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Drug Delivery System and Technologies 95
molecularly imprinted polymers, intelligent biomaterials, quantum sensing, CRISPR CAS9 based systems, 3D printing, and so on. The innovations in related technologies will promote the new design of drug delivery system, which will ultimately provide patients with personalized medication and improve therapeutic efficacy.
Acknowledgements Lei Nie acknowledges the support from the Nanhu Scholars Program for Young Scholars of XYNU.
Conflicts of Competing Interest The authors declare no competing financial interest.

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Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future Directions

N. B. Singh, Tanaya Kundu, and Mridula Guin
Abstract The carbon-based nanomaterials are promising candidates in the field of
drug delivery. Their unique physicochemical properties and remarkable biocompati­bility are garnering major interest for their application in drug delivery. This chapter delivers a comprehensive overview of the past, present, and future directions of utilizing carbon-based nanomaterials for drug delivery and other biomedical appli­cations. The chapter discusses in detail about drug delivery by nanomaterials based on graphene, graphene quantum dots (GQDs), carbon nanotubes (CNTs), carbon nanodiamonds (NDs), carbon nano-onions (CNOs), carbon nanohorns (CNHs), and fullerene. Through this comprehensive examination of the past, present, and future of carbon-based nanomaterials for drug delivery, the chapter aims to provide valuable insights to researchers, scientists, and clinicians involved in developing next-generation drug delivery systems with enhanced efficacy and reduced adverse effects.
Keywords Drug delivery Carbon nano-onions
· Graphene · Carbon nanotubes · Nanodiamond ·

