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166 Carbon-Based Nanocarriers for Drug Delivery
6.4 FUNCTIONALIZATION OF GRAPHENE QUANTUM DOTS
The science world is currently concentrating on GQDs due to their inherent surface
characteristics, which make them suitable for various biomedical and photovoltaic
applications. Thecharacteristics of GQDsmay be tuned by adjusting the size, shape,
surface chemistry, edge orientations, and chemical functionalization. GQDs are well
adaptable for their functionalization, which signicantly contributes to various biomedical applications such as drug delivery, biosensing, phototherapy, bioimaging,
and gene delivery [53].The chemical adsorption of molecules avoids the breakdown
of the carbon skeletonwithout interstitial contaminants, rendering the functionalization process in GQDs a potential strategy. Functionalization within the GQDs is
much more signicant since it assists in tuning their surface characteristics, which
is favorable for various applications, including biomedical. The surface functionalization process also contributed to altering the optical, catalytic, and biologicalcharacteristics of GQDs by promoting electron transfer and the existence of functional
entities such as carboxyl, amine, hydroxyl, and other biological receptors targeted
groups. The existence of these functional entities on the surface as well as on the
edge of GQDs has broadened the eld of study [54]. Through selecting raw substrates
that have the desired functional entities, functionalization can take place throughout
the synthesis processof GQDs or bypost-synthesis via molecular attachment. Qian
etal. (2013), during their theoretical and experimental study of the surface chemistry
of functionalized GQDs,found that the diamines had the highest potential to govern
the optical characteristics or quantum yield of GQDs due to their extraordinary protonation phenomena (Figure6.3) [55].
In some instances, cross-linking with alkylamines such aspolyethylene glycolamine (PEG-amine) and poly-ethylenimine (PEI) and amino compounds cause a
red and blue shift in the PL of GQDs. For example, Jin etal. (2013)examined both
theexperimental and theoretical evidence to demonstrate that the band gap is lowered by the charge transport out from surface functional entitiesto GQDs as a result
ofthe higher electron density and the inducedred-shifted PL [56]. To investigate the
biocompatibility of functionalized GQDs, Yuan etal. (2014)have compared the cytotoxic effects of three GQDs tailored via various functional groups (NH2, COOH, and
CO-N (CH3)2, respectively) on the distribution of the cells in A549 and C6 cells. The
results obtained after the cytotoxicity study indicated thateven at a concentration of
200 µg/mL, there was no upsurge in apoptosis or necrosis, which demonstratesthat
even after being modied with distinct functional entities, GQDs wereableto maintain their outstanding biocompatibility. Such an exclusive characteristic of GQDs can
signicantly enhance their adaptability in numerous biomedical applications [57].
Markovic etal. (2012)investigated the molecular pathways of GQD-mediated photodynamic cytotoxicity, discovering that the development of oxidative stress resulted in
in-vitro photodynamic cytotoxicity, with consequent activation of both theapoptosis
and autophagyhaveprogrammed cell death [58]. However, investigations on human
breast cancer have demonstrated that GQDs may quickly enter the cytoplasm and
do not obstruct cell growth, as they are not harmful substances.These cytotoxicity
research ndings at the cellular level support the use of GQDs in biological applications. But as a warning, greater emphasis must be placed on the efcacy of GQDs
167Graphene Quantum Dots for Drug Delivery
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FIGURE 6.3 Schematic Representation of Synthesis of Functionalized GQDs with Specied
Diamines, Glycols, and Dithioglycols. [Reproduced with permission from Qian et al. (2013)] [55].
by researching their cellular absorption processes and intracellular and in-vivo metabolic routes of toxicity [59].
