, organic dyes have revealed many limitations for clinical applications such as photobleaching and dye degradation [112]. The ability of PTA for enhancing the absorption selectivity of low laser signal to induce heated production inside the target tumour microenvironment [113]. Additionally, GO and rGO have been widely applied in vitro and in vivo studies as PTAs and characterized with strong absorbance of NIR light (wavelength range 700–1300 nm) [114]. Due to the transparency of biological tissues for NIR, highdepth penetration of light and significant photothermal conversion efficacy into cancer tissues [115]. Notably, the heterogeneous distribution of induced heat is not very suitable for tumour cell death. Graphene nanomaterials act as intelligent light absorbance with wide surface area for absorption or conjugation with cancer tissue. For instance, doxorubicin-rGO-PEG has been applied for in vivo cancer experiments as a photothermal-chemotherapy strategy. Triple therapeutics were established by conjugated epidermal growth factor receptor antibody with PEGylated nano GO to carry epirubicin for cancer tissue targeting. Such a strategy prolonged the survival rate of mice (more than 50 days) by increasing the drug concentration (6.3 fold) and significant suppression of tumour size [116, 117].

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Nanocomposites of rGO-mesoporous silicon-amorphous carbon have been used for the improvement of the photothermal conversion, biopenetrability and biodegradability, as well as active drug transport as applied in MDA-MB-231 cells with high loading of hydrophobic drug-(S)-(+)-camptothecin-. The well-gathered rGOMDAMB-231 cells nanocomposite, the tumour cell was destructed proficiently devoid of any additional lateral special effects in vitro and in vivo, especially for PTT and localized drug discharge [118]. In the same way, nano-rGO -bovine serum albumin was studied for PTT. NS (passive targeting) was effectively applied to destroy breast cancer cells [119]. The in vitro outcome of nano-rGO was tried counter to MCF-7 cells exposed to a NIR laser with a wavelength of 808 nm and produced apoptosis in the target cancer cells in a concentration dependent manner. Moreover, the mice were administered with the nano-rGO presented thermal cell necrosis. Besides, it has been demonstrated that grafting ligands of the Arg-Gly-Asp tripeptide with nano-rGOs could induce active targeting, consequently resulting in a higher/better photothermal ablation towards the target cells. Additionally, nano-rGO has been established to be able to cargo non-covalent doxorubicin drugs via p-stacking. Therefore, along with its ability for surface adjustments, nano-rGO has abundant potential for promising synergism between targeted PTT and chemotherapy [112]. Furthermore, graphene quantum dots (GQDs) could have many practical applications in photodynamic therapy because of their ability for killing tumour cells by reactive oxygen species (ROS) production in the presence of oxygen and under irradiation. Additionally, photodynamic therapy is non-invasive as compared to radio or chemotherapy with fewer side effects. On the other side, GQDs act as promising photosensitizers compared to current agents in photodynamic therapy such as (porphyrins) due to providing photostability and high water dispensability as well as biocompatibility and low toxicity [102]. Recently, it has been stated the combination between photodynamic therapy and photothermal therapy through multifunctional GQD systems. It has been reported production of GQDs by hydrothermal reaction of the mechanically shearing derivation of organic matter from plant leaves. The produced GQDs after 5 min irradiation (808 nm laser) have photothermal ability (43 °C at 100 µg/ml) in addition to ROS production. Such synergistic effects decreased the viability of MDA-MB-231 cells significantly compared to GQDs treatment alone [120]. GQDs also have been applied in vitro and in vivo applications. GQDs with irradiation revealed cell death and a significant reduction of tumour volumes compared to GQDs alone due to ROS generation. Moreover, wavelengths of irradiation with GQDs are longer than those used with other photothermal agents (UV–Vis range) which have tissue penetration limitation and less efficiency [102].

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4.4 Drug Resistance Reversing drug resistance (MDR) is the blockage of cancer chemotherapy [121]. A new strategy for the conjugation of chemotherapy with graphene based nanomaterial’s (GBNs) has been considered for such a problem. There are several known MDR mechanisms such as detoxification enhancements, a decline of drug uptake, stimulation of DNA repair system, expression increment of P-gp transporter as well as the escape of drug-induced apoptosis [122]. For example, these stimulated detoxification actions acquired can alter chemotherapeutics into innocuous products, leading to diminishing anticancer properties [93]. GBNs could be helpful in the overcome of detoxification activities via accumulative cellular uptake and drug absorption. It has been studied GO-conjugated with Adriamycin for reversing drug resistance and stimulating cellular drug uptake of MCF-7/ADR cells with decent biosafety [123]. Another MDR mechanism, pumping out of drugs from cancer cells by increasing the expression of P-gp transporter [124]. Li et al. tried to use two molecular beacons for GBNs modification and reversing MDR VIA inhibiting the P-gp expression of multiple genes with a nontoxic effect [125]. Another approach is to block P-gp export properties for reversing MDR in breast cancer cells [126]. GBNs enter cancer cells in endocytosis-independent and endocytosis-dependent manners. After the entrance of GBNs into cancer cells by the endocytosis process, the drug is released into the cytosol at low pH in lysosomes or endosomes, avoiding the export effects [125]. Based on these, Adriamycin could localize into the nuclei of cancer cells avoiding the recognition and export properties of P-gp transporter by using GO as a carrier, causing the drug resistance to reverse [127]. These results recommend that the use of GBNs as chemotherapeutic carriers could be very helpful for MDR cancer treatment.