1 Introduction

In recent times diagnosis and treatment of chronic diseases are done through tradi­tional approaches such as chemotherapy, radiation therapy, immunotherapy, and hormonal therapy.In most of these cases, the diagnosis is delayed and target-oriented action of drugs is a major issue. This also requires several shot drug doses [1, 2]. In this respect, nanotechnology has made a great impact to overcome the shortcom­ings in this field. Now, nanotechnology-based drug delivery systems are developed
N. B. Singh · M. Guin (B) Department of Chemistry and Biochemistry, Sharda University, Greater Noida, India e-mail: mridula.guin@sharda.ac.in
T. Kundu Undergraduate Programmes, Indian Institute of Science, Bangalore 560012, India
99
100 N. B. Singh et al.
for diagnostic and treatment of diseases [35]. Drug delivery systems are defined as formulations and approaches to protect, release, and transport therapeutic agents into a targeted site [612]. Drug delivery is a process to administrate pharmaceutical compounds in humans or animals [13]. Researchers are being conducted to buildnew and novel materials for effective delivery of drugs at targeted sites [14]. Such systems have the power to treat multiple diseases very effectively. The traditional methods of drug administration have several issues. However, using of nano drug carriers has the potency of several benefits, such as selective and stronger binding to a particular site, lesser dosing frequency, better absorption, and enhanced stability and efficacy of the drug, with reductions in toxic metabolites. In recent times, different technologies using different nanomaterials havebeen developed and used [6]. Innovations in mate­rials chemistry have initially fuelled the progress of drug delivery systems, creating carriers that are biocompatible, biodegradable, targeting, and stimulus-responsive. Nanoparticles (NPs) can be employed for delivering a variety of pharmaceuticals, which is safer, and more effective [15]. Size and shape of NPs can help in navigating biological carriers. Inorganic and organic nanocarriers can be used for delivery of drugs at appropriate sites. Some important organic nanocarriers include dendrimers, polymeric nanoparticles, polymeric micelles, solid liquid nanoparticles, liposomes, and virus-based nanoparticles. Examples of inorganic nanoparticles are mesoporous silica NPs and carbon nanotubes (CNTs). Variousnanocarriers having applications in drug delivery are shown in Fig. 1 [16]. Among the nanomaterials, CNMs are found to be of much interest in the biomedical field. CNMs show different chemical reactivity and structural, morphological, and physical characteristics. Different allotropes of carbon with different applications are s hown in Fig. 2 [17].
Allotropic forms of carbon like graphite, diamonds, amorphous carbon, carbon nanotubes, carbon quantum dots, graphene, graphene oxide (GO), reduced graphene oxide (rGO), Carbon nanohorn, carbon nano-onion, and fullerene have some unique properties, which make them exciting material for diagnosis and treatment of critical diseases. They are effectively used for drug delivery system for oxidative stress­related diseases, for example, cancer, neurodegenerative diseases, and inflammation [18]. In comparison to other conventional materials, CNMs have a large specific surface area and unique features that are more suitable for use in drug delivery and medicinal applications. In this chapter, different types of CNMs have been discussed for drug delivery. Past, present, and future directions on the subject are also discussed.
2 Historical Background of Carbon-Based Nanomaterials
for Drug Delivery Applications
The historical background of carbon nanomaterials (CNMs) for application in drug delivery is a journey marked by significant discoveries, challenges, and advance­ments. CNMs for drug delivery are rooted in the development of nanotechnology and the exploration of various nanomaterials for medical applications. CNMs including
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 101
Fig. 1 Different nanocarriers for drug delivery applications. Reproduced with permission from Elsevier [16]
carbon nanotubes (CNTs), graphene, and fullerenes, have garnered a great deal of attention due to their unique properties and potential of application in drug delivery systems. The history of carbon nanomaterials begins in 1985 with the discovery of fullerenes by famous scientists Richard Smalley, Robert Curl, and Harold Kroto. Fullerenes are spherical molecules composed entirely of carbon atoms organized in
102 N. B. Singh et al.
Fig. 2 Different allotropes of carbon nanomaterial and their applications. Adapted and modified with permission from Elsevier [17]
a special way to a structure resembling a soccer ball. This discovery led to the Nobel Prize in Chemistry in 1996 [19, 20]. In the early 1990s, Sumio Iijima discovered carbon nanotubes (CNTs), which opened a new avenue for nanomaterial research, including their potential for drug delivery due to their hollow structures and control­lable dimensions [21]. During the 2000s, researchers began exploring the potential of carbon nanomaterials, particularly CNTs and fullerenes, in drug delivery applications [22].
In 2004, researchers isolated and characterized graphene that consist of a mono­layer of carbon atoms organized in a 2D honeycomb lattice. Its 2D structure and functionalizability offered advantages for loading and delivering drugs. As research advanced, carbon nanomaterials began showing promise in preclinical studies for various drug delivery applications. They were investigated for the targeted delivery of various therapeutic agents such as proteins, nucleic acids, and tiny molecules to target specific illness. The ability to functionalize their surfaces allowed for improved targeting, controlled release, and enhanced drug stability. In recent years, due to dose reduction, prolonged action, quantum behavior,target ability,etc., nano drug delivery systems particularly CNTs as drug delivery and drug carrier have increased consid­erably [23]. It is one of the most impressive element that transform material science immensely.Carbon nanotubes (CNTs) are now being used in drug delivery and diag­nostics [24]. CNTs have drawn a lot of interest in the field of biomedical science because of their extraordinary properties such as high stability, drug loading capacity, high surface area, needle-like structure, flexible interaction with cargo, biocompati­bility, excellent electrical and mechanical characteristics, considerable strength, and the capacity to supply drugs to the exact location of tissues. Apart from a number of advantages, it has some demerits such as toxicity and low biodegradability [25].
Cancer is a serious concern and it increases the mortality rate. Thus people are in search of drug delivery systems that are safe, target specific, and highly effec­tive for curing cancer. In 2021, 1,898,160 new cases of cancer and 608,570 deaths were reported in USA alone. To overcome some problems of cancer, nanomedicines were tested in diagnosis. CNMs were found to be effective drug delivery agents. They have the property of controlled drug release, prolonged delivery, and target
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 103
specific delivery of the drug, which improvesthe pharmacological activityof the drug. Therefore, CNMs specifically carbon nanotubes, carbon quantum dots, graphene, and graphene oxide, can easily replace and overcome the defect and side effects of conventional cancer treatment methods [26]. Different data bases from 1965 to 2021 were analyzed, in order to have publications on the use of CNMs for drug delivery. A lot of data on this topic were obtained from SCOPUS, within the time span of 1985 to February 7, 2022 [27]. After careful inspection of SCOPUS database, it was found that a total of 1846 publications were based on drug delivery applications of CNMs.

3 Current Status in Drug Delivery by CNMs

Carbon nanomaterials (CNMs) such as graphene quantum dots, carbon nanotubes, nanohorns, nanodiamonds, nano-onions, and graphene quantum dots have significant applications in the biomedical field. Recent development of various forms of carbon nanomaterials for drug delivery applications are discussed in this section.

