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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5882_Библиотеки_им_академика_М_И_Перельмана.pdf
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 105
interactions, π–π stacking interactions are utilized for non-covalent modification of
GO. For example, Liu et al. prepared pyrene-based polymers for modification of rGO
using π-π stacking interaction [39].
Graphene-based nanomaterials show great potential in stimuli-responsive drug
delivery, as suitable functionalized graphene has the capability to respond to peripheral stimuli like PH, temperature, magnetic field, electric field, sound, near-infrared
radiation, etc. Lower pH of tumor cell (5.5), compared to the physiological pH
of 7.4, acts as a stimulus for pH-sensitive drug delivery systems [40]. Kavitha et al.
combined pH-sensitive PEDA group poly 2-(diethylamino ethyl methacrylate) to the
GO covalently to deliver camptothecin drug to the tumor cell. This drug was attached
to PDEA-GO using non-covalent, hydrophobic, and π–π stacking interactions [40,
41]. Recently, Boddu et al. reported pH-sensitive rGO-embedded chitosan beads for
the co-delivery of two anticancer drugs curcumin and 5-fluorouracil [40, 42]. Fe
3O4
magnetic nanoparticles are deposited to develop a magnetic graphene oxide drug
carrier for DOX [32]. To improve DOX efficiency towards human breast cancer treatment Pooresmalili and coworkers have grown copolymer brushes composed of acrylated β-cyclodextrin (Ac-β-CD) and N-isopropylacrylamide (NIPAM) on magnetic
graphene oxide surface [38, 43]. Kim et al. designed redox-sensitive GO derivative
functionalized with methoxy poly(ethylene glycol) (MePEG) to release chlorin e6
drug to treat cholangiocarcinoma [40, 44].
Applications of graphene-based nanomaterials are not only restricted to cancer
therapy but also extended towards other treatments, like wound dressing, neurological disorder, drug addiction, etc. In 2021, Wang et al. reported NIR light
responsive nanocarrier based on rGO and chitosan to deliver teriparatide drugs for
repairing osteoporotic bones [45]. Xiong et al. developed lactoferrin functionalized graphene oxide (GO) nanosheets to load and transport puerarin to the brain
across the blood–brain barrier to cure Parkinson’s disease [46]. Excessive reactive
oxygen species (ROS), like H
, free radicals (O
2O2
•−
,OH•) singlet oxygen, etc.,
2
are responsible for inflammation, aging, cancer, and atherosclerosis. Wu et al. fabricated nanofiber membrane of rGO coupled with ROS-responsivePEGDA-EDT (poly
(ethylene glycol) diacrylate -1, 2-ethanedithiol) copolymer for the delivery of fucoxanthin as the anti-oxidative and anti-inflammatory drug [40, 47]. Various surfacemodified graphene derivatives have shown promising performance as nanocarriers
in drug delivery. Some compounds have been functionalized to modify the graphene
surface to improve their performance in drug delivery. Some of the recent reports on
graphene-based nanomaterials for drug delivery applications are listed in Table 1.
Apart from drug delivery, graphene nanomaterials also have potential applications in
bioimaging, biosensing, gene delivery, and tissue engineering [28, 38]. The concerns
associated with their usage are toxicity,inadequate information about their metabolic
process, and uncertainty of long-term impact on various tissues and organs. Though
a lot of research have been done to overcome these challenges, further efforts must
be dedicated to expand their practical applications in biomedicine.
