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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5362_Библиотеки_им_академика_М_И_Перельмана.pdf
Graphene-Based Nanomaterials for Drug Delivery 235
Fig. 2 Evolution in utilization and advancement of drug delivery system stating from conventional
to nanomedicine-based drug carrier. Reproduced with permission from MDPI [11]
distribution of drugs to certain areas, where drugs can be selectively delivered to
targeted cells or tissues, minimizing adverse effects, and optimizing the therapeutic
benefit all at the same time [13]. Graphene-based nanomaterials, such as GO and rGO,
have demonstrated their potential in encapsulating a wide range of drugs, including
small molecules, proteins, and nucleic acids, ensuring their stability and controlled
release at the appropriate location. The unique properties of graphene-based nanomaterials enable active targeting and controlled release of drugs. Functionalization
with ligands that are targeted, such as antibodies or peptides, for example, allows
for specific recognition and binding to target cells or tissues. This active targeting
strategy enhances drug accumulation at the desired site, increasing treatment efficacy
[14]. Additionally, graphene-based nanomaterials may respond to external stimuli,
including light, temperature, and pH, enabling controlled drug release upon triggering. These stimuli-responsive systems provide spatiotemporal control over drug
release, ensuring that the medication is exclusively distributed at the desired location,
further reducing systemic side effects [15]. One of the key considerations in drug
delivery systems is the biocompatibility and biodegradability of the materials used.
Graphene-based nanomaterials have shown excellent biocompatibility, making them
suitable for biomedical applications [ 16]. Surface modifications and functionalization can further enhance biocompatibility and minimize potential toxicity concerns.
Additionally, graphene-based nanomaterials can be designed to be biodegradable,
ensuring their safe clearance from the body after drug delivery [17]. Biodegradable
graphene-based nanomaterials offer a promising solution for temporary drug delivery
needs, eliminating long-term accumulation and potential complications. Despite the
236 A. Mohamed Noor et al.
remarkable potential of graphene-based nanomaterials in drug delivery, several challenges remain unsolved. Ensuring long-term biocompatibility, scalability, and regulatory approval are areas that require further research and development [18]. In addition, it is essential to have a solid grasp of the possible toxicity as well as the long-term
consequences of nanomaterials based on graphene. However, with ongoing advancements and collaborations between researchers, the future of graphene-based drug
delivery holds immense promise [19]. Graphene-based nanomaterials have emerged
as promising tools in drug delivery systems. Their special properties, which specifically include the enhanced drug loading, active targeting, controlled release, biocompatibility, and biodegradability, make them highly attractive for precise and efficient
therapeutic interventions. Ongoing research and development in this particular field
will serve as a catalyst for the emergence of innovative drug delivery approaches,
therefore fundamentally transforming the therapeutic landscape for a wide range of
medical conditions [20].
2 Synthesis of Graphene
2.1 Chemical Reduction Method
By oxidizing graphite flakes under the conditions of exposure to oxidizing agents
and strong acids, graphitic oxide can be produced. According to Yu et al., chemical
modification of graphite oxide through mechanical or thermal exfoliation primarily
produces graphene oxide, where it includes the presence of carboxyl-functionalized
edges and an abundance of reactive oxygen functional groups on the basal plane
[21]. Based on their acidity or basicity in aqueous solutions, the oxygen-containing
functional groups present on the surface of carbon compounds can be divided into
three kinds. These include basic functional groups like quinone and carbonyl as
well as acidic functional groups like carboxyl and carboxylic anhydride and neutral
functional groups (sometimes known as weakly acidic functional groups), such as
phenol hydroxyl, epoxy, and ether groups (Fig. 3).Duetothesp
in the GO being broken, it has a high electrical insulation. By reestablishing the
network by a quick reaction referred to as reduction, the electrical conductivity
properties can be restored.
The final product has many names, including graphene, chemically reduced
graphene oxide (CrGO) and mostly reduced graphene oxide (rGO). But for this
chapter, “rGO” was used. Nevertheless, the restoration of the sp
as the complete reduction of oxygen functional groups remains undocumented. The
electrical conductivity of pure graphene surpasses that of rGO, rendering the latter
unable of competing in terms of conductivity. Numerous strategic efforts have been
undertaken to effectively reduce GO at elevated levels, including diverse approaches
such as chemical, thermal, and electrochemical reduction.
