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106 Carbon-Based Nanocarriers for Drug Delivery
Diverse characterization techniques may be employed to explore the structural
and morphological properties of GO, rGO, and GO-based nanocarriers. These characterization methods include transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS),Fourier transform infrared spectroscopy (FTIR),
atomic force microscopy (AFM),energy dispersive X-ray analysis (EDX), X-ray
diffraction, and Raman spectroscopy. The single-layer geometry of GO and
GO-based nanocarriers may be observed through TEM, and AFM analysis can
be used to determine the thickness of the GO sheets. The elemental composition
may be conrmed by EDX; however, FTIR was utilized to demonstrate the existence of carboxyl, hydroxyl, and epoxyfunctional entities present withinGO. The
extent and stage of GO hybridization are investigated using XPS and Raman spectroscopic studies. After graphite has been oxidized, the defect concentration over
GO nanosheets canalso bedetermined by Raman spectroscopy. However, the XPS
survey offers details about the degree of oxidation, bonding, functional groups, and
elemental makeup. The X-ray diffraction analysismay be employed to ascertain
theinterlayer spacing, crystal structure, and crystal size of GO along with GO-based
nanocarriers.
4.3 FUNCTIONALIZATION AND MODIFICATION OF GO
In real-world applications, GO has displayedsignicant advantages due to its oxygen-
rich functional sites, large interfacial area, hydrophilic nature, and surface alteration potential. However, the aqueous stability and inclination for aggregation of
GO nanosheets haveprompted serious questions about their uses in the biomedical
eld [12,48]. Moreover, morphological and surface modication of GO to increase
its physiochemical properties is an important aspect of applications-driven studies,
which is another vast and fast-increasing eld of study. The tendency of GO to aggregate can be reduced with adequate functionalization. GO can be functionalized by
introducing additional moieties or sites that might deliver distinctive and enhanced
features to the parent GO despite losing its core characteristics [27,49,50]. Even
though the various oxygen functional groups in GO have varied properties, functionalizing GO causes a modest decrease in their oxygenated sites, which causes its
reduction and formsrGO.
The GO was functionalized via various inorganic and organic molecules to
improve its solubility and biocompatibility under physiological conditions for biomedical and drug-delivery applications. Currently, there are two techniques for functionalizing graphene oxide: covalent and non-covalent conjugation. The subsequent
sections describe the specics of each form of functionalization.
4.3.1 coValenT FUncTionaliZaTion oF go
The GO has an abundance of oxygenated sitesofcarboxy, hydroxy, and epoxy
functional groups. In GO, covalent bonding is used to link existing functional
groups to newly introduced functional groups. Covalent cross-linking is primarily used to enhance the surface properties, bio-compatibility, loading effectiveness, and release behavior of GO in drug delivery systems (DDS) [6]. Anumber
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of typical reactions, including acetylation, isocyanation, diazotization, and others,
may be carried out using the functional groups located in GO. Covalent functionalization of GO may be achieved in various ways, including by functionalizing
hydroxyl, carboxyl groups, and aromatic rings. The covalent functionalization
approach entails binding polymers with excellent solubility and biocompatibility
via esterication, click chemistry, amidation, nitrene chemistry, and radical addition [51]. Polyethylene glycol (PEG) is the most common and established polymer
that has been utilized for the functionalization of GO. Alongside, poly (vinyl alcohol) (PVA), polyacrylic acid (PAA), chitosan, and dextran are some of the other
polymers that have been extensively explored for GO functionalization in line with
drug delivery[6].
4.3.1.1 Carboxyl Group Functionalization
Due to its availability and excellent reactivity, the carboxyl functional group has been
frequently utilized to functionalize GO, which is found in enormous proportions near
theedges in GO nanosheets. The most common kind of carboxyl functionalization
comprises reaction activation, proceeded by the dehydration of hydroxyl andamino
groups to produce amide or ester couplings. Several reagents, including hexauorophosphate, thionyl chloride (SOCl2), N,N-dicyclohexylcarbodiimide (DCC), and
1-ethyl-3 (3dimethylaminopropyl)-carbodiimide (EDC), are used to carry out the
activation. Recently, Liu etal. (2019) have developed highly biocompatible and stimuli-responsive nanoparticle-assisted anticancer DDS. The nanocarrier was obtained
via covalent cross-linking of carboxyl functional groups of GO with chitosan oligosaccharide (CO), which was further adorned with γ-polyglutamic acid (γ-PGA).