4.5 Angiogenesis Angiogenesis is defined as the development of innovative blood vessels from the pre-existing vasculature in a complex process [128, 129]. The word ‘Angio’ means (in Greek) blood vessel besides ‘genesis’ means production. The process of angiogenesis is a complex process, which involves multiple important steps, including the enhancement of endothelial cells via growth factors, extracellular matrix degradation via proteolytic enzymes, endothelial cell migration and proliferation, as well as the formation of a capillary tube [130]. Certainly, a healthy body preserves the equilibrium of the angiogenesis process. Primary tumour growth or metastasis (approximately size of 1–2 mm3 ) requires angiogenesis vascularization. Hereafter, the tumour changes to an angiogenic phenotype switch and appeals to nearby stroma blood vessels, which are regulated by several pro- and anti-angiogenic factors [131]. For tumour growth, angiogenic stimulators should be upregulated and angiogenic inhibitors should be downregulated to induce the angiogenesis transduction pathway [132]. Accordingly, the angiogenesis

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process has a significant role in tumour growth, metastasis, and cancer progression. It is theorized that angiogenesis obstruction might be an effective approach to control tumour growth. Conversely, few aggressive cancer cases can expand without neovasculature such as IDH1 mutated glioblastoma, which could destroy blood– brain barrier and misbalance of intracerebral and extracerebral molecule trafficking of blood vessels [133]. Recently, researchers developed and designed many nanoparticles with antiangiogenic characters have been developed, which is considered a promising and alternative strategy for cancer therapy. Numerous carbon based nanosystems and their several allotropes showed insightful anti-angiogenic actions, detected by many in vitro and in vivo experiments. Several reports have stated that Graphene and Graphene oxide display cytotoxicity for the angiogenesis process in tumour growth due to the uncontrolled development of ROS. ROS has an essential role in the cellular machinery of angiogenesis [134]. It is well known that lower ROS concentrations can stimulate the proliferation of the endothelial cells, migration, as well as the formation of blood vessel tube. On the other side, higher ROS concentration could kill the cells [135]. GO and rGO and their relation to ROS-dependent switchover of anti-angiogenesis and angiogenesis have been assayed by numerous in vitro and in vivo experiments [136]. It has been reported that high concentrations of Graphene oxides (GO) and reduced Graphene oxides (rGO) (>100 ng mL−1 ) showed proliferation inhibition of endothelial cells as well as depletion of migration and formation of blood vessel. This could be explained by GO and rGO stimulating excessive ROS generation which leads to down regulation of both pAKT in addition to peNOS, enhancing the antiangiogenesis process as explained in Fig. 4. On the other side, small concentrations of GO and rGO result in low ROS concentration which stimulate angiogenesis process [51].

Fig. 4 Effect of graphene oxide (GO) and reduced graphene oxide (rGO) angiogenesis mechanism in dose dependent manner via probable mechanism via hypoxia and ROS production; pAKT: biomarker for human cancer; peNOS: phosphorylated endothelial nitric oxide synthase; NO: nitric oxide; SOD: superoxide dismuatase

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4.6 Potential Toxicity of Graphene The important question is what is graphene toxicity for in vitro and in vivo applications? Zhang et al. stated that graphene arranged via the deposition technique of chemical vapor elevated caspase 3 activation (major apoptotic marker), the liberation of lactate dehydrogenase and ROS production, in neural cells of pheochromocytoma derived PC12 [137, 138]. Additionally, It has been demonstrated that a high concentration of GO (above 50 mg/l) would stimulate high cytotoxicity of human fibroblast cells [137, 139]. Notably, the non-functionalized GO (physiologically unstable owing to non-specific electrostatic binding with proteins) revealed pulmonary toxicity (in dose-dependent manner, 10 mg/kg) for a long time after intravenous administration into mice or rats, inducing pulmonary toxicity in dose-dependent [139–141]. As numerous nanomaterials are applied in biology and biomedicine, the toxicity effect of graphene is strictly related to its surface modification and functionalization. The first destination for GO after its intravenous administration is the accumulation into the lung via blood circulation. However, the coating of GO with PEG significantly enhanced the biocompatibility and in vivo behaviors. It has been reported that photothermal therapy of GO-PEG (10–50 nm) for mice treatment (40 days) revealed no observable toxic effects [74]. The main accumulation of radiolabeled PEG-NGO was in the reticuloendothelial system (spleen and liver) with very low lung accumulation, and it might be progressively expelled from mice without any obvious side toxicity (a dose of 20 mg/kg, 3 months) [140, 142]. Therefore, the coating of GO nanomaterials with PEG revealed better stability in the presence of high protein and salt concentrations with less in vitro or in vivo or toxicity. Moreover, the additional essential parameter affecting the in vivo performance of graphene nanoparticles is the nano size, which requires more long-term investigation and toxicology [65, 137].

5 Conclusions and Perspectives The use of nanographite and its derivatives for therapeutic applications has increased quickly in recent years because of its outstanding shape and compositional capabilities. This new biomaterial has considerable promise for biological applications, as evidenced by prior studies, which show that substantial and promising development has indeed been achieved in this sector. There are still a lot of obstacles before this technology may be used in clinical studies. Even if first preclinical studies are positive and constructive graphene and GO have a variety of benefits over alternative drug delivery methods, including the potential to offer high drug loading capacity for a wide range of medicines and therapeutic compounds while requiring less pretreatment [143]. Last but not least, the recent improvements in graphene based nanocarriers for drug delivery applications are indeed a major breakthrough in nanomedicine that provides an intriguing potential for the future and widespread usage of nanoparticles in actual clinical circumstances.