2
bonding connections
2
network is altered,
Graphene-Based Nanomaterials for Drug Delivery 237
Fig. 3 Chemical composition of graphene oxide, which has carboxyl-functionalized edges and is
enriched with hydroxyl and epoxide groups. Reproduced with permission from Elsevier [22]
The earliest report on the reduction of colloidally distributed graphene oxide
(GO) using hydrazine monohydrate was provided by Stankovich et al. [23]. Its highwater reactivity led to its use as a reducing agent for aqueous GO dispersion. The
objective is to diminish the Van der Waals force between the sheets of graphite by
introducing water molecules into the interstitial spaces, therefore augmenting the
interlayer separation. The exfoliation of GO caused by the weak Van der Waals force
will result in the electrostatic repulsion of the graphite layer and could generate a
monolayer, bilayer, or few-layer graphene layer. The reaction will cause the brown
hue of GO to transform to black and precipitate readily, which may be attributed to
the reduced hydrophilicity of the material resulting from the absence of the oxygen
functional group.
The GO has been reduced using a variety of reducing agents, including sodium
borohydride, NaBH
[24], hydrazine hydrate [25], and tannic acid [26]. The chemical
4
process is often performed at room temperature or ambient temperature, therefore
facilitating ease of handling, reducing costs, and ensuring chemical stability. NaBH
has a higher reduction level than hydrazine, according to Muruganandi et al. nevertheless, the resistance to rGO exhibits a lower reduction level than the rGO generated
using hydrazine [ 27]. According to Song et al. rGO may be produced using a one-pot
preparative method using tanic acid, making it a very economical and environmentally responsible method of reducing GO [26]. Garlic, ginger, vitamin C, and glucose
4
238 A. Mohamed Noor et al.
are examples of green, natural reducing agents that can be employed for chemical
reduction of graphene oxide [28, 29].
2.2 Thermal Reduction
The most well-known way for creating rGO is thought to be chemical reduction, but
there are other effective methods that can also be used. Due to its thermal instability,
GO can be reduced more effectively with heat treatment than it can with a chemical
reductant. To achieve the thermodynamic stability of carbon oxide species, such as
exfoliation and reduced graphene oxide (rGO), it is necessary to subject graphene
oxide (GO) to rapid thermal heating [30, 31]. The expulsion of carbon monoxide
or carbon dioxide gas from the interlayer space between the graphene oxide (GO)
layers induces the exfoliation of the stacked GO structure. The abrupt creation of
these gases at high temperatures will produce a pressure of 130 MPa at 1000 °C, which
subsequently separates the graphene sheets from one another [32]. This pressure will
also be generated within the stacked GO sheets. Despite the approach being easy and
promising for generating vast amounts of graphene, the end product exhibits modest
lateral dimension and structural flaws [33, 34]. The measured electrical conductivity
exhibited a value of 10
to that of pure graphene, despite the presence of various imperfections [34].
–23
Scm−1, indicating a much smaller magnitude compared
2.3 Electrochemical Reduction
According to numerous researchers [35–37], electrochemical elimination of the
oxygen functional group is another efficient way to reduce GO. Due to its versatility, rapidity, user-friendliness, and environmentally friendly nature, which aligns
with the principles of the “go green” initiative by removing the need for dangerous
reducing agents (N
cally two methods for conducting electrochemical reduction of GO, such as one step
reduction strategy and two step reduction approach. The one-step technique involves
the direct reduction of target substrates, including ITO, glass, glassy carbon electrodes, and others, from an aqueous solution in the buffer electrolyte. In a typical
three-electrode electrochemical cell, the electrochemical reduction process can be
monitored using cyclic voltammetry (CV) [38], linear sweep voltammetry (LSV)
[39], or at a constant voltage [40]. According to Tong et al., the reduction process is
hypothesized to take place when the GO layers are in proximity to a certain electrode,
resulting in the direct formation of a graphene layer on the surface of the substrate
[40].