The GO–CO–γ-PGA composites were obtained by an amidation coupling reaction,
and the activation of carboxylic groups of γ-PGA and GO was done with the help of
NHS and EDC. The impregnation of CO and γ-PGA on GO was further conrmed
by XPS and FTIR analysis. A well-known anticancer agent Doxorubicin (DOX)
was also loaded over the synthesized nanosystems. The designed nanocarrier had
shown superior solubility in physiological conditions with sustainable and controlled
delivery of DOX. In-vitro analysis of the synthesized nanocomposite revealed easier
transfer of nanocarriers within the HeLa cells with good compatibility to the normal
cells and higher anticancer activity for the tumor cells. The stated formulation was
found to be suitable for their future application in anticancer biomedicines [52].
In the other study, Sousa etal. (2018) developed a carboxyl-activated and functionalized nanocarrier based on the folic acid (FA) and GO of potential and targeted
drug delivery of Camptothecin (CPT) for anticancer activity. Initially, FA was conjugated with the PEG, and later it was coupled with the surface of GO. The respective
conjugation and coupling of FA-PEG and GO were conrmed via FTIR, magic-angle
spinning carbon-13 nuclear magnetic resonance (CP/MAS 13C NMR) spectroscopy,
and electrospray ionization (ESI) mass spectrometry. In FTIR spectra, the intensity
of the carboxyl functional groups declined signicantly during the functionalization process, which conrms the successful impregnation of FA-PEG conjugate on
the GO surface. The toxicity of GO-FA and GOFA + CPT was evaluated in two
extensively researched preclinical cell models: J774 and HepG2. It was observed that
the toxicity of the nanocarrier without a drug is cell type-dependent, with a higher
108 Carbon-Based Nanocarriers for Drug Delivery
survival rate for J774 and toxicity for HepG2 tumor cells. Also, the existence of FA
in the nanocarrier loaded with CPT was found to be critical for inducing apoptosis in
both cancer cell types [53].
Similarly, various other biocompatible polymers, such as PAA and PVA, have
been used for the carboxylic functionalization of GO [54]. However, the major concern regarding their application in the drug is the lack of targetability, adaptability,
and sustainable and controlled release behavior, which must be addressed.
4.3.1.2 Hydroxy Group Functionalization
A substantial proportion of hydroxyl functional groups, like carboxyl groups,
were located on the surface of GO nanosheets. The presence of the hydroxyl
group not just gives GO substantial hydrophilicity as well as better surface characteristics, but it also serves as a spacer for the covalent bonding of other ligands
at the perimeter of GO nanosheets. Through selectively functionalizing hydroxyl
groups toward orthogonal reactions under mild circumstances, Vachhi et al.
(2018) examined the reactivity of graphene oxide (GO). AWilliamson process
with an amino-terminated linker was used to functionalize the hydroxyl functional sites of GO. The acquired data revealed the formation of ether bonds. The
study described previously was also extended to ketones in order to investigate
their derivatization through the Wittig reaction. Unfortunately, the ineffective
reactions suggested that the surface of GO lacked a substantial number of ketone
functional sites. [55]. Namvari etal. (2017) demonstrated the cutting-edge innovative Reversible addition-fragmentation chain-transfer RAFT-CTA adapted rGO
for the esterication process. The proposed nanomaterial was utilized to polymerize methacrylamide (N-acryloyl-L-phenylalanine methyl ester) monomer based
on amino acids. The thermogravimetric investigation validated nanoparticles’
thermal stability over GO. In addition, the aqueous stability was examined using
zeta potential analysis; the ndings were much more acceptable. It was discovered
that the polydispersity index (PDI) diminishes as the number of monomers rises,
suggesting a well-controlled polymerization [56]. Such improvement in the hydrophilicity and the aqueous stability of GO via hydroxyl group functionalization
may provide signicant advantages for their application in the biomedical sector,
including drug delivery.
