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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5882_Библиотеки_им_академика_М_И_Перельмана.pdf
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 445
minimal toxicity, biological compatibility, sustainability, environmental sensitivity,
and biodegradability [10].
Chitosan (CTS), a straight-chain bio-polyaminosaccharide, is formed after chitin
is alkaline deacetylated. The structure of the substance is composed of N-acetyl-Dglucosamine and D-glucosamine components, each of which comprises two hydroxyl
groups and one amino group [11]. Under mild reaction conditions, CTS’s hydroxyl
compounds and amino chains acts as the point of interaction enabling an extensive
variety of distinct chemical affiliations, giving it versatility. Due to the amino group’s
protonation by CTS, which increases solubility,a poly-cationic molecule is preserved
in lower pH values. The exceptional properties of CTS polymer, including skin adhesion, activated immunity, faster wound closure, antimicrobial, anaesthetic and hemostatic properties, among others, contributed to advancement across number of industries [12, 13]. Tragically, these devices had drawbacks including inadequate physical features and pharmaceutical exploded discharges, which meant they couldn’t
Fig. 1 Challenges and the future of drug delivery. Reproduced with permission from ACS [5]
446 R. Priya et al.
completely guard against the serious side effects of medication therapy. Therefore,
a number of researchers are working to discover an approach that addresses this
problem through using nanofiller to increase the drug therapeutic action of CTS
polymer [14].
Due to their ability to control the release of drugs amount, greater mobility through
cell membranes, as well as additional advantages for the delivery of medicines,
nanomaterials can also be employed as drug carriers [7]. Numerous researchers have
been conducted on the characteristics of metallic or metallic oxide particles, quantum
dots, dendrimers, polymeric micelles, liposomes, carbon-based nanomaterials, and
different tiny carriers complexes [15, 16]. Graphene and its related compounds,
such as graphene (GR), graphene oxide (GO), and reduced graphene oxide (rGO),
have potential use in biomedicine owed to their appealing characteristics, such as
their substantial particular area of surface, exceptional conductive properties, thermal
insulation, mechanical strength, and others.
The anticancer drugs underwent structural alterations as a result of the functionalization process with GR. This prolongs arterial circulation duration, improves
extravasation capacity, prevents rapid excretion, and improves bio-distribution, all
of which lead to more precise drug administration [7]. Two significant limitations
of using GR and its related compounds for drug delivery are the insoluble property of GR with water along with the presence of irregular or rugged ends, whose
might perturb regular cells. Additionally, investigations have demonstrated that it
has a dose-dependent hemolytic action [17]. To get over the issues outlined above,
polymers are routinely coated on GR and its derivatives. Polymer nanocomposites,
created by combining polymer and nanocarrier, have a distinctive structure that overcomes all challenges faced by each separate drug carrier and the combination as a
whole. Gomari et al. [18] created sustainable CTS/GR nanocomposites with a range
of GR loadings (0.25, 0.5, 1, 2, and 5 wt%) and found that the nanocomposite with
a 2 wt% GR loading outperforms CTS polymer in terms of mechanical qualities as
well as being a feasible, controllable, and pH sensitive drug delivery systems. It had
a slower rate of biodegradation compared with CTS polymer and released 48% less
medicine in an acidic media than in a neutral one [19].
This chapter discusses CTS/GR nanocomposite-based drug delivery devices for
controlled release in biological applications. To create a bio-stable, controlled-release
drug delivery systems, polymer was combined with varying weight percent (wt%)
amounts of GR. A thermal along with mechanically strong polymer composite was
used in the drug delivery application. The synthesis of CTS/GR nanocomposites with
different GR concentrations and their corresponding F loaded nanocarrier systems,
as well as the examination of the thermal and mechanical characteristics of spraydried CTS/GR nanocomposites were all firsts. The spray drying method converts
an emulsified substance into a solid powdery form in a single step using a gases
hot air medium. This approach is commonly used in the dietary supplement and
drug sectors. The generated polymer matrix was examined through infrared spectroscopy, electron microscopy with field emission, thermal gravimetric examination,
differential scanning electron calorimetry, and dynamic mechanical analysis.
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 447
2 Chitosan: Structure and Properties
CTS shares many similarities with cellulose in terms of chemical makeup, which
made up of countless numbers of β-(1–4) linked with D-glucose (Fig. 2). In the
structure of chitin and CTS, the hydroxyl group that is found at the C-2 spot of
cellulose was substituted with an acetamide molecule. CTS is an N-deacetylated
chitin derivative formed through transforming acetamide groups into major amino
groups [20]. It is 2-amino-2-deoxy-b-D-glucopyranose with a β-(1–4) link.