The two-step procedure involves the first application of GO onto the substrate,
followed by a subsequent drying process that results in the formation of a thin layer
covered with GO. In order to generate a reduced graphene oxide (rGO) layer on the
,NaBH4), this method is particularly alluring. There are typi-
2H4
Graphene-Based Nanomaterials for Drug Delivery 239
electrode substrate, the substrate that has been coated is subjected to electrochemical
reduction inside a conventional three-electrode electrochemical cell. This cell is
equipped with a buffer solution or supporting electrolyte. According to Eda et al.,
van der Waals interactions are what hold the GO to the substrate [41]. It is thought
that the electrochemical reduction of GO that occurs in the pre-deposited GO film
on different films can be controlled in terms of thickness, size, and shape. According
to Peng et al., the quantity of GO placed into the substrate can affect the desired
size and thickness of a film [42]. However, the deposition techniques have an impact
on several aspects including uniformity, surface morphology, thickness, and area
coverage [43].
2.4 Chemical Vapor Deposition Method
A bottom-up technique called chemical vapor deposition (CVD) is used to create
monolayer or few-layer graphene. The flexibility of this method, particularly in
medical applications, has garnered significant attention from researchers, since it
is often used for the deposition of diamond and carbon-related materials. Methane
) and hydrogen (H2) are typically used as carbon sources in this process [44,
(CH
4
45]. In a high temperature and high vacuum environment, thermal breakdown of
the carbon source produces a new carbon species, which is subsequently adsorbed
onto the surface of a catalytic substrate like copper [46], nickel [47], or cobalt [48]
to form monolayer or few-layer graphene. In the recent years, scientists have been
looking into the best method for producing single-layer and multiple-layer graphene
with higher quality through a variety of conditions, including deposition duration,
pressure, substrate type, substrate temperature, and gas composition. When heated
to a high temperature, the segregated carbon atom can form a solid solution due to
the intermediate and high carbon solubility qualities of the Ni and Co substrate. The
produced carbon atoms from the substrate will then precipitate as a layer of graphene
during the cooling process [49]. According to study by Yu et al., the rate of cooling
and the concentration of scattered carbon atoms on the metal substrate can be used
to control the thickness and quality of graphene layers [21]. Bae et al. demonstrated
the benefit of this method by reporting the synthesis of 30 inches of single-layer
graphene on a copper foil roll [50]. Three phases make up the procedure: sticking a
polymer base (polyethylene terephthalate, or PET); etching copper; further applying
graphene layers to the intended substrate.
2.5 Mechanical Exfoliation
In 2004, Geim and Novoselov, researchers affiliated with the University of Manchester, published their first discovery about the process of exfoliating monolayer
graphene from graphite [51]. The process included the deposition of the material
240 A. Mohamed Noor et al.
Fig. 4 Shows the Scotch tape method for monolayer and few-layer graphene. Reproduced with
permission from Springer Nature [52]
onto a silicon dioxide substrate with a thickness of 300 nm. The mechanical extraction of graphene from highly oriented pyrolytic graphite (HOPG) may be achieved
by the use of tape as a means of detachment, as seen in Fig. 4. Despite the fact that
graphene layers are very transparent to the naked eye, an optical microscope was
used to see them owing to the optical differentiation between the graphene sheet
and SiO
substrate. The measurement of the thickness of many layers of graphene
2
was s ubsequently conducted using atomic force microscopy (AFM). This method
produces very high-quality graphene with no imperfections that could be found.
However, the graphene produced using this specific method lacks controllability and
is not appropriate for mass production.
2.6 Epitaxial Growth Method
Epitaxial growth is the process of depositing a crystalline layer on a crystalline
substrate. Silicon carbide (SiC) is heated at high temperatures (>1000 °C) at low
pressures (10–6 torr) in order to create graphene. As the silicon atoms move away
from the surface, the carbon atoms are rearranged, creating a thin layer of graphene.