4.3.1.3 Aromatic Ring Functionalization
The functionalization of the carbon skeleton is brought on by the C=C in graphene
oxide’s aromatic rings. One example of aromatic ring functionalization is the fundamental reaction that produces diazonium salt or its derivatives inside the aromatic
rings of GOthrough diazotization. In a study by Jin etal. (2011), 4-propargyloxy
diazobenzene tetrauoroborate was mixed with 2% sodium cholate as a surfactant
for eight hours at 45 oC to functionalize graphene. Later, click chemistry was used
to elucidate the addition process in the carbon skeleton for functionalization. The
suggested technique is most advantageous, adaptable, and practical and may be utilized to develop GO composites for cancer therapeutics [57]. Unfortunately, there is
limited information in the literature on the functionalization of aromatic rings inside
GO; as a result, further investigation will be necessary.
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4.3.2 non-coValenT FUncTionaliZaTion oF go
Non-covalent functionalization is the better cross-linking approach in terms ofelectrostatic force and hydrogen bondingbetween GO and GO functional compounds
for preserving the core structure and distinctive characteristics of GO while improving stability and dispersibility in an aqueous solution. The key components of noncovalent functionalization include hydrogen bonds, electrostatic interactions, and π-π
bonds. The notable characteristics of these types offunctionalization approach are
the gentle working conditions, which preserve the parent structure and characteristics
of GO. Various research outputs have claimed signicant improvements in the drug
loading capacity, controlled and sustainable release behavior with better biocompatibility and anticancer activity of the nanocarriers synthesized via non- covalent
bonding of functional entities to the GO. Some of them are discussed subsequently,
along with the details of the functionalization mechanism.
4.3.2.1 Hydrogen Bond Functionalization
The most adaptable approach for the functionalization of GO and rGO in the noncovalent functionalization approach ishydrogen bond functionalization. The importance of GO functionalization via hydrogen bonding has been demonstrated by a
number of research ndings. Xie et al. (2016) synthesized chitosan (CS)/dextran
(Dex) functionalized GO via a non-covalent layer-by-layer self-assembly method.
The cationic and anionic polyelectrolytes, namely, CS and Dex, were deposited
directly over the surface of GO, and the process was conducted through both hydrogen bonding and electrostatic interactions. Both of these polyelectrolytes are biocompatible, providing suitable adaptability for drug delivery. In this regard, the GO/CS/
Dex nanocomposites were further used for the loading of the anticancer drug DOX.
It was observed that the polyelectrolyte deposition had upgraded the dispersibility
of both the DOX-loaded and pristine GO in physiological surroundings, along with
the reduction in the nonspecic protein adsorption of GO. The DOX-loaded nanocomposites showed prominent pH-responsive drug release behavior and exhibited
signicant anticancer activity toward the MCF-7 cancer cells [58].
Similarly, Hu etal. (2016) demonstrated a novel one-pot synthesis of Dex-coated
rGO nanocomposites for the targeted photo-chemotherapy, where rGO was synthesized using Dex as a reducing agent. During the reduction process, the Dex was
directly coupled with the rGO nanoparticles via hydrogen bonding to form a selfassembled rGO/Dex nanocomposite. In this study, the Dex conjugation improved
the DOX loading capacity (10.85%) and the aqueous dispersibility and biocompatibility of the rGO/Dex nanocomposite. The DOX-loaded rGO/Dex nanocomposite
displayed efcient anticancer activity for B16F10 cells and achieved the therapeutic level in a short time with a lower concentration of DOX. In addition, the oligopeptide molecules (RGD) were introduced over the rGO/Dex nanocomposite to
improve the intracellular uptake. The DOX-loaded rGO/DOX/Dex and rGO/DOX/
RDex nanocomposites exhibit greater cytotoxicity under NIR irradiation than the
control groups, indicating their efcacy in photo-chemotherapy [59]. Overall, the
functionalization of GO with CS/Dex via hydrogen bonding resulted in improved
dispersibility and stability in aqueous conditions, as well as sustained and regulated
110 Carbon-Based Nanocarriers for Drug Delivery
drug release, which is enormously helpful for biomedical applications. Nevertheless,
the drug loading capacity of the GO functionalized nanocarriers was not satisfactory
for the DOX, which can be improved via the impregnation of nanomaterials such as
metal-organic frameworks (MOFs) of porous structure and higher surface area.