6.5 APPLICATION OF GRAPHENE QUANTUM
DOT-BASED NANOCARRIERS
GQDs have been used extensively for several years for theirapplications in the biomedical eld dueto their favorable cytotoxicity, numerous receptors, facile surface
modication, and superior biocompatibility.In several instances, GQDs have demonstrated certain exceptional abilities that enable them to take the place of the conventional nanomaterials presently used across this eld. Researchers areconstantly
investigating the prospects of GQDs for various cutting-edge medical applications
owing to the intriguing and encouraging results. This section primarily focuses on
the most current developments in the utilization of GQDs in the elds of drug delivery, gene delivery, and photodynamic therapy.
6.5.1 DrUg DeliVery
GQDs have drawn much attention for applications in drug administration because
of their intriguing physicochemical and biological characteristics. Numerous functional groups found on the edges of GQDs offer effective binding sites fortherapeutics, drugs, and targeted ligands. Additionally, the occurrence of sp2 carbon in
168 Carbon-Based Nanocarriers for Drug Delivery
the structure of GQDs enables the attachment of chemotherapeutic drug compounds
that often involve aromatic rings to the surface of GQDs, boostingthe drug loading efciency [22,60]. Moreover, owing to the poor water solubility ofchemotherapy, drugs like doxorubicin (DOX)andmethotrexate (MTX) cannot be efciently
transported to a particular tissue in the body. Such chemotherapeutic agents can be
efcientlytransported through a hydrophilic carrier of a highersurface-to-volume
ratio, such asGQDs. GQDsprovide multiple binding sites for theliking of drug moleculesthrough π-π stacking onto the basal plane. According to Nahain etal. (2013),
the use of hyaluronic acid (HA) (GQD-HA) as a targeting mediator allows for the
effective and precise distribution of graphene quantum dots (GQDs). Their study
hasdemonstrated that HA has been attached to a GQD that admits the intriguing
adhesive characteristics of the catechol moiety dopamine hydrochloride attached to
HA (Figure 6.4a) [61]. The uorescence spectra showed substantial uorescence
intensity despite the attachment of HA, and the transmission electron microscopy
determined that the particles were around 20 nm in size. In-vivo bioavailability analysis showed that the tumor tissue emitted more intense uorescence when the produced GQD-HA was administered to CD44 receptor highly expressed tumor-bearing
female mice (Balb/c). In-vitro cellular imaging revealed high uorescence from
CD44 overexpressed A549 cells. Outcomes from both in-vivo and in-vitro experiments demonstrated the benet of employing HA as a targeting agent. Thekinetic
study on the loading and release behaviorof the hydrophobic drug DOX from a GQD
under moderately acidic circumstances demonstrated that a GQD might be believed
to be a novel drug carrier. In addition, the MTT assaygreatly endorsedthe designation of GQD-HA as a biocompatible conjugate [61].
Further, Wang etal. (2013) demonstrate that the unique structural characteristics of GQDs provide an excellent potential for drug distribution and an upsurge in
anticancer effectiveness despite prior premodication (Figure 6.4b) [23]. Employing theDOX/GQD conjugates, they might effectively distribute DOXto the nucleus
since the nanoconjugates follow distinct cellular and nuclear internalization routes
than free DOX. Additionally, the nanoconjugates might signicantly increase DOX’s
DNA cleavage activity. This improvement greatly increased DOX’s cytotoxicity
when coupled with effective nuclear delivery. Moreover, the DOX/GQD conjugates
could upgrade the chemotherapeutic efcacy of anticancer agents whose effectiveness is subpar owing to drug resistance by increasing the nuclear absorption and
cytotoxicity of DOX to drug-resistant cancer cells [23].