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Carbon Nanohorns in Drug Delivery and Medical Applications Gouranga Dutta, Nilayan Guha, Abimanyu Sugumaran, and Md. Kamaruz Zaman

Abstract In 1999, Iijima discovered a new component named Carbon nanohorns (CNHs) or Single walled carbon nanohorns (SWCNHs) along with other carbon nanostructures such as carbon nanotubes, fullerenes, and graphene. CNHs are ~25 nm-diameter, 40–50 nm-long sp2-bonded carbon atom cages. Their tight cage construction with elongated structure makes them a high-aspect-ratio fullerene subclass and a good comparison with single-walled carbon nanotubes. These nanohorns having range of applications like energy conversion, gas storage, supercapacitors, biomedicine, and drug delivery. The mass production at room temperature and the absence of a potentially hazardous metal catalyst are advantages of carbon nanohorns over carbon nanotubes. Pentagons, hexagons, and heptagons make up nanohorns, providing them a wide spectrum of chemical properties. CNHs have special features that make them useful in a wide range of biological contexts due to their conical form and surface chemistry. The tip of CNHs can be chemically functionalized with certain ligands and other molecules to improve its hydrophilicity and stability, and the conical form may also aid entrap drugs or other chemical, biomolecules and substances. CNHs, are extremely light absorbent, which makes them effective in phototherapy for a wide range of medical conditions possible. For the purposes of drug delivery and different medical applications, this chapter summarises the advancement of carbon nanohorns, including their properties, functionalization, and its possible potential in those fields.

G. Dutta Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India N. Guha · Md. Kamaruz Zaman Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh 786004, Assam, India e-mail: [email protected] A. Sugumaran (B) Department of Pharmaceutical Sciences, Assam University (A Central University), Silchar 788011, Assam, India e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. S. Hasnain et al. (eds.), Carbon Nanostructures in Biomedical Applications, Advances in Material Research and Technology, https://doi.org/10.1007/978-3-031-28263-8_4

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Keywords Carbon nanohorns · Carbon nanotubes · Drug delivery · Biomedical application

1 Introduction A novel nanocarbon material structure, single-walled graphitic carbon nanohorns (SWCNHs), was found by Iijima in 1999 [25], alongside other carbon nanostructures: carbon nanotubes, fullerenes, graphene, etc. Carbon nanohorns (CNHs), also known as nanocones, are closed cages of sp2-bonded carbon atoms measuring 25 nm in diameter and 40–50 nm in length. They may be thought of as a high-aspect-ratio subclass of fullerenes due to their closed cage architecture [60, 103]. Albeit they may be opened by oxidation to increase surface area and provide access to their interior chamber. Because of their elongated form, they have similar chemistry to singlewalled carbon nanotubes. Nanohorns are being investigated as potential alternatives for nanotubes in a variety of applications, including energy conversion, gas storage, super capacitors, biomedicine, and drug delivery [38, 60]. Carbon nanohorns offer two major advantages over carbon nanotubes: they are synthesized without the use of a potentially hazardous metal catalyst and they can be mass-produced at room temperature. They prefer to agglomerate clustered CNHs during synthesis, forming “Dahlia-like,” “bud-like,” and “seed-like” structures [103]. By interacting with one another, thousands of these nanocones may form spherical clusters with a diameter of ~100 nm. This structural property impeded the functionalization of individual carbon nanohorns. To overcome this restriction, a novel approach for separating these “dahlia-like” clusters into individual nanocones was recently created [28]. Nanohorns are composed of a variety of structural shapes and forms, including pentagons, hexagons, and heptagons, which results in a wide diversity of chemical properties. As a result, CNHs exhibit unique properties owing to their conical shape and surface chemistry, which allow a variety of biological applications [99]. Furthermore, the conical form may aid in the entrapment of pharmaceuticals or other compounds inside the structure, and the tip can be chemically functionalized by the coupling of targeting ligands and a variety of other molecules. This makes CNHs more hydrophilic and stable. CNHs, on the other hand, are extremely light absorbent materials at a broad range of wavelengths, from infrared to ultraviolet. As a result, phototherapy may be used to treat a variety of medical conditions [50, 99]. The purpose of this chapter is to summarize the advancement of carbon nanohorns, their characteristics, functionalization, and potential uses in drug delivery and medicine.

2 Structure of CNHs The CNHs is an irregularly formed single-graphene tube with non-uniform diameters of ~2–5 nm, a length of ~30–50 nm, and a horn-shaped tip. Cone angles of ~19° are

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often seen at the tips, suggesting the presence of severely stretched five-membered rings. CNHs aggregate in a variety of shapes, with a layer of conical single-layered tips projecting in all directions from the spherical nanostructure, and with an average diameter of ~80–100 nm for the surrounding tips. According to DSC analysis, CNHs are composed of, 15% faulty carbon (due to open tips), 70% tubular carbon, 12% graphitic carbon, and the rest amorphous carbon. Three distinct SWCNH aggregate types have been discovered so far: “dahlia-like, bud-like, and seed-like” [31]. SWCNHs clusters exhibit both microporosity and mesoporosity as a consequence of their unique structure, and the porosity of CNHs has been investigated in several types of research. Micropores with a pore capacity of 0.40 mL/g were detected using N2 isotherm analyses in one investigation of CNHs. There are two distinct kinds of pores seen in CNHs clusters. (1) The pores between the nanohorns, (2) the pores within the nanohorns [55, 86]. CNHs include mostly closed pores. Numerous investigations have been conducted to determine the best approach for opening specific pores and increasing the pore volume. By oxidizing CNHs with oxygen [18], CO2 [85], or oxidative acids (H2 SO4 , H2 O2 /H2 SO4 , HNO3 ) [8, 92] followed by heat treatment, increased microporosity was achieved. The oxidation conditions influence the quantity and size of the nanoholes formed. Oxidation with a gradual temperature rise of 1 °C/minute at a low O2 concentration (21% in air) results in hole expansions [18]. Like O2 treatment, acid treatments are notably remarkable for opening nanoholes. Treatment with an H2 O2 /H2 SO4 mixture and heat increases the total surface area and the micropore volume by almost 5.5-fold. Respectively, treatment of SWNHs with nitric acid (HNO3 ) induces the development of microporosity due to increases in both the internal and interstitial pore volumes [86, 92].