106 N. B. Singh et al.
Tabl e 1 Recent reports of graphene-based nanomaterials for drug delivery
Graphene nanomaterial Drug Application References
Transferrin/folic acid
double-targeting
graphene oxide
(TFGP/DOX)
Cyclodextrin
dendritic-Graphene oxide
β-cyclodextrin/
cystamine/ polyethylene
glycol functionalized
graphene oxide
(GO-Cys-CD-PEG)
Ferric oxide/ chitosan/
Reduced graphene oxide
nanocomposite
Graphene oxide/
chitosan/
montmorillonite
nanocomposite
Gemcitabine/ reduced
graphene oxide
(GEM-rGO)
Cyanine5 modified
miRNA/graphene oxide/
folic acid/ poly ethylene
glycol/ platinum
nanocomposite
Topotecan (TCN) loaded
thermo sensitive
nanocargos
(TCN-TS-NC)
Methotrexate/GO Methotrexate Controlled delivery of drug were
Fas ligand conjugated
rGO system
Daidzein-Graphene
oxide(GO-DZ) complex
DOX Non-toxic, controllable drug delivery
DOX Good release and effectiveness of
DOX Redox and pH dual-responsive
DOX pH-triggered and magnetically
Gemcitabine
(GEM)
GEM Notable cytotoxic activities towards
Platinum Multifunctional platform for ovarian
Topotecan Intramuscular (IM) administration of
Sevoflurane Deliver the drug towards the brain
Daidzein GO-DZ is antiosteoporoticoraldrug,
system has potential application for
the treatment of hepatocellular
carcinoma
DOX studied towards MCF- 7, human
breast cancer cells
nanocarrier with high drug loading
efficiency and used to treat human
liver cancer cell line (HepG2 cells)
controlled DOX release towards A549
and MCF-7 cancer cells
Controlled delivery of GEM and
cytotoxic effect was studied in vitro
towards MDA-MB-231 breast cancer
cell line
A549 and HEL-299, lung cancer cells
cancer therapy against cisplatin
resistant SKOV3 cells
the drug showed control release
against SCC7 cells, which can be
used for the treatment of various
tumors like ovarian and rectal cancer
studied for hepatocellular carcinoma
cells (HepG2), porcine skin
fibroblasts (PEF) and human
embryonic kidney cells (HEK293A)
ischaemic region, can be explored to
treat cerebral ischaemia
its cytotoxicity was studied towards
human osteosarcoma cell lines
(MG-63)
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 107
3.2 Drug Delivery by Graphene Quantum Dot-Based
Nanomaterials
Graphene quantum dots (GQDs) are graphene-based nanoparticles, consisting of
one or a few layers of graphene sheets with size generally less than 20 nm [40,
59]. The methods of GQDs synthesis are broadly categorized into two types: top-
down and bottom-up processes. In top-down strategies, GQDs are generally synthesized by cutting the graphene sheets or different carbon materials, such as graphite,
coal, fullerene, and carbon nanotubes by physical or chemical methods. Bottom-up
approaches generally involve assembly of the small molecules, such as amino acids,
sugar, citric acid, and other organic precursors by pyrolysis or stepwise organic
synthesis [60]. The advantages of GQDs over graphene are their excellent luminescence behavior, low cytotoxicity, and high aqueous dispersibility and stability
[61]. Unlike graphene, GQDs have nonzero band gap that can be altered by varying
size, shape, and surface morphology [62]. Their large surface area, very small size,
and better biocompatibility make them ideal for biomedical applications like drug
delivery, biosensing, and bioimaging. Similarly, like graphene, GQD can easily
interact with drug molecules using π–π interactions and its surface can be factionalized suitably. It also shows stimuli-responsive behavior towards different stimuli,
like light, pH, magnetic fields, and ultrasound [63]. Due to these unique properties,
GQDs have great potential in drug delivery processes.
Recent reports on GQDs based nanocarrier for drug delivery applications are
summarized here. Felix et al. incorporated anticancer drugs, imatinide on GQDsurface for the treatment of leukemia [64]. Lee et al. employed green fluorescent
protein (GFP) nucleic acid, and branched polyethyleneimine (PEI) functionalized
GQDs to encapsulate DOXfor colon cancer therapy. It was a pH-responsive nanostar
drug carrier which successfully released the drug in the acidic tumor microenvironment [65]. Gelatin-coated magnetite (Fe
nanocomplex was developed by Pooresmaeil et al. to carry DOX to the breast cancer
cells [66]. To enhance fluorescence imaging and biocompatibility, nitrogen doped
GQDs (N-GQD) have been utilized by Frieler et al. Fluorescence tracking and
delivery of DOX by N-GQDs towards MCF-7 and HeLa cancer cells have been
investigated by them [67]. MiRGD peptide functionalized GQDs were designed by
Ghafary et al. for targeted delivery of DOX and curcumin to the tumor cells [68].
Some recent reports are listed in Table 2. Figure 4 represents a schematic diagram of
drug delivery by GQDs based nanocarrier. Beyond a drug carrier, graphene quantum
dots act as a good therapeutic agent for various diseases, like, Alzheimer’s disease,
Parkinson’s disease, hepatitis, diabetes, psoriasis, and cancer. It also has antimicrobial
activity and wound healing properties [59].