4.3.2.2 Electrostatic Interaction
An additional approach for the functionalization of GO is the electrostatic interactions among the negatively charged surface of GO and other nanomaterials or
functional entities with a positive surface charge, such as chitosan, liposomes, and
metal nanoparticles. Prasad etal. (2019) recently developed novel graphene oxidefortied liposomal (GOF-Lipo) nanohybrids for the red emissive nano delivery system. The nanohybrid was further functionalized with the tumor-targeting ligand,
folic acid (FA). The functionalization was established via electrostatic interaction
among the negatively charged GOF and positively charged dipalmitoylphosphatidylcholine (DPPC) lipids. The obtained GOF-Lipo and GOF-Lipo-FA conjugates
were loaded with a chemotherapeutic agent, DOX-HCL, and studied further for the
in-vitro cytotoxicity over the breast cancer cell lines, MDA-MB-231 and 4T1 for
combined chemo-photothermal therapy (PTT). The nanohybrids have shown superior aqueous dispersibility, quick photothermal response with 90% cell viability and
hemocompatibility. The combined Chemo-PPT was more effective than the sole
chemo or PTT therapy [60].
Kavinkumar et al. (2017) proposed a green chemical approach for the synthesis of silver nanoparticles (AgNP) and the composites of GO and rGO with AgNP
using vitamin C as a reducing agent. The functionalization was established via electrostatic interaction between negatively charged GO, rGO surface, and positively
charged AgNP. Further, the anticancer activity of AgNP, GO, rGO, GO-AgNP, and
rGO-AgNP nanocomposites were demonstrated for the human lung cancer cell line.
The rGO-AgNP nanocomposites have displayed superior anticancer for A549 cells
among the other nanocomposites, with an IC50 value of 30 µg/mL. The higher anticancer activity of the rGO-AgNP was accomplished due to its de-agglomeration tendency. In addition, the electrostatically functionalized rGO-AgNP nanocomposite
was found to be more biocompatible while reducing the toxicity and corrosiveness
of AgNP [61].
It was found that in cancer therapeutics studies, the electrostatic interaction phenomenon was extensively used for material functionalization. However, the drug
loading capacity of the functionalized materials was not very signicant, which can
be improved via the introduction of micro-mesoporous materials. As the loading
capacity and sustainable release are important parameters for reducing the dosing
frequency of chemotherapeutic agents/drugs, further efforts must be made to address
these issues.
4.3.2.3 π-π Bond Functionalization
As the structure of GO comprises sp2 hybridized carbon atoms, additionally, the
GO sheets offer strong π-π bond interactions, which render them favorable for
protein adsorption, photodynamic treatments, and interfacial adhesion for the
reinforcement ofpolymer matrix. Recently, Zhao etal. (2018) developed various
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polymer chain congurations to explore the interactions across polymers and rGO
through π-π bonds. Several polymers of diverse chain congurations were used
for the investigation, including 2-vinyl naphthalene with naphthalene rings and
4-cyanostyrene with substituted phenyl rings. The polymer-rGO nanocomposite
has been developed byutilizing the solution blending technique with chloroform
as a solvent. To assess the strength of π-π bond interactions, Raman spectroscopy
and TGA analyses were conducted to examine the developed nanocomposites [62].
The π-π stacking was observed as a common phenomenon for drug loading. In
most of the studies, the hydrophobic interaction and π-π bond functionalization are
considered a mechanism behind the attachment of drug molecules to the hydrophilic surface of GO [63,64]. There is no direct evidence over the functionalization
of GO by certain additives via π-π bond functionalization for the drug deliveryrelated application.