3 Properties of CNHs SWCNHs, like other carbon nanostructures such as carbon nanotubes and fullerenes, offer various intriguing properties that have been exploited for a wide range of applications. There are many properties are evaluated by different researchers through many instrumental analyses. To investigate the surface area, optimal shape, dispersibility, stability, and electrical characteristics of SWCNHs, several theoretical computations were employed. These properties open various applications by using the CNHs. (a) SWCNHs demonstrated semiconducting and electronic properties that were highly impacted by gas adsorption, such as O2 (an electron acceptor) and CO2 (an electron donor) and electrical conductivity increased with increasing temperature [74]. This property highly influences gas absorption, gas sensing, and energy absorption application. (b) The electronic properties are strongly interrelated to the magnetic properties in SWCNHs. The magnetic properties of SWCNHs were investigated using electron spin resonance (ESR) and static magnetic susceptibility measurements.

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These studies indicate a value of the diamagnetic susceptibility [7]. Several investigations have shown that SWCNHs have structural deficiencies at the tips of single nanohorns, the heptagon rings present in the CNHs forming twodimensional graphene sheets. These flaws are necessary for exhibiting their unique electrical and magnetic properties [22]. These two characteristics open the windows for the development of supercapacitors, electrodes, fuel cells and catalyst supports [50]. CNHs and SWCNHs can be readily functionalized following oxidation to oxCNHs or ox-SWCNS, respectively, in a regulated manner. The addition of different functional organic, inorganic (metal NPs), and biomolecular (drugs, enzyme, protein) compounds may functionalize in a two-way covalent or noncovalent approach. There are several CNHs-related applications that may benefit from this functionality [50, 61]. Several research have explored the porosity of SWCNHs. There are two types of pores in SWCNHs: inter-nanohorn pores and intra-nanohorn pores. The pore diameters of SWCNHs were much narrower, and they can be enlarged by heating them in an O2 or CO2 environment. Which boosted the quantity and size of pore windows [18, 54]. Due to their extreme hydrophobicity, normal CNHs and SWCNHs cannot be dispersed in water, but they may be disseminated in a variety of organic solvents. Although this feature may be altered by oxidation or functionalization of CNHs or SWCNHs, which provides dispersibility in water and improved stability and benefits a variety of other applications [15, 28]. CNHs are prepared without using any metallic catalyst. So the CNHs are more metal-free than other carbon nanostructures, for this reason, it is less toxic for biomedical applications, several studies reported the toxicity levels of CNHs are very less unless given a greater lethal dose (≥2000 mg/kg body weight) [47, 66]. Hence it can be used for various biomedical and therapeutic applications such as drug delivery, biosensor, tissue regeneration, etc. Another advantageous feature that paves the way for therapeutic applications, particularly in cancer treatment and its biodistribution. These CNHs are very efficient in absorbing photon energy and enhancing photodynamic properties. This photothermal energy conversion characteristic has phototherapeutic effects on several disorders [27, 50].

All of these qualities are used for diverse applications, and with functionalization, the synergistic potential of CNHs and SWCNHs for specific applications has also developed. Various biological applications connected to these features were described in this chapter (Fig. 1).

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Fig. 1 Schematic representation of the structure of CNHs or SWCNHs, properties, and synthesis method

4 Synthesis of CNHs Numerous synthesis techniques have been developed since its discovery. All of these technologies rely on the application of energy to break down and rearrange carbon formations, which are typically graphite rods. All existing nanohorn production methods involve injecting enough energy into a carbon target to vaporize and rearrange it, followed by fast quenching in an inert condition generally. Nanohorn synthesis is different from making nanotubes because there are no metal catalysts. Even though nanohorn samples show that they are very pure, with only 5–15% byproducts, they are mostly “fullerenes, graphite particles, and large carbon onions, with some amorphous carbon,” depending on the synthesis method [4]. However, by preheating the carbon source before synthesis, these contaminants may be reduced significantly [84]. As a result, the synthesis processes being classified into three based on how energy is introduced in to the carbon, such as laser ablation, arc discharge, and joule heating synthesis methods.

4.1 Laser Ablation Synthesis Method The energy source for the laser ablation technique is a high-intensity CO2 laser that operates at room temperature. CNHs is produced when a high-power CO2 laser is

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directed at a carbon source (graphite) in an argon (Ar) environment without any catalyst (Fig. 1). This simple procedure was pioneered by the Iijima and their coresearcher in the early stages of dahlia-like CNHs production [25]. They reported that CO2 laser creates aggregated dahlia soot that is typically 85–90% pure. Other investigations have shown that this process yields bigger dahlias than other methods of synthesis (∼100 nm in diameter). Many other inert gases were used, but it was discovered that the Ar environment (20 kW/cm2 surface laser power density with 500 ms on/off pulses) produced the highest dahlia yields when compared to the Ne gas environment, where it produces half the size of dahlia aggregates that are equal in size to arc discharge. However, In this method, the N2 environment, nanohorn dahlias get damaged and excessively nitrogen-doped [6, 91]. XPS analysis revealed that nitrogen atoms were integrated into a graphene lattice of CNHs in the pyridinelike and threefold coordinated sp2 bonding configuration. Iijima et al. and NEC [Japanese multinational information technology and electronics corporation.] later commercialize industrial-scale CNH manufacturing. A three-chamber apparatus was developed for industrial-scale CNH manufacturing, integrating the laser ablation chamber, target reservoir, and collecting chamber. The Ar carrier gas sweeps the CNHs into the collecting chamber, keeping the target clean and allowing the laser to operate continuously. A revolving graphite rod is employed for large-scale manufacturing, which continually exposes the fresh surface to the laser beam. The system can manufacture 1 kg of CNHs per day with a purity of 95% [6].