3.1 Graphene-Based Nanomaterials in Drug Delivery

Graphene has received enormous research interest due to its exceptional character­istics and widespread applications in various science and technological fields, since
2
its discovery. It is a carbon allotrope comprised of monolayer sp
hybridized carbon with π-electron clouds. It has a two-dimensional honeycomb planar lattice structure. Graphene’s unique geometrical and structural features lead to its remarkable phys­iochemical properties. Young’s modulus (~1000 GPa) and fracture strength (~130 GPa) are of greater value for graphene [28]. It has a very large theoretically calcu-
2
lated specific surface area of ~ 2630 m
/g. It is a zero-band gap semiconductor whose
valence and conductance bands meet at Dirac points [29]. Graphene has low resis-
4
tivity, exceptionally high electrical (~10 mK), and rapid charge carrier mobility with a reported value of 2 × 10
S/cm) and thermal conductivity (~5000 W/
5cm2
/Vs [28, 29]. It has high mechanical strength and optical transmittance [30]. Along with these exceptional properties, graphene and its derivatives are capable of crossing biological barriers making them an attractive platform for biomedical applications, particularly in delivering drugs and biomolecules [31].
Graphene generally refers to monolayer sheets with single atom thickness. However, graphene nanomaterials include few layer graphene, bilayer graphene, graphene oxide (GO), and reduced graphene oxide (rGO). They differ in thick­ness, in-plane dimensions, purity, surface chemistry, and compositions[28]. Bilayer graphene consists of two single layers of graphene and the thickness of few layer graphene is up to 10 layers [32]. Graphene nanomaterials are mainly prepared from graphite using either mechanical or chemical method. Graphene has low solubility
104 N. B. Singh et al.
in aqueous media because of its high hydrophobic character. Its derivatives, for example, GO, which is a chemically functionalized and highly oxidized form of graphene, are often employed in biomedical applications. GO has better aqueous solubility, as it is decorated with polar functional groups having oxygen atoms, like hydroxyl (-OH), carboxylic acid (-COOH), and epoxide (–O–). The basal plane of GO has the unmodified hydrophobic graphene domains which can easily load drug molecules efficiently using π–π interactions. GO has been reduced to prepare rGO, where the oxygen containing functional groups are mostly reduced (Fig. 3)[33].
Oral administration of the drug may induce its degradation by stomach acids and enzymes, uneven distribution, rapid clearance, and low bioavailability. Drug molecules may not cross the cellular membrane or distribute poorly when these are administered intravenously [32]. Therefore, a drug carrier is desirable for immo­bilizing drug molecules to overcome these disadvantages. Graphene surface can easily be functionalized and modified to improve its characteristics, biocompati­bility, stability, and target specificity of drugs. In 2008, Dai research group reported the utilization of graphene as an effective drug carrier for the first time [34, 35]. Doxorubicin (DOX) is an anticancer drug use to treat various types of cancers by destroying the cell DNA [36]. GO has shown significant result to entrap DOX and release it to the target cell. Quinine part of DOX is involved in hydrophobic and π-π interaction with basal plane of GO, where as hydroxyl and amino groups of DOX are involved in hydrogen bonding interactions with the carboxyl and hydroxyl groups present on GO surface. These bonding interactions are strong in neutral media and become weak in acidic pH (tumor environment), which leads to the release of DOX [30, 32]. Many other anticancer drugs, such as 5-fluorouracil, camptothecin (CPT), cisplatin, paclitaxel, protocatechuic acid, mitoxantrone, zolendronic acid, have been delivered by graphene-based nanomaterials [36, 37].
Various covalentand non-covalentfunctionalization is utilized to modify graphene surfaces. Dai research group has incorporated a hydrophilic biocompatible polymer, polyethylene glycol (PEG) functionalization on GO for drug delivery applications [3436]. Other polymers, such as polyvinyl alcohol (PVA), polyethyleneimine (PEI), poly(N-isopropyl acrylamide) (PNIPAM), polysebacic anhydride (PSA), poly-L­lysine (PLL) have been coupled covalently with GO to enhance the biocompatibility [36, 38]. Electrostatic interactions, van der Waals interactions, hydrogen bonding
Fig. 3 Conversion of graphene into GO and rGO. Reproduced with permission from Springer Nature [33]