4.4 GO-BASED NANOCARRIERS AS DRUG DELIVERY SYSTEMS
The procedure of administering a pharmaceutical ingredient within an organism to
obtain a therapeutic effect is called drug delivery. Synthesis of the active pharmaceutical ingredient, mode of administration, target site selection, metabolism, and
toxicity are all aspects of drug delivery that fall under this category. Some current
initiatives in the arena of drug delivery focus on enhancing the efciency of the drug
in a resistant system or developing tailored delivery systems that are only active in
their intended location.
Graphene oxide (GO) has several characteristics that make it appealing for therapeutic and biomedical pertinence. The most attractive is its water solubility. It also
enables hassle-free attachment of drugs through functional group linkages. The
enormous surface area of GO aggrandizes the drug loading efciency. GO at the
nanoscale level has been used to deliver anticancer medicines and aptamers for gene
delivery directly in living cells [65]. This section discusses the different approaches
in which GO-based nanocarriers are employed to release therapeutic moieties at specic places within an organism to alleviate calamitous ailments like cancer, genetic
disorders, and neurodegenerative diseases.
4.4.1 cancer TreaTmenT
The practice in which chemicals are used to destroy cancerous cells is known as
chemotherapy. Chemotherapy is one of the most prevalent cancer treatment options,
among others, such as radiation therapy, hormone therapy, surgery, etc. The mainstream drugs used in this procedure are insoluble or less soluble in water. Thus,
the capacity to properly administer nonsoluble cancer medications has emerged as a
critical focus of research [6].
In 2008, Liu et al. used GO as a nanocarrier to convey insoluble chemo-drugs
for the rst time [66]. SN38, Camptothecin (CPT) analog, was loaded onto GOPEG
via physical adsorption to create GOPEG-SN38. In this situation, water-soluble
GOPEG-SN38 demonstrated identical toxicity to SN38 in DMSO and considerably
greater effectiveness than iriotecan, with a loading drug percent estimated at 10%
112 Carbon-Based Nanocarriers for Drug Delivery
(CPT-11). The rst-time doxorubicin (DOX) binds to an NGO PEG was reported by
Sun etal. in the NGO PEG/DOX DDS [67]. The previously mentioned studies are
considered pioneers in the GO-polymer drug delivery system. Various other drugs
were investigated for chemotherapy that was delivered via GO nanocarriers. Pham
etal. (2019) employed alendronate (AL), an FDA-approved second-generation bisphosphonate for treating tumor-associated hypercalcemia and various bone-related
disorders, coupled with PEGylated graphene oxide nanocarriers to increase DOX
accumulation. The DOX@PEG-GO-Al was reported to release more than 60% of
the load at pH 4.5. In comparison, about 14–18% of DOX was released in a pH 7.4
environment, demonstrating the pH selectivity of the nanocarrier. According to these
ndings, PEG-GO-ALs seem to be helpful in treating bone cancer by increasing
antitumor effects and reducing off-target toxicity [68].
Kakran etal. (2011) functionalized biocompatible and hydrophilic moieties such
as Maltodextrin (MD), Pluronic F38 (F38), and Tween 80 (T80), to GO in 2011
for loading and delivery of ellagic acid (EA), a sparingly water-soluble antioxidant
and anticancer medication. This system had a 114% load capacity for the GOMD, a
100% loading capacity for GO-F38, and a 122% loading capacity for the GO-T80. In
human breast cancer cells (MCF-7) and human colon adenocarcinoma cells, the EA
release rate was pH-dependent and reported to have a more potent cytotoxic effect
than free EA dissolved in DMSO (HT29) [69].
Although in-vitro and in-vivo studies have been carried out successfully for several chemo-agent loaded onto GO-based nanocarriers, clinical trial studies have not
been concluded yet due to the government’s stringent regulations worldwide.
4.4.2 gene Therapy
Gene therapy refers to any method that involves genetically altering a patient’s
cells to combat the ailment. Genes oligonucleotides or gene fragments that have
essentially been introduced into patient cells are the drugs in this situation. Vectors that can be used to deliver genetic material within a host cell may be viral or
nonviral. Overall, there has been some success with very few adverse effects. For
instance, compared to the former cancer treatment via gene delivery, retrovirus
integration into the human genome with the danger of mutagenesis and subsequent malignancies, risk of virus or tumor immunogenicity, and treatment resistance followed by resumption of the disease are some of the factors that have all
been considerably lowered [6]. With great biocompatibility, the ability to identify
cancer cells by surface alterations, and controlled release techniques, GO-based
nanocarriers seem to be a compelling option as a nonviral vector for delivering
genes into cancer cells.