Recently, Nasrollahiet al. (2020) have used ferritin protein nanocages to incorporate GQDs in order to establish multifunctional platforms for cancer treatment and multimodal imaging. It wasanticipated that encapsulating ultra-small
GQDs would improve overall bioimaging performance whileslowingdown their
rapid elimination from the body. GQDs and iron are encased within the core of
AfFtn-AA to increase the usefulness of protein nanostructure as multimodal
imaging nanoprobes, which areprocient for both uorescence and magnetic resonance imaging (MRI).The AfFtn-AA isan articial ferritin nanocage made from
Archaeoglobus fulgidus, an archaeon. The development of the GQD-iron complex
in the ferritin nanocages ((GQDs/Fe)AA) is accomplished by iron-mediated selfassembly of ferritin dimers that results in the co-encapsulation. The (GQDs/Fe)AA
FIGURE 6.4 (a) Hyaluronic Acid (HA)-Based Target Delivery of GQDs and Subsequent Drug Release from the GQD’s Surface in a Habitat of Cancer
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Cells. [Reproduced with permission from Nahain et al. (2013)] [61], (b) Mechanism for the Delivery of DOX from GQD/DOX Nanoconjugate. Reproduced with permission form Wang et al. (2013) [23], (c) Schematic Representation of Synthesis of CMC/GQD Hydrogel for the Loading and Release of
DOX from the DOX-Loaded CMC/GQD Nanocomposite. [Reprinted with permission from Javanbakht et al. (2018)] [63], (d) Formation of the Drug-
Loaded GQDs-CS Hybrid Xerogel. [Reproduced with permission from Lv et al. (2016)] [64].
169Graphene Quantum Dots for Drug Delivery
170 Carbon-Based Nanocarriers for Drug Delivery
demonstrates excellent pH-sensitive uorescence with excellent relaxivities on
MDA-MB-231 cells as well as substantial relaxivities in MRI. (GQDs/Fe)AA displays minimal cytotoxicity on the cells with higherloading efciency(35%) for
DOXas a drug carrier as well as an imaging agent. Overall, the pH-responsive
uorophore, MRI agent, and drug nanocarrier properties of the (GQDs/Fe)AA
demonstrate intriguing implications in cancer diagnostics and therapeutics [62].
Javanbakht etal. (2018) synthesizeda new hydrogel nanocomposite lm exhibiting antitumor capabilities byemploying GQDas a nanoparticle in carboxymethyl
cellulose (CMC) hydrogel with DOX of broad-spectrum anticancer activities
(Figure6.4c) [63]. Three distinct buffer solutions ofpH 7.4, 7, and 4.5were used
for drug release investigations, and the MTT assay was used to assess the effectiveness of DOX-loaded CMC/GQD nanocomposite hydrogel lms toward blood
cancer cell lines(K562). The produced hydrogel lms displayedimproved in- vitro
swelling, breakdown, permeability, and pH-sensitive drug delivery capabilities
while being nontoxic to blood cancer cells (K562). The acquired ndings support the application of these nanocomposite hydrogel lms as antitumor lms and
DDS [63]. Lv etal. (2016) established the synthesis of highly uorescent GQDschitosan (CS) hybrid xerogels. The proposed method provided a space to regulate
the morphology of the xerogels by altering theamount of GQDs in the xerogel
(Figure6.4d) [64]. It was observed that when the GQDs concentration in the xerogel
approached 43% (wt%), the GQDs-CS displayed a porous andthree- dimensional
(3D) framework, which was advantageous for theloading as well as the sustained
release of drug molecules. The GQDs-CS may be used for in-vivo imaging in its
as-prepared state as it demonstrated robust blue, green, and red uorescence upon
stimulation at various wavelengths. Additionally, the pH-dependent drug release
behavior of thexerogel can be mediated by the pH-tempted protonation/deprotonation of the -NH2 groups on chitosan chains [64].
Similarly, numerous research ndings have advocated the application of GQDs
and GQD-based nanoconjugates in drug delivery. However, the toxicity of these formulations is still demanding improvement for their large-scale synthesis and commercial use. The use of green synthesis approaches and natural chemotherapeutic
agents can improve the biocompatibility of GQD-based nanoformulations, which
must be explored for their applicability.
6.5.2 gene Therapy
Despite most studies focusing on drug delivery to tumors, GQDs have demonstrated
signicant potency for the distribution of various substances, including DNA and
peptides. Delivering nucleic acids (DNA or RNA) to cells with the goal of increasing or restoringgene expression to treat disease is a crucial aspect of gene therapy.