)/graphene quantum dots hybrid
3O4
108 N. B. Singh et al.
Tabl e 2 Graphene quantum dots-based nanocarriers recently used for drug delivery
Graphene nanomaterial Drug Application References
GQDs decorated with dextran/
poly(N-isopropylacrylamide)GQDs-Dex/
PNIPAM copolymeric hydrogel
Cytarabine (Cyt) loaded on carboxyl
functionalized GQDsand wrapped with
chitosan-CS/GQDs/Cyt
Epidermal growth factor receptor
(EGFR)-specific antibody
(scFvB10) conjugate to GQDs
(SvFvB10-GQDs)
GE11 peptide functionalized GQDs
(GQDs@GE11)
Tryptophanconjugated graphene quantum
dots (Trp-GQDs) nanocomposite
Buprenorphine Temperature
Cytarabine pH-sensitive drug
Cisplatin Targeted
Cisplatin and
doxorubicin
Curcumin pH-dependent,
triggered drug
delivery for pain
management
release towards
cancer cells
delivery and
pH-dependent
release of cisplatin
to breast cancer
cells
(MDA-MB-231)
GE11 peptide was
used as targeting
agent to EGFR
receptors present
on cancer cells and
simultaneous
release of two
drugs boost the
effect of
chemotherapy for
nasopharyngeal
carcinoma
nontoxic drug
delivery to MCF-7,
human breast
cancer cell line
[69]
[70]
[71]
[72]
[73]
3.3 Drug Delivery by Carbon Nanotube-Based
Nanomaterials
Carbon nanotubes (CNTs) are cylindrical shape carbon allotrope. CNTs are
in general classified as single-walled (SWCNTs) and multi-walled carbon
nanotubes (MWCNTs) depending on the graphene sheets number that rolled up
to form the nanotubes. For example, SWCNTs and MWNTs contain single and
multiple concentric graphene cylinders, respectively [74]. When CNTs contain only
two layers encompassing two graphene sheets folded one upon another, it is referred
to as double-walled carbon nanotubes (DWCNTs). Both the end of CNTs can be
open ended or capped with a fullerene dome [75]. SWCNTs usually have a diameter
of around 1 nm, in the range of 0.4 to 3 nm [74]. The length-to-diameter ratio of
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 109
Fig. 4 Diagram of
receptor-mediated drug
delivery by targeting ligand
conjugated GQDs into a
tumor cell. Reproduced with
permission from Elsevier
[59]
nanotubes is about 1000 and hence they are considered as one-dimensional nanomaterials [32, 76]. MWNTs have inner diameter in the range of 1 and 3 nm and outer
diameter varies from 2 to 100 nm [77]. The length of the CNTs is the micrometer
range. The separation between two concentric cylinders has been observed in the
range of 0.27 to 0.42 nm for DWCNTs and MWCNTs [78].
CNTs are produced following three main techniques, electric arc discharge, laser
ablation, and chemical vapor deposition (CVD). In electric arc discharge method,
two graphite rods are used as cathode and anode inside a chamber. Direct current is
passed, at very high temperature around 4000 K, anode sublimates and is deposited
on cathode. MWCNTs are generally produced without using a catalyst, where
as SWCNTs are synthesized utilizing a metal catalyst [30, 79]. In laser ablation
approach, a pure graphite target is vaporized by laser radiation at high temperature
and condensed on cooled copper rod in nanotube form. Large amounts of SWCNTs
are produced by this method when transition metal particles are added as catalysts.
But this method is expensive.In CVD method, carbon precursors (acetylene, benzene,
carbon monoxide, methane, etc.) are decomposed and CNT is formed on the surface
of metal catalyst particles [80]. Compared to other techniques, thermal or plasmaenhanced catalytic chemical vapor deposition technique is commonly employed as
this method is more economic and produces large quantities of CNTs in pure f orm.
CNTs are very strong materials with high tensile strength. Young’s modulus
for SWCNTs and MWCNTs are in the range of 2.8–3.6 TPa and 1.7–2.4 TPa,
110 N. B. Singh et al.
respectively [80]. These materials have very high thermal and electrical conductivity. Depending on the structure and diameter, CNTs can be conducting or semiconducting [76]. They are resistant to very high temperatures (750 °C in air and
2800 °C in vacuum) [32]. CNTs show interesting electrochemical properties and
optical activity. Moreover, they have unique structures with low density, high surface
area to volume ratio, and ability to cross cellular membranes. All these properties are
responsible for a wide range of applications in various fields. But CNTs agglomerate
in water because of strong van der Waals attraction and π–π stacking interactions.
Thus, for biomedical applications proper functionalization of carbon nanotubes is
essential to improve their aqueous solubility and biocompatibility.
Functionalized CNTs have attained remarkable importance in the field of drug
delivery [30]. Various functional groups (like hydroxyl, carboxyl, amine, sulfonyl,
etc.), molecules (including polymers and surfactants), and ionic or metallic species
can be introduced on the surface of CNTs. Fullerenes, porphyrins, and metals have
been incorporated inside the cavity of CNTs using hydrophobic interactions [76].