Feng etal. (2011) developed GO-PEI complexes with two distinct PEI molecular weights, GOPEI-1.2k and GOPEG-10k, for the purpose of gene transfection.
The GO-PEI nanocomplexes were shown to attach to plasmid DNA (pDNA) and
were then utilized to transfect HeLa cells intracellularly with the enhanced green
uorescence protein (EGFP) gene. The high level of EGFP expression seen with
GOPEI-1.2k/10k and the lower toxicity of the GO carriers demonstrate the systems’
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suitability for use in this sort of application [70]. Additionally, several studies
employed the GO-PEI method to determine transfection effectiveness and the optimal transport of pDNA to the nucleus [71]. Feng etal. (2013) created a dual-polymer
GO. They created a dual-polymer-GO (GO-PEG-PEI) by combining PEG and PEI.
GO-PEG-PEI demonstrated better gene transfection efcacy without serum interference and decreased cytotoxicity [72]. For the rst time, aided transfection was
investigated using low-power NIR laser irradiation, where the photothermal effect
may have increased the permeability of the cell membrane, resulting in increased
transfection efciency. The precise contribution describes utilizing the same nanocarrier to distribute siRNA under regulated conditions.
Chen et al. (2021) linked anti-EpCAM, a tumor-specic monoclonal antibody,
to GO-CS via a π-π interaction after chitosan (CS) was conjugated to GO surface
via amide bonds (GO—CS). To properly distribute siRNA, a new carrier GO—CS/
anti-EpCAM (GCE) was synthesized. The delivery mechanism of GCE was studied in detail using survivin-siRNA. Survivin-siRNA was well protected in-vitro by
the GCE, which demonstrated improved loading performance, stability in various
solutions, and good protection in-vitro. Apoptosis is enhanced by silencing survivin,
which prevents cancers from developing and metastasizing. The study reported that
the GCE encapsulated survivin-siRNA and slowed the growth of MCF-7 breast cancer cells [73].
The promising results from various other studies in gene therapy via GO nanocarriers have raised the hopes of those awaiting treatment. Though this is still a farfetched idea, the approvals from regulatory bodies will take substantial time since
the technology and its effect on humans are relatively unfamiliar.
4.4.3 Therapy For oTher inFirmiTies
The recent advances in biomedical and pharmaceutical research have led to expanding various systems to treat life-threatening diseases. The role of these systems was
either therapeutic or diagnostic, or both in the form of theranostics. Among various
nanomaterials, GO has been extensively implemented for biomedical applications
due to its countless excellent properties, like facile preparation methods, higher
drug loading capacity, and decent biocompatibility. Previous research ndingshave
demonstrated that the use of GO also offers numerous benets in treating severe
braindisorders of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease, along with tissue engineering and regenerative medication. The neurodegenerative diseases (NDs) are characterized by continuous damage of brain neurons,
resulting in vocal, cognitive, and motor dysfunction. Such neuron dysfunction can be
recovered via sustainable delivery of the natural drug puerarin (Pue) via nanocarriers
to the brain cells. GO, with a 2D structure and higher surface area with its functionalized form, can be used as a biocompatible drug nanocarrier for NDs as well as a
substrate for cellular interactions and can carry biomolecules, including DNAs for
tissue engineering (TE).