Chitin, on the other hand, is rarely completely deacetylated, and CTS or deacetylated chitin has some acetamide molecules. Compared to cellulose, CTS has 5–8%
nitrogen. This nitrogen can be found in primary aliphatic amine groups in CTS
and acetylated amine groups in chitin, which makes them appropriate for common
amine reactions [20]. Because CTS has amine groups on every deacetylated unit
and primary and secondary hydroxyl groups on every following unit, it is chemically more reactive than chitin. These responsive chemicals can simply chemically
changed to modify the physical and mechanical properties of the CTS. Because it
allows for specific biological roles and the employment of modification reactions,
the existence of amines bonds in CTS offers a significant advantage [22]. These
polysaccharides’ exceptional qualities, including their compatibility with biological, biodegradable properties, biological action, bio-resorptivity, non-toxicity, and
high adsorption capabilities, define them as ideal biomaterials and attract a lot of
industrial interest as potential substitutes for synthetic polymers [23]. Owing to its
unique qualities, CTS can be used in a variety of applications. However, because
of their fascinating qualities, such as their robust antibacterial activity, biodegradable, environmental friendly, and excellent retention of moisture, they are becoming
Fig. 2 Morphology and characteristics of films composed of composites made of chitosan and
sodium dodecyl sulfate. Reproduced with permission from RSC [21]
448 R. Priya et al.
increasingly popular [12], CTS have become increasingly used in the medical and
pharmaceutical industries. Additionally, several researchers have reported on additional biological features like analgesic, cancer prevention, hemostatic, hypocholesterolemic, antimicrobian, and antioxidant capabilities in certain recent investigations
[24, 25].
A significant number of the natural characteristics of CTS are directly related
to its chemical and physical characteristics for usage in biomedical applications.
CTS’s physicochemical features include molecules weight, destruction level, and
water content [12]. CTS molecular mass and functional classes both play significant
parts in CTS-mediated microbial growth suppression. Electrostatic behaviour of CTS
also influences its biological characteristics and antibacterial action. It is linked to
CTS polycationic composition, which probably interacts with the primarily anionic
components to modify permeability and cause intracellular component leakage,
which ultimately causes cell death [26]. Additionally, CTS can attach to the electronegative substrate of microbe protein in the cell, disrupting the physiological
functions of the microbe and ultimately causing cell death [27]. Strong electrostatic interaction results in a higher positive charge concentration, and the amount of
deacetylated CTS and its by-products has a major impact on its electric charge density.
Furthermore, it was observed t hat CTS with a substantial amount of deacetylated may
have a higher positive charge density, conferring better antibacterial properties than
CTS with a moderate deacetylated [28].
3 Graphene: Structure, Types and Properties
GR constitutes a carbon allotrope that has a 2D, atomic-scale hexagonal lattice with
one atom creating each vertex via sp
a length of about 0.142 nm. Each lattice includes three strong interconnections that
form a solid hexagonal structure. The majority of GR’s electrical conductivity is
attributed to the bond that is positioned vertically to the lattice plane. GR is stable
due to its densely packed carbon atoms and sp
combination of orbitals s, p
, and pythat make up the -bond (Fig. 3). The last p
x
electron forms the π-bond. The π band and the -bands are created when the π-bonds
come together. These bands can responsible for the majority of GR’s remarkable
electronic features, thanks to the half-filled band that allows electrons to move freely.
GR can be seen of as a unit structure comprising graphite, carbon nanotubes, and
fullerene, as well as infinitely small aromatic molecules like highly planar polycyclic
aromatic hydrocarbons.
GR is made up of a single layer of tightly packed carbon atoms that form a twodimensional honeycomb lattice structure (Fig. 4). Carbon atoms in single layer GR
form an unpaired electron-donating benzene ring via sp
boring carbon atoms. GR’s structure is remarkably stable, despite this. To prevent
atom reconfiguration, the bond between carbon atoms is strong enough to withstand
the external force applied by a twisting lattice plane. A nanoribbon can be a limited
2
hybridization. The carbon–carbon bond has
2
orbital hybridization, which is a
2
hybridizing with neigh-
z
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 449
Fig. 3 a The makeup of an atom of carbon. b The energy states of carbon atoms’ outer electrons.
c The production of hybrids with sp
and a2and carbon atoms A and B from different sub-lattices. e illustrates how sp2hybridization
forms sigma and pi links. Reproduced with permission from Taylor & Francis [30]
2
. d The crystal lattice of graphene, with unit cell vectors a
structure of GR in which lateral charge flow causes an energy barrier to build near
to the center point. This energy barrier increases as the width of the nanoribbon
decreases [29]. As a result, the energy barrier may be precisely regulated by varying
the width of the GR nanoribbon, which is a promising feature for potential GR-based
electrical devices.
Due to light refraction and interference, GR with multiple layers would exhibit
varying hues and contrasts, which can be used to distinguish the layers of GR [32].
Both the experimental and theoretical findings point to a great visual characteristic
that is able to be altered by varying the width of the GR. When combined with its
exceptional conductivity, GR converts into a