4.2 Arc Discharge Synthesis Method Carbon nanohorns were discovered as a by-product of fullerene manufacturing using a direct current (DC) arc-discharge process (Fig. 1). Carbon nanohorns were discovered in soot leftovers of fullerene arc discharge manufacturing. In a positive-hearth electron gun heated to 2500–3500 K for ~4 h, soot is converted into a combination of single-walled and multi-walled nanohorns [73]. The first arc-discharge experiment for the direct fabrication of high-purity nanohorns used a pulsed arc discharge on two electrodes equivalent to pure carbon rods separated by a distance of 1 mm in the presence of air pressure [83]. The residual amorphous carbon was eliminated by drying it at 500 °C. The resulting dahlias have mean sizes of ~50 nm. Preheating the carbon rods to 1000 °C shortly before arc ignition increases the sample quality. The arc discharge between the carbon rods is conducted under an atmospheric pressure of air, water, CO2 , or carbon monoxide (CO) [34]. The resulting dahlias have mean sizes of ~50 nm, which is smaller than the laser ablation method. Submerged arcdischarge methods have shown promise for large-scale nanohorn manufacturing. The arc zone remains gaseous either due to the evaporation of the host liquid or the injection of carrier gas. Submerged arc discharge was first performed in liquid nitrogen, utilizing DC arc discharge between graphite electrodes to produce nitrogen-doped nanohorns, and more recently in liquid Ar. The “arc in water” technique employs arc discharge in water to provide N2 to the gaseous zone around the arc [77, 78].

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According to recent research, a perfected version of this technology, in which N2 or Ar gas is introduced into the arc zone through holes in the graphite electrode, might create 1 kg of nanohorns daily [28, 65].

4.3 Joule Heating Synthesis Method Induction heating produces nanohorns by producing high-frequency eddy currents in graphite rods, causing Joule heating [75]. A 30 kilowatt (kW) prototype reactor generated surface carbon plasma by heating graphite rods to more than 3200 °C on their surface in the presence of Ar or He carrier gas, resulting in dahlia or bud-like formations of CNHs [30]. The authors suggest scaling up to megawatt (MW) plans producing 10 kg/h using this deceptively easy technology. The process yields wrapped and unwrapped graphene sheets, amorphous carbon, and 80% after 24 h exposure

L929 fibroblast cell [157]

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[159]

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detecting isocarbophos and imaging living cells. Viability studies on human bladder carcinoma cell lines using MTT assay confirmed that the obtained CDs are less toxic even at a 300 µg/mL concentration after 1-day exposure [98]. Dehvari et al. prepared nitrogen-doped CDs from crab shells that can be used for targeted cell imaging. The toxicity of the derived CDs was examined using an MTT assay. At a concentration of 1000 µg/mL of the CDs, significant changes were observed in the viability of HeLa cells. However, the cell viability was > 90%, ensuring their safe application as imaging probes [99]. Through the acid oxidation of Muskmelon Fruit, Desai and co-workers synthesized CDs that were tuned to emit different colors (blue, green, and yellow) by changing the experimental conditions. The CDs were identified as excellent probes for the detection of Hg2+ ions. They were also successfully used for the cell imaging of Cunninghamella elegans, Aspergillus flavus, and Rhizoctonia solani. The biocompatibility of the CDs was examined by MTT assay on NRK cells, and non-toxicity was observed up to 1.0 mg/mL concentration [100]. Havrdová et al. synthesized CDs decorated with quaternary ammonium groups by thermal oxidation of Tris(hydroxymethyl)aminomethane hydrochloride. With the presence of obtained CDs (400 µg/mL concentration and 24 h exposure) in the nucleus, no remarkable variations were observed in NIH/3T3 cells. However, rapid apoptosis was observed with L929 cells. Fluorescent images and a graphical representation of the above results are shown in Fig. 2 [101]. Vale et al. used three different synthesis approaches (hydrothermal-based, microwave-based, and calcination-based synthesis) to prepare CDs from Citric acid and urea. Toxicity studies were done with an MTT assay. Normal breast epithelial MCF-10A cells were exposed to different concentrations (0.01–1 g/L) of CDs for different timings (24, 48, and 72 h). Calcination-based CDs and microwave-based CDs exhibited significant toxic effects after 48 h and 72 h of exposure, respectively. Hydrothermal-based CDs are less toxic than the other two types [102]. Yue et al. synthesized fluorescent CQDs from riboflavin, a natural vitamin, through the hydrothermal method. Cytotoxicity results showed that the obtained CDs possess good biocompatibility and negligible toxicity, as more than 95% of 4T1 cells were viable even after exposure to 400 µg/mL concentration of CQDs [103]. In another work, the toxicity of hydrothermally synthesized N-doped oxidized CDs derived from urea and citric was studied on three different human cell lines

Fig. 2 Fluorescent images: L929 cells treated with CDs decorated with quaternary ammonium groups for 24 h: (a) 50 µg/mL; (b) 100 µg/mL; (c) 200 µg/mL; (d) 400 µg/mL concentrations (Nu-nuclei). Reproduced from [101] under the terms and conditions of the Creative Commons Attribution (CC BY) license http://creativecommons.org/licenses/by/4.0/

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Fig. 3 Dose-dependent toxicity of CDs on (a) HeLa cells, (b) HepG2 and (c) HEK-293. Reproduced from [107] under the terms and conditions of the Creative Commons Attribution (CC BY) license http://creativecommons.org/licenses/by/4.0/