Different functionalization strategies, like covalent attachment, non-covalent attachment, and biocompatible surface modification are applied to design CNT-based
drug delivery systems [76]. Drug molecules can be attached onto the surface or
inside the internal space of the functionalized CNTs and then CNTs transport and
deliver these molecules into the targeted cells. Dong et al. functionalized MWCNTs
by transactivator of transcriptionpeptide-chitosan(MWCNTs-TC) to load anticancer
drug DOX effectively. pH-controlled release of DOX was studied using BEL-7402
cells, a hepatoma cell line [81]. Cao et al. developed multifunctional MWCNTs,
where polyethyleneimine (PEI) functionalized MWCNTs were covalently attached
to a targeting ligand, hyaluronic acid (HA), and an imaging dye fluorescein isothiocyanate (FI). MWCNT/PEI-FI-HA encapsulated DOX with high drug loading efficiency (72%) and delivered it to the target HeLa cancer cells over expressing CD44
receptors [82]. A platinum(IV) complex having a folate derivative was connected to
the surface of an amine-functionalized SWCNTs. These functionalized SWCNTs
carried the Pt(IV) complex to the cancer cell and delivered Pt(II) produced by
intracellular reduction of Pt(IV) [83]. Recently, externally controllable SWCNTs
based drug delivery system was designed by Madani et al. First SWCNTs-liposome
complexes (CLCs) have been prepared and incorporated into 3D alginate hydrogel.
Fluorescein isothiocyanate dextran is used as a model drug, which is released from
CLCs when stimulated by NIR laser [84]. Some more recent applications of CNTs
in drug delivery are briefed in Table 3.
3.4 Nanodiamond Based Drug Delivery Systems
Nanodiamonds (NDs) are the latest found carbon allotropes with single crystal size
of 2–8 nm and large surface area. They are mainly composed of carbon atoms with a
diamond like framework. The carbon atoms constituting the NDs, are in tetrahedral
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 111
Tabl e 3 Recent applications of CNTs in drug delivery
CNTs Drug Application References
SWCNTs attached with
Congo Red (CR)
supramolecular
ribbon-like assemblies
SWCNTs Paclitaxel Developed two models to
Carboxylated MWCNTs Isoniazid Isoniazid-conjugated MWCNTs
Ethylenediamine and
phenylboronic
acid group
functionalized
MWCNTs
Carboxylated MWCNTs Griseofulvin and
Carboxyl-SWCNT
functionalized with
polyethylene glycol/
polyethyleneimine
Doxorubicin SWNT-CR complexes have high
Paclitaxel High drug loading capability and
Sulfamethoxazole
Methotrexate Use in treatment of rheumatoid
drug binding capability and
pH-control drug release ability
determine the efficiency of
paclitaxel towards the inhibition
of cancer cell growth
showed effective drug delivery
and good antibacterial activity
towards Mycobacterium
tuberculosis
targeted drug release to colon
cancer cells
Improve the dissolution of
hydrophobic antifungal drugs
arthritis
[85]
[86]
[87]
[88]
[89]
[90]
arrangements in a 3D cubic framework. The crystal structure consists of two interpenetrating cubic close packed face centered lattices. The functional groups present
in the ND’s surface allow for a variety of compounds to get attached to it. A large
portion of atoms in NDs occupy the defect sites on grain boundaries on the surface
and thus can alter the bulk properties strongly than that of macro or micro crystalline
diamonds. NDs belong to two different types, e.g., detonation NDs (DND) and fluorescent NDs (FND) based on their size and synthetic strategy. DNDs are produced
from explosives such as RDX or TNT. They are monodispersed in nature with a size
about 5 nm. Alternatively, FNDs are manufactured at high temperature and pressure
[91]. They exhibit polydispersity with wide size distribution.
NDs have some superior and special properties making them an interesting material in diverseareas. It is about fifty times harder than stainless steel and titanium. This
quality of ND is utilized in biomedical applications for cutting and implanting tools
for surgical purposes. Their high surface area, biocompatibility, and easy synthetic
and doping methods are highly exploited in different applications [92]. NDs demonstrate interesting optical and photophysical phenomena which are utilized in making
fluorescent probes in the bioimaging field [93]. For example, NDs exhibit fluorescence emission at 550 to 800 nm from the nitrogen vacancy defect centers which are
employed as fluorescent probe in tracking single particle. NDs are also applied for