Recently, Xiong etal. (2021) developed a GO-based targeted DDSs for Parkinson’s disease (PD). The GO nanosheets were loaded with the Pue, which has shown
114 Carbon-Based Nanocarriers for Drug Delivery
superior drug loading efciency of 69.01% with modied surface functional groups
and better biocompatibility. The Pue was successfully carried across the blood-brain
barriers (BBBs) into the brain with the help of lactoferrin (Lf) targeting ligand. The
obtained Lf-GO-Pue nanosystems presented reasonable efciency for brain targeting in both the in-vitro and in-vivo analyses. In addition, this nanoplatform did not
show any toxicity or adverse effects on the major organs, indicating its potential for
treating Parkinson’s disease [74]. Wang etal. (2021) demonstrated a dauricine (Dau)
loaded GO nanoformulation for investigating the collective antioxidative and antiinammatory stress effects of Dau with avoiding the aggregation and misfolding of
amyloid-β (Aβ) protein by GO. Aβ1–42 was used to induce in both the in-vitro and
in-vivo models, and the nanoformulation was delivered nasally to mice. The results
showed that for in-vitro, GO-loaded with Dau signicantly decreased oxidative stress
by raising superoxide dismutase levels and lowering malondialdehyde and reactive
oxygen species (ROS) levels. In addition, nanoformulation has lightened cognitive
memory decits and activated the brain glial cells in mice. The study had proven the
effectiveness of GO loaded with Dau for protecting against Aβ1–42-induced oxidative damage for Alzheimer’s disease [75].
The tissue engineering (TE) eld regenerates or reproduces the damaged organs
or tissues by engineering scaffolds, a combination of cells and biologically active
molecules. Aperfect scaffold may transport active biomolecules, provide appropriate physiological signals, stimulate the mechanical features of native tissue,
and serve as a platform for live cells to connect, proliferate, and differentiate. The
use of GO as a biocompatible material for tissue regeneration and drug delivery
has recently piqued the interest of investigators. GO has the capacity to adsorb
numerous proteins and stick to cells due to its huge surface area and π-conjugated
structure, making it an effective and viable candidate for use in ligament tissue
regeneration. The specic application of GO in tissue engineering is presented in
Figure4.4 [76].
Recently, Purohit et al. (2020) synthesized graphene oxide-nanohydroxyapatite
(GO-nHAp) nanocomposites as reinforcing agents for developing gelatin-alginate
(GA)-based 3D polymeric scaffold. The scaffold was made by freeze-drying, which
demonstrated the collaborative inuence of each component in tissue regeneration
and established signicant physicochemical properties. The substantial swelling of
the scaffold in the presence of water suggests that it is muchhydrophilic, implying that it is suitable for tissue regeneration. It was found that the incorporation of
GO-nHAp nanocomposites has improved the compressive strength of the scaffold to
14.72 MPa while reducing the biodegradation rate. The biocompatible and less biodegradable property of the scaffold provides signicant advantages for bone tissue
engineering [77].
Similarly, numerous studies have demonstrated the effective utilization of
GO-based nanocarriers for skin regeneration [78], cardiac tissue regeneration [79],
and muscle regeneration [76,80]. Overall, GO presented superior performance and
ability for drug delivery in cancer therapeutics, gene delivery, and regenerative medication, which could signify a versatile solution for diseased patients. Despite the
encouraging results of biocompatibility studies of GO, further investigations are
required on the side effects and toxicity aspects of GO.
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FIGURE 4.4 Application of GO in Tissue Engineering. [Reprinted with permission from
Maleki et al. (2021)] [76].
4.5 SUMMARY AND FUTURE PROSPECTIVE
The unique characteristics of graphene-based nanomaterials have encouraged the
world community for their application in various scientic and technological sectors, including the biomedical eld. Specically, GO, with its oxygen-enriched
functional entities, better surface area, and functionalization abilities, is a standout
candidate for biological application where the interaction/combination of molecules with the surface of nanocarriers is obligatory. At the initial stages, GO-based
nanocarriers suffered from low solubility and aqueous stability issues, limiting
their use as drug delivery vehicles for biomedical applications. However, covalent
and non-covalent functionalization approaches can resolve these issues, fortifying
GO as an effective nanocarrier for the DDS. The present chapter elaborated on
the details related to the synthesis, functionalization, and application of graphene
oxide, graphene oxide-based nanocarriers in drug delivery for cancer treatment,
neurodegenerative treatment, and tissue engineering. GO, rGO, and functionalization of GO through covalent bonding and non-covalent bonding interactions
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