GQDs’ capacity to penetrate the blood-brain barrier (BBB) and transport nucleic acid
cargo to cell cytosols and nuclei is due to their small size. GQDs are a great possibility for gene carriers due to their minimaltoxicity, strong solubility, and luminescent
features that make it simple to monitor drug release.
Recently, Ghafary etal. (2017) developeda novel nanoconjugate with gene delivery and real-time tracking and capabilities, which is made up of GQDs, the chimeric
171Graphene Quantum Dots for Drug Delivery
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peptide MPG-2H1, and plasmid DNA (pDNA) (Figure 6.5) [65]. Through noncovalent interactions among each component, the nanoconjugate was developed. In
comparison to the standard peptide-pDNA combination, the improved complex has
achieved transfection efciency that was almost eight times higher. The ndings of
this work indicate that GQDs may be an effective transfection vector for applications involving gene delivery. GQDs offer increased drug loading relative to certain
other nanomaterials drug carrier systems because of the substantial existence ofthe
sp2 domainand the potential for π-π stacking. Unfortunately, the active sites on the
edge of GQDs are likely to be conned to ligands, which makes it unlikely that they
will be used in gene delivery applications as these biomolecules must be covalently
attached to the edge groups [65].
FIGURE 6.5 Assembling of MPG-2H1/pDNA/GQDs Complexes by Non-covalent Interactions, Transfection into Cells, and Excitation. [Reprinted with permission from Ghafary et al.
(2017)] [65].
172 Carbon-Based Nanocarriers for Drug Delivery
Additionally, novel nanoconjugates were designed by Xiao et al. (2016), in
which the GQDs were coupled with neuroprotective peptide glycine-prolineglutamate (GQDG) andgiven to APP/PS1 transgenic mice. It was demonstrated that
GQDs and GQDG might prevent the agglomeration of Aβ
brils in-vitro tests
1–42
using ThT and CD. To test the memory and learning abilities of APP/PS1 transgenic
mice, a Morris water maze was used. In comparison to the Tg control groups, the surface area of Aβplaque deposition decreased in the GQDG group. Likewise,immunohistochemistry testing was performed on freshly formed neural precursor cells
and neurons. Moreover, neurons were gene-gun-impregnated with DiI to display a
dendritic spine. The ndings of this study displayedan improvement in memory and
learning function, and more dendritic spines were detected. ELISA and suspension
array were used to test amyloid-β (Aβ)and inammation factors, respectively.
As compared to the control group, the levels of many pro-inammatory cytokines
(IL-1α, IL-1β, IL-6, IL-33, IL-17α, MIP-1β, and TNF-α)were lower in the GQDG
group. In contrast, the GQDG group showed advanced levels of anti-inammatory
cytokines (IL-4 and IL-10) than the Control group. Thus, they have shown that the
GQDG is an effective medication for treating neurodegenerative conditions like Alzheimer’s disease [66]. Recently, Ahn etal. (2021) demonstrated the synthesis of positively charged NGQDs and utilized them to transport genes like pDNA and mRNA.
PEI and citric acid were employed as substrates for the NGQD synthesis to result in
positive charges. By using microwave-assisted hydrothermal processes, NGQDs were
synthesized, and they were examined using TEM, DLS, FT-IR, XPS, and Raman
spectroscopy. The comprehensive characterization results indicate that NGQDs are
made up of hydrophilic groups like carboxylic acid and amine and a hydrophobic
graphene domain. It has been established that thepositively charged NGQDs effectively transfect cells and engage to model pDNA and mRNA, which are representative forms of gene therapy constituents. When compared to Lipofectamine, the “gold
standard” for in-vitro gene transfection agents, NGQDs’ gene transfection efciency
was found to be equivalent. The NGQDs performed better against Lipofectamine,
even in the instance of mRNA transfection. Given the past research on the intracellular distribution of NGQDs, they have anticipated that NGQDs would be used in the
therapeutic setting byfollowing more research on their toxicity and metabolism [67].