MDA-MB-231, A549 and HEK293. The biocompatibility of the CDs was confirmed using an MTT assay [104]. Bu et al. synthesized nitrogen and oxygen (N–O) co-doped CQDs from o-phenylenediamine & 2-hydroxyisophthalaldehyde via the hydrothermal method. The obtained CQDs are excellent fluorescent probes to detect Zn2+ . Cytotoxicity studies showed that the material has low dark toxicity [105]. Jeong et al. prepared water-soluble fluorescent CQDs from TTDDA & EDTA monomers via a microwave-assisted synthesis method. The obtained CQDs with different functionalities and chemical structures were modified by different initial polyamidation monomer ratios. All derived CQDs were less toxic and biocompatible toward MDCK and MDA-MB-231 cells. The in vivo studies were done on zebrafish, and these CQDs could not induce any abnormalities in the development of the model. The in vivo results revealed that the hatching rate of zebrafish is highly influenced for the precursor materials of the derived CQDs [106]. Liu et al. synthesized CDs from Polyethyleneglycol (PEG) and glucose through microwave pyrolysis. The toxicity of CDs was tested on HeLa cells, HepG2 and HEK-293 cells. Irradiation-dependent toxicity was observed with these CDs (Fig. 3) [107]. Wang et al. investigated the toxicity of Chlorine doped CDs derived from 4-chlorophenol and cytotoxic studies were conducted on HeLa cells. The toxicity of CDs depends on the exposure time and concentration [108]. In another cell viability study, non-doped, N-doped and Nitrogen Sulphur co-doped CDs were prepared from citric acid. Cell viability studies were held on HaCaT and HEK-293 cells. These cell lines were protected from oxidative stress in the N-doped CNDs than in non-doped CNDs [109].

3.2 Carbon Nanotubes (CNTs) CNTs are tubular-shaped carbon allotropes that exhibit extraordinary properties with high surface area, flexibility, and excellent chemical stability. One of the promising features of CNTs is their easy penetration into human cells. Based on the number of side walls, CNTs are of two types named as single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs). Both SWCNTs and MWCNTs have been widely used for various medical applications such as biosensors [110], drug delivery [111],

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gene therapy [112], cancer therapy [113], infection therapy [114], immunotherapy [115], hyperthermia therapy [116], etc. Functionalized CNTs have grabbed particular interest via enhanced biocompatibility of the final material. CNTs possess an asbestos-like structure which is the primary source of their toxic nature [117]. The toxicity issues of CNTs are mainly related to the production of reactive oxygen species (ROS) and oxidative stress. Exposure to CNTs may lead to pulmonary inflammation, mesothelioma, teratogenicity, etc. Impurities related to the synthesis, surface functional groups, surface charge aggregation state, shape, size, and layer number are various factors that can influence the toxic effects of CNTs [118]. To guarantee their safe application, there is a fundamental need to characterize multi-walled carbon nanotubes (MWCNTs) toxicity. Several toxicology assessments have been done on pristine CNTs and functionalized CNTs to investigate their toxicity level in various biological atmospheres. Baghdadchi et al. studied metabolic alterations in mice after being exposed to – OH functionalized MWCNTs via NMR-based metabolomics. Mice were exposed to three different concentrations of CNTs through intraperitoneal injection. Results showed that various metabolic pathways, such as steroid hormone biosynthesis, lysine biosynthesis, biotin metabolism, taurine and hypotaurine metabolism, lysine degradation, etc., were highly affected by CNT exposure [119]. Icoglu et al. exposed embryos and larvae of zebrafish to various concentrations of -COOH functionalized MWCNTs and studied the resultant toxic effects. With increasing concentrations, the samples showed irregularity in different biological functions. The CNTs triggered oxidative stress, increased mortality, delayed hatching, disordered heartbeat, and developmental disorders. These defects are attributed to the modifications in the immune system and gene expressions after CNT exposure. The increased toxicity of COOH-MWCNTs compared to pristine ones is ascribed to the large agglomerates of carbon formed with the oxidation process [120]. In another work, the biological responses of SWCNTs and MWCNTs are evaluated on MC4L2 cells. Timedependent apoptosis was observed in the mice breast (MC4L2) cells, which is clear from the results of the flow cytometry assay (Fig. 4) [121]. Marcos et al. synthesized SWCNTs functionalized with PEG by electric arc discharge and studied the concentration-dependent toxicological effects in zebrafish embryos after 3 - 96 h post-fertilization exposure. Increased mortality rate, delayed hatching, distortion of body parts, and DNA damage were observed with increasing concentrations. However, the body tissues of the larvae were found to be free from the presence of SWCNTs. This indicates that the derived CNTs can induce toxicities in aqueous media without being absorbed into the zebrafish body [122]. Ahmadi et al. studied the toxicity of PEGylated and Tween functionalized SWCNTs using proteomics analysis, oxidative stress, and histological examination. Except for the lesions in the liver, no significant changes in any organic compounds or enzymes were observed by the CNT exposure [123]. On the other hand, Morozesk et al. investigated the toxicity of oxidized MWCNT with cadmium on zebrafish larvae via MTT, neutral red, trypan blue, and lactate dehydrogenase assays. The necrosis and apoptosis effects were studied by flow cytometer. Though the exposure of ox-MWCNT alone did not induce any cytotoxic effects, the same disclosure with CdCl2 resulted