On a silicon carbide, SiC (0001) substrate, Van Bommel and team developed and
presented monolayer carbon, now known as graphene, in 1975 [53]. Since then,
scientists have paid a lot of attention to epitaxial growth. For instance, Hass et al.
have discussed their work on the development process of graphene layer on SiCs
and its electrical properties [54]. Furthermore, Juang et al. conducted a study where
they made many alterations to the process of epitaxial development. Specifically,
they achieved the growth of epitaxial graphene on a silicon carbide (SiC) substrate
Graphene-Based Nanomaterials for Drug Delivery 241
at a relatively low temperature of 750 °C [55]. Epitaxial graphene was produced by
Kruskopf et al. on a SiC substrate at atmospheric pressure and an argon environment,
and it has a very high potential for industrial production as well as in situ use in the
development of electrical devices [56]. It should be highlighted, too, that controlling epitaxial graphene thickness—which is essential for electrical performance—is
challenging.
2.7 Growth in Solvothermal and Hydrothermal Systems
An easy, low cost and robust in order to create pristine graphene, two very practical
and flexible processes are famously used: hydrothermal (aqueous) and solvothermal
(non-aqueous). The process starts with the precursor namely GO in a liquid solution,
is reduced hydrothermally or solvothermally at a high temperature in an autoclave.
A range of parameters varies in the high pressure hydrothermal and solvothermal
processing environment to produce graphene. This straightforward process has been
utilized to produce graphene-based nanocomposite materials based on metal oxides
like ZnO [57], TiO
process is that it may produce nanostructured materials with high crystallinity, high
yield such as nanoparticles, nanowires, nanoflowers, nanorods, and nanotubes, and
without annealing or calcination being necessary.
[58], CuO [59], Fe3O4[60], and NiO [61]. The benefit of this
2
2.8 Electrochemical Deposition
Another popular method that can be used to create pristine graphene is electrochemical. This method is particularly appealing because it is well recognized to be quick,
simple, and non-toxic. Layers of graphene may be created on a range of substrates
by electrochemically reducing the precursor solution while increasing voltage and
current. To the best of our knowledge this technique is also the best method in order
to prepare graphene-based nanocomposite material. Electrochemical reactions function as a driving force to overcome van der Waals forces, which causes graphite
to expand structurally. Careful manipulation of process variables such as applied
electrical potentials, currents, processing time, and the composition of electrolytes
has allowed for the fabrication of graphene materials with a wide range of defect
densities, oxygen concentrations, graphene layer counts, and lateral diameters. Additionally, during electrochemical exfoliation, chemical interactions with functionalizing agents can occur simultaneously in order to perform in situ chemical doping
(functionalization) of graphene materials to create different types of graphene-based
composite materials. Graphite can be utilized as working electrodes by immersing it
in liquid electrolytes in a range of geometries, including powders, foils, rods, flakes,
and plates. There are two types of exfoliation techniques: cathodic (which applies a
negative bias to graphite electrodes) and anodic (which uses a positive bias) (Fig. 5).
242 A. Mohamed Noor et al.
Fig. 5 Schematic illustration of electrochemical synthesis of graphene. Reproduced with permission from Elsevier [62]
Numerous studies on the electrochemical creation of graphene-based nanocomposites have been published as of this writing, including Au [63], Pt [64], Ag [65], Cu
[66], ZnO [67], NiO [68], and even CdSe [69]. The integration of metal, metal oxides,
and metal alloys onto the graphene layer appear to be easily facilitated by an electrochemical process. According to Yin et al. the conductivity of rGO affects the structure
of ZnO, allowing for the growth of nanostructured particles with low conductivity
and the accumulation of nanorods with high conductivity [70]. As a result, it can be
used to improve the synthesizing method and different applications. The process of
depositing graphene combined with MnO
on textile layer for capacitor application
2
Graphene-Based Nanomaterials for Drug Delivery 243
was reported by Yu et al. by applying a small constant current of 100 A/cm2for 30–
300 min of time required for the deposition to happen in a complex aqueous solution
of 20 mM Mn (NO
and 100 mM NaNO3. This technique, however, depends on
3)2
a multi-step processing method [71]. It is notable that solution-exfoliated graphene
nanosheets can be conformably coated from solution on porous textiles structures
for high loading of active electrode materials and to make it easier for electrolytes to
access those materials. The works demonstrate that MnO
nanoparticles have been
2
evenly distributed throughout the fabrics’ surface decoration. It’s interesting to note
that this method can also be used to create the graphene Cu
O and graphene ZrO
2
nanocomposite.