Although GQD research and gene delivery applications are still in their early
stages, the remarkable prospective of GQD-based nanocarriers has recently been
demonstrated, and we have good cause to think that this innovative nanomaterial can
give more types of medications.
6.5.3 phoToTherapy
Phototherapy is a nonintrusive therapeutic procedure that utilizes uorescent light to
address a variety of diseases. It is separated into two sections: photodynamic therapy
(PDT) and photothermal therapy (PTT). During diagnostics, the therapeutic agent is
supplied to the ailment site (tumors), which is further photoexcited via exposure to
light of a certain wavelength. Cells are destroyed in PTT by the photothermal agent
(PT), which absorbs near-infrared (NIR) light and produces heat. Contrarily, PDT
uses photosensitizers (PSs), which, when triggered by light, produce ROS that, in
response, inducescell damage. Figure6.6 illustrates the phototherapy mechanism
FIGURE 6.6 Schematic Representation of the Phototherapy Mechanism of GQDs. [Reproduced with permission from Kumar et al.
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(2022)] [21].
173Graphene Quantum Dots for Drug Delivery
174 Carbon-Based Nanocarriers for Drug Delivery
of GQDs. The upsurge in thesystemic adverse effects when standard radio and chemotherapies are used to treat tumors is the biggest concern [21,68]. Due to their
exceptional features, much more effective treatment behavior, and negligible adverse
effects, nanomaterials such as GQDs designed for PTT and PDT have demonstrated
remarkable prospects.
The development of therapeutic agents of the next generation indicates thatphototherapy willbe the best method of treating cancers. In addition to killing cancer
cells, phototherapy treatments can also assist in makingother therapeutic treatments
like radiation, gene therapy, and chemotherapy more effective [21]. PTT, in particular, enhances the therapeutic impact of radiotherapy and chemotherapy. PTT
induces hypothermia, which increases blood ow inside tumors and boosts oxygen
delivery to tumors. In addition, enhancing the permeability of the cell membranes at
the tumor locations may improve drug absorption as well as a release into the cells.
In a similar manner, ROS produced by PDT encourages drug distribution at the
location of the tumor and prevents drug release from tumors to increase the effectiveness of chemotherapeutic drugs. Phototherapies can be effectively enhanced by
the application of different photothermal (PT) and photosensitizer (PS) substances.
These substances might be, among other derivatives of carbon, metal nanostructures, 2D oxide nanoparticles, and semiconducting polymer quantum dots. Such
nanoparticles were employed as possible phototherapeutic agents, particularly for
cancer treatment [21,69].
In contrast, carbon nanomaterials with adequate dimensions and substantial surface areas work well as drug carriers for therapeutics. The effective usage of nanostructured materials in phototherapies such as CNTand graphene with its derivatives
are ascribedto their signicant instinctual absorption properties in the wide wavelength range (750–1700 nm). In addition, the carbon-based nanomaterials aggregate
specically in tumor locations as a result of their superior retention and permeability
characteristics. Because of their small size, nanoparticles can attain these characteristics and offer perfect contenders for a variety of therapeutic applications. The
GQDs have also drawn the greatest attention over the past decade among all other
carbon nanostructures because they possess good characteristics that make them
ideal phototherapeutic agents [70,71].
Due to their comparatively tiny diameters (20 nm), which enable easy clearance
and excretion via kidneys, GQDs exhibit biocompatibility and nontoxic behavior.
They can be used for phototherapy due to their low cytotoxicity, biocompatibility,
and capacity to produce ROS during photoexcitation. Furthermore, GQDs may
transport electrons to photothermal agents and conjugated drugs, which could also
improve their chemotherapeutic efcacysynergistically [72]. Recently, Choi etal.