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Fig. 4 Flow cytometry assay; effect of MWCNT on the MC4L2 cell apoptosis. Reproduced from [121] under a Creative Commons Attribution 4.0 International license https://creativecommons. org/licenses/by/4.0/

in enhanced toxicity developed by synergistic effects [124]. Cimbaluk et al. selected two different species of fish (Danio rerio and Astyanax altiparanae) to study the toxic effects of CNTs on them. As a result of acute and subchronic exposure of the samples through water, neurotoxicity was identified in both fish species [125]. Ferreira and co-workers investigated the toxic effects of Pyrene-polyethylene glycol-modified MWCNTs in V79-4 fibroblast cells. The genotoxicity of the samples was studied by comet assay and the cytokinesis-block micronucleus cytome assay. MTT assay and Cell Titer Blue methods were used for cell viability studies. Using fluorescence in situ hybridization chromosomal changes were detected. Along with metabolic activation, the samples observed chromosomal damage [126]. Jiang et al. studied toxicity issues related to the MWCNTs exposed to 3D brain organoids. Dose-independent cytotoxicity was detected in the samples. The neuronal nitric oxide synthase was affected by the direct and indirect interaction of CNTs at a concentration above 64 µg/mL [127]. Liu et al. exposed equal mass concentrations of MWCNTs and halloysite nanotubes to human umbilical vein endothelial cells and compared their cytotoxic effects on the same. Thiol depletion and ultrastructural changes were observed by MWCNTs exposure, whereas halloysite nanotubes did not induce any toxic effects. Results showed that MWCNTs are more harmful than halloysite nanotubes with their potential to stimulate endoplasmic reticulum stressmediated lipid accumulation in human umbilical vein endothelial cells [128]. Zheng

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et al. investigated the impact of pulmonary inhaled MWCNTs on rats’ blood pressure and heart rate. The authors could observe that the MWCNTs altered the normal functioning of the autonomic nervous system, which can affect the cardiovascular system. Results showed that pulmonary inhaled MWCNTs reduced the volume of blood ejected from the heart in each cardiac cycle and slowed the heart rate of rats [129]. Salih et al. reported dose-independent genotoxicity and carcinogenicity of MWCNTs in different mouse groups. The toxicology studies were done by gene co-expression network analysis. It was observed that CNT exposure affected the immune system and cellular response pathways [130]. Knudsen et al. investigated the impacts of pulmonary exposure to 11 types of MWCNTs (MWCNTs with different sizes and surface states) in mice after one year of their introduction. Aggregation of thin CNTs and single fibres of long and thick ones were found in the lungs even after one year of exposure. Thus all 11 types of CNTs are found to be biopersistent. Thin CNTs exhibited comparatively high toxic effects as they induced inflammation in the lungs in connection with the accumulation of lymphocytes, a cluster of white blood cells, and macrophage infiltration. CNTs did not persuade any pulmonary tumours or fibrosis. DNA strands were damaged with thin and tangled type CNT [131]. Thompson et al. investigated the impact of MWCNTs on cardiovascular adenosinergic systems. Suspensions of commercialgrade, COOH, and nitrogen-doped MWCNT were instilled into mice. Cyclic adenosine monophosphate concentrations were checked after 24 h. Reduced concentrations in the C-grade group were observed by 17.4% and in the N-doped group by 13.7%. It is evident that surface functional groups can influence the biological response of CNTs and stimulate cardiac injury [132]. Siegrist et al. compared the genotoxicity of MWCNT-7 with MWCNT exposed to high temperature and MWCNT synthesized with nitrogen in human lung epithelial cells (BEAS-2B & SAEC). MWCNT-7 showed higher genotoxicity compared to the other two types. CNTs exhibited dosedependent and time-dependent reduction of cell viability towards BEAS-2B & SAEC cell lines. The highest decrease was observed in MWCNT-7. A remarkable reduction was noticed with the exposure of 24 µg/mL concentration of all three types of CNTs. Cellular division, fragmented centrosomes, DNA-related disorders, and spindle poles were noticed with the exposure of each kind of CNTs. Genotoxicity increased with the increase in the diameter of CNT. The results of this study indicated that MWCNT-7 could potentially induce tumours and carcinogens in rats [133]. Holian et al. investigated the lung pathology and particle distribution effect of Functionalized MWCNTs in Balb/c mice after 7 and 28 days of instillation. Acute inflammation in the lung tissues is observed with all CNTs and found to be higher in the case of non-functionalized MWCNT. As the degree of functionalization increased, the lung burden and dispersibility of the samples increased. The presence of carboxyl groups changed the surface chemistry of MWCNTs. They could uniformly spread on the epithelial cells with reduced aggregation tendency, indicating reduced pathology for the safer application of these CNTs as a targeted delivery system [134]. Mostovenko et al. tracked neuropathological variations in Male C57BL/6 mice after hours of MWCNT exposure by oropharyngeal aspiration. The authors analyzed the peptidomics fraction derived from cerebral spinal

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fluid. The results showed that neuropathological variations in the brain are related to neurodegenerative diseases such as Alzheimer’s [135]. Kim et al. investigated pulmonary deposition and retention of tangled MWCNTs through an inhalation toxicity study in male Sprague Dawley rats exposed to different concentrations of MWCNTs. Haematological and biochemical parameters remained constant even after exposure. Aggregated MWCNTs were observed in other parts of the lungs. Results suggest that tangled MWCNTs are less toxic with a shorter clearance halftime than rigid MWCNTs [136]. Beyeler et al. studied the impacts of MWCNTs on primary bronchial epithelial cells in chronic obstructive pulmonary disease patients. The CNTs did not change the experimented cells’ cell viability or epithelial integrity [137]. Russ et al. conducted a comparative study on the pulmonary function variations of rats exposed to different concentrations of MWCNTs and nitrogen-doped MWCNTs for 6 h. At a high dose of 5 mg/m3 remarkable variations were observed. Nitrogen-doped MWCNTs exhibited relatively low toxicity than that pristine MWCNTs [138]. Many works associated with the toxicity and biosafety of CNTs revealed that in animal cells, the toxicity arose due to ROS, oxidation in cell constituents, interference of electron transfer through the membrane, and cell penetration. It is suggested that the effectively functionalized CNTs are much more secure for animal cells than plain CNTs.