3 Types of Graphene-Based Materials
Due to their distinct physicochemical characteristics, high surface area, and biocompatibility, graphene-based nanomaterials have demonstrated enormous potential in
the field of drug delivery. We examine different kinds of graphene-based materials
in this chapter, including graphene nanoribbons, GO, GQDs, oxidized graphene
nanoribbons, and graphene nanoflakes. Each of these substances has unique qualities thereby making them all desirable candidates for applications involving medication delivery. We explore these graphene-based materials’ production processes,
characteristics, and most recent developments in drug delivery.
2
3.1 Graphene Quantum Dots, (GQDs)
Small graphene pieces known as graphene quantum dots (GQDs) are typically less
than 10 nm in size. They display special quantum confinement phenomena that lead to
discrete energy levels that are distinct from those of bulk graphene. There are several
ways to make GQDs, including hydrothermal, microwave-assisted, and laser ablation processes [72]. These fluorescent nanomaterials are well suited for bioimaging,
biosensing, and drug delivery applications because of their high water solubility,
outstanding photostability, and tunable emission characteristics. Due to their large
surface area and abundance of functional groups, GQDs have been employed as
malleable carriers for drug administration. Drug delivery systems that are selective
for certain cells or tissues can be made by functionalizing GQDs with therapeutic
drugs or targeting ligands. Furthermore, the remarkable photothermal capabilities
shown by these materials have been harnessed to provide a very promising approach
for the treatment of cancer, which integrates photothermal therapy with targeted drug
delivery.
244 A. Mohamed Noor et al.
3.2 Graphene Oxide (GO)
Graphene oxide (GO) is an important graphene derivative because it can be chemically modified to boost its reactivity and hydrophilicity by adding oxygen-containing
functional groups such as epoxide, hydroxyl, and carboxyl. The production of GO,
a two-dimensional nanomaterial with remarkable water dispersibility, involves the
oxidation of graphite. Its surface is oxygen-rich, making functionalization and conjugation with medicinal drugs simple. GO has demonstrated significant promise in
applications involving drug delivery, serving as a platform or a drug carrier [73]. It
is a desirable candidate for controlled drug release systems because of its capacity to
encapsulate hydrophobic pharmaceuticals in its layered structure and release them in
response to environmental factors like pH, temperature, or light. Additionally, due to
GO’s adaptability, targeting ligands can be added for improved therapeutic efficacy
and targeted cellular uptake.
3.3 Graphene Nanoribbons (GNRs)
Graphene nanoribbons (GNRs) are slender strands of graphene strips with widths
that range from a few nanometers to a few nm. They can be made by a number of
techniques, such as unzipping carbon nanotubes, molecular self-assembly, and CVD.
GNRs have distinctive edge effects, and their width and edge structure determine their
electrical and optical characteristics. Due to their enormous surface area and potential
for functionalization, GNRs have been investigated in drug delivery as carriers for
nucleic acids and small molecule medications [74]. They are desirable for targeted
medication administration due to their limited width and customizable characteristics
since they can be designed to interact only with cancer cells or other sick tissues.
However, more investigation is required to comprehend the biocompatibility and
in vivo behavior of GNRs for applications including secure and efficient drug delivery.
3.4 Oxidized Graphene Nanoribbons
Oxidized graphene nanoribbons (GNRs) are made by introducing oxygen-containing
functional groups to the edges and surfaces of GNRs. The hydrophilicity and biocompatibility of the nanoribbons are enhanced by these functional groups, making them
more applicable to biomedical research. Oxidized graphene nanoribbons have shown
promise in encapsulating and delivering pharmaceuticals as well as in gene delivery
in the field of biomedicine. Drug distribution to particular cells or tissues is made
possible by functionalizing these nanoribbons with targeting ligands, which minimizes off-target effects. They can also be used for photoresponsive drug delivery,