112 N. B. Singh et al.
Tabl e 4 Some recent drug delivery applications of nanodiamonds
Functionalized
component
N-Hydroxy- succinimide
and
1-(3-dimethylaminopropyl)
-3-ethylcarbodiimide
hydrochloride
Dicumyl peroxide and
methyl 3-sulfanylpropanoate
Nitric acid, sodium
octanoate, sodium-laurate,
sodium oleate
Targeted drug Method Comments References
Cetuximab and
cisplatin
Doxorubicin Conjugation
Paclitaxel Detonation,
Conjugation Inhibition of
by thiolene
click reaction
PEG
conjugation
HepG2 cells
pH-dependent
slow release of
drug with high
drug loading
capacity
High dispersion
in water
[98]
[99]
[102]
drug deliveryof compounds which have low solubility. pH-dependent drug release by
ND is reported for G9a inhibitor for hepatocellularcarcinoma therapy [94]. They are
currently getting increased interest in theranostic field. NDs are successfully applied
in tissue engineering, gene delivery, and bone surgery [95]. Biocompatibility of
functionalized NDs is found to be superior to CNTs [96]. In drug delivery system,
nanodiamonds have shown immense potential due to their biocompatibility. Wide
varietyof molecules are absorbed by functionalized NDs and used for targeting tumor
cells [97]. Li et al. fabricated bioconjugate of cetuximab-NDs-cisplatin for inhibition
of HepG2 cells [98]. Ester functionalization on NDs surface helps in dispersion in
water with enhanced loading capacity [99]. Controlled release of DOX in acidic environment has been tested using the composite of functionalized ND with polymers.
Grafting of polymers on the surface of amine-functionalized NDs have been studied
by Lu et al. [100]. Delivery of an anticancer drug gemcitabine by ND-PEG (polyethylene glycol) has been successfully studied by them. Various beneficial properties and
applications of nanodiamonds are presented pictorially in Fig. 5 [101]. Some recent
progress and application of functionalized NDs for drug delivery is listed in Table 4.
3.5 Nano-Onions in Drug Delivery
Carbon nano-onions (CNOs) are zero dimensional cages like structures [103]. They
have multilayered close shells like onion (Fig. 6)[104]. The diameter of CNOs with
or C80fullerene core is varied from 1.4 to 50 nm and interlayer gap of 3.4 Å
C
60
[103–105]. Depending on their fabrication method structural variations with different
sizes and shapes are observed. Electron beam irradiation, arc discharge, thermal
annealing, thermal reduction, etc., are some of the techniques used for t he production
of CNOs. Pristine CNOs undergoaggregation in water and organicsolvent due to their
Carbon-Based Nanomaterials for Drug Delivery: Past, Present, Future … 113
Fig. 5 Schematic representation of beneficial properties and applications of nanodiamonds.
Adapted and modified with permission from MDPI [101]
hydrophobic nature. However,the solubility can be altered by surface modification by
functionalization [106]. CNOs can be manufactured easily,are highly stable and pure,
and have small polydispersity index. Their distinctive properties make them highly
useful as drug carriers [107]. Various studies have proved their biocompatibility.
Their properties can be tailored by covalent and non-covalentfunctionalization [108].
Fig. 6 High-resolution transmission electron microscopy (TEM) image of a Carbon nano-onion;
Reproduced with permission from Elsevier [104(a)] b Structure of carbon nano-onion. Adapted
with permission from Elsevier [104(b)]
114 N. B. Singh et al.
Various applications of functionalized CNOs in biomedical sector in sensing,
drug delivery, bioimaging, tissue engineering, etc., are explored by many research
scientists [109]. CNOs are successfully examined for controlled release of drugs in
ph-responsive manner. Composite of poly[N(4-aminophenyl)methacrylamide)] with
CNOs is investigated for controlled release of DOX spanning over 15 days. 99.2%
release was observed at pH 4.5 while at pH 6.5 release amount was only 59.3%
[110]. Functionalization of CNOs with hyaluronic acid-phospholipid improves the
solubility. This non-covalent functionalization is used for targeting different cancer
cells Fig. 7.[111]. Composites of CNOs with surfactants display high solubility
due to the hydrophilic nature of surfactants and improved physicochemical properties. Bobrowska et al. functionalized CNO with different surfactants such as CTAB,
SDS, SDBS, Triton X-100, and Tween 20 for investigating their biological activity
against E. Coli. [112]. The results indicate a synergistic effect of the functionalized
nanocomposite compared to pure surfactant. Graphite based water soluble CNO has
been successfully employed for cell imaging of E. Coli. and Pseudomonas putida. The
fluorescence property of this CNO is also used for the detection of glucose molecules
[113]. Table 5 lists some recent progress of application of CNOs in biomedical field
[114].
Fig. 7 Non-covalent functionalization of pristine-CNOs with hyaluronic acid-phospholipid conjugate and its fluorescent counterpart. Reproduced with permission from Elsevier [111]