3.3 Carbon Nano Onions (CNOs) Carbon Nano onions (CNOs) are carbon-based nanostructures consisting of concentric muti-fullerene shells with a large surface-to-volume ratio of less than 100 nm. Functionalized CNOs have low toxicity and excellent biocompatibility [139]. The concentric cage-like structures of CNOs and attractive properties like water dispersibility and negligible toxicity make their way in safe biological applications. Gunture et al. discovered that functionalized CNO-NH2 are water-soluble and act as non-toxic sensing and cell imaging probes. They exhibit Excitation-dependent fluorescent emission and show high quantum yield, which is used as a fluorescent probe for HeLa cells [140]. In recent work, onion-like carbon nanoparticles (OCNPs) from grilled turbot Scophthalmus maximus L. tested cytotoxicity in MC3T3-E1 cells and could not find any cell death up to 20 mg/mL. For higher concentrations of OCNPs, higher oxidative stress was spotted, and the fluorescence images of MC3T3-E1 cells with OCNPs are shown in Fig. 5 [141]. D’amora et al. synthesized B/N Co-Doped CNOs by the thermal annealing of Detonation NDs with boric acid. By reflux reaction of obtained material with nitric acid, oxidized B/N Co-Doped CNOs were also prepared. The toxicity of the samples was examined with different In Vitro and In Vivo biological methods. With 10 µg/mL of B/N Co-Doped CNOs on NIH 3T3 and MCF7 cells, the cell viability after 24 h was 90% and 92%, respectively. It was 92% and 93% for its oxidized form, respectively, after 48 h incubation. Both of the samples did not show any adverse impacts

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Fig. 5 Fluorescence images of MC3T3-E1 cells with OCNPs. Reproduced from [141] under a Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/ 4.0/

on zebrafish embryos [142]. The author has also reported the synthesis of noncovalently functionalized CNOs with hyaluronic acid-phospholipid that can be used for the selective targeting of cancer cells. The biological responses of the material were studied on human breast carcinoma cell lines overexpressing the CD44 + receptor and human ovarian carcinoma cells that do not over-express the CD44 + , CD44-. According to their report, the conjugates did not affect these two cell lines. Moreover, the functionalized CNOs did not perturb zebrafish development during different stages [143]. Garcia-Hernández et al. synthesized CNOs that are promissory candidates for different biomedical applications. The CNOs were tested with human keratinocyte cells and exhibited localization in the early and late endosomes of human keratinocyte cells. No inflammatory responses were observed up to 120 µg/ml concentration. Significant changes were observed in protein expressions that are related to metabolic, cellular and immune system processes, which may be a plausible way for intracellular traffic of CNOs [144]. Through the pyrolysis of NDs, Jang et al. synthesized CNO NPs and surface functionalized them into carboxyl groups via the Hummers’ method to obtain CNO– COOH. The biological response of the material is examined with various tests and assays such as the Hemolysis test, Intracellular Reactive Oxygen Species Measurement, Cytokine Profiling Assay, CCK-8 assay etc. Both CNO and CNO–COOH NPs

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did not show any toxic effects against human dermal fibroblast cells and peripheral blood mononuclear cells for concentrations 80% after 24 h treatment of dextran-coated C70. Mitochondrial membrane potential, the integrity of nuclei and the functioning of lysosomes, etc., were unperturbed [157]. Prylutska et al. examined the biocompatibility and safety of the C60 fullerene–cisplatin nano complex in Lewis lung carcinoma cells. Even higher concentrations of the sample could not induce any toxic effect on the lung carcinoma cells. However, C60–Cisplatin-Pt nano complex reduced the cell viability, disrupted the morphology, and perturbed the adhesion and cell migration [158]. Using MTT assay, Imai et al. investigated the cell viability of mouse iPS cells treated with C60 fullerene. The observed cell viability at 50 mg/ml concentration was 80.2% [159]. Kyzyma et al. studied the toxicity of fullerenes C60 and C70 on mammalian fibroblasts of Chinese hamsters. Solvent-dependent toxic effects were observed with the samples [160].

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4 Conclusion and Future Prospectives The necessities of biologically safe and biocompatible CNMs are pertinent nowadays due to the elevating requirements of non-toxic and environmentally friendly implementations, especially in medical diagnosis and therapeutics. This chapter discusses the contemporary explorations in toxicity and biosafety of diverse CNMs. CNMs are anticipated to have enormous advantages for animal and human well-being in the upcoming times of their non-toxic CNMs functionalization. The harmfulness of CNMs to animal cells is predominantly due to ROS, oxidation in cell constituents, interference of electron transfer through the membrane, and cell penetration. Size, shape, functional groups, precursors, and impurities significantly influence the toxicity levels of CNMs. Hence, wise selection of precursors and proper regulations of these aspects should be considered for more secure employment of CNMs in the medical field. Developing biodegradable CNMs with specific biological purposes is preferable to avoiding toxicity by accumulation in tissues and organs. Harmless, effectual, and eco-friendly catalysts are also needed to reduce enduring deleterious effects from anti-oxidant depletion and oxidative stress. To reduce the toxic effects of impurities, adequate purification methods for CNMs have to be introduced. Different and specific functionalization helps CNMs reduce their severe toxicity than raw CNMs. Non-toxic caping or stabilizing agents and solvents also play a vital role in the biosafety of CNMs. When CNMs are used for light-induced treatments, their phototoxic effects have to be studied in prior. Available reports suggest that more research is needed to analyze the long-term and inherent toxic effects of CNMs on the biological system. Acknowledgements and Funding Aleena Ann Mathew is grateful to DST for the fellowship grant DST/INSPIRE/03/2021/000566, and Manoj Balachandran is thankful to DST for his major research fund DST/TMD/CERI/RES/2020/37(G).

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