(2017)describedthe fabrication and utilization of core-shell nanoparticles that have
a graphene oxide quantum dot (GOQD) for the shell and an upconversion nanoparticle (UCNP) for the core. The UCNP was created and used for imaging-directed
upconversion luminescence investigations. In their study, GOQD was produced and
utilized as a prospective drug delivery vehicle to enhance the effectiveness of anticancertherapy. Aunique nanostructure was made by combining the special qualities
of UCNPs and GOQDs to provide desirable drug administration and cell imaging
functionality.
175Graphene Quantum Dots for Drug Delivery
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Additionally, GOQDs were loaded with Hypocrellin A (HA) for photodynamic
treatment (PDT). GOQD was coupled with HA by a π-π interaction and loaded on
PEGylated UCNP without a complex synthetic procedure that may have broken the
structure of HA. These core-shell nanoparticles were employed in the MTT assay to
reveal that the GOQDs shells with UCNPs-loaded with the HAmightbe theideal
candidates for multifunctional agents for cell imaging, drugadministration, and cell
therapies [73].The effects of γ-irradiation on the photoluminescent characteristics
of GQDs have been studied by Jovanovic etal. (2015). The key result indicates that
low-dose γ-irradiated GQDs are viable contenders for PDT because they perform as
superior photo generators when exposed to lower doses of γ-irradiation compared to
elevated doses of γ-irradiation [74]. Wang etal. (2015) designedtargeted therapeu-
tic and diagnostic GQDs that were linked to the aptamer AS1411. GQDs are able
to target tumor cells with excellent selectivity and demolish cells despitelow dosages owing to the employment of aptamers. Due to their superior qualities, including size, uorescence, cytocompatibility, and NIR sensitivity, GQDs are a perfect
companion to the aptamer when it comes to targeting tumors [75]. When targeting
tumor cells in PDT, photosensitizer solubility is a challenge. The hydrophobic properties of compounds like verteporn and Ce6 (derivatives of porphyrins) discourage
their usage as photosensitizers [21]. By combining the photosensitizers with PEG,
these solubility challenges can be xed, and GQDs will consequently be sequestered inside the conjugated PEG shells. Therefore, PDT may be redox-triggered on
synthesized PEGylated GQDs. Additionally, photosensitizer adhesion increases their
hydrophilicity without reducing PDTefciency, preventing quick discharge from the
circulation, and improving their hydrophilicity. Overall, thePEGylated GQDs have
greatly improved bioimaging and biocompatibility, and they have produced excellent
therapeutic efcacy during PDT [76].
Liet al. (2017) revealed the GQDs-FA nanostructures’ ability to load the theragnostic drug IR780 after functionalizingGQDs using folic acid. The IR780 offers
concurrent uorescence and phototherapeutic imaging. The presence of carboxyl
2
groups around the margin of an undamaged sp
domain was believed to be the cause
of the GQDs-FA ability. The signicant π-π stacking interactions between IR780 and
GQDs-FAhave been made possible. The interfacial carboxyl units increase the solubility of IR780 in waterby a factor of approximately 2400. This molecular conguration signicantly increased the tumor targeting and photo-stability and provided
87.9% of the photothermal conversion efcacy of IR780/GQDs-FA. When tumor
cells are exposed to an 808 nm laser, these properties enable signicant hyperthermia over cells and totally eliminate them [77]. Tian etal. (2017) developed amultifunctional system for simultaneous chemo and photothermal treatment byusing
a straightforward one-pot process, whichconsists of implanted GQDsas localized
photothermal seeds and zeolitic imidazolate framework-8 (ZIF-8), which serves
as drug carriers. The ZIF-8/GQD nanoparticles’ structure, drug release behavior,
photothermal impact, and simultaneous therapeutic efcacy were all thoroughly
examined. The ndings demonstrated that the narrow size distribution of ZIF-8/
GQD nanoparticles ofparticle size 50–100 nm haveencapsulated DOXthroughout the production process and triggered DOX release under acidic circumstances.
The near-infrared (NIR) radiation could be effectively transformed into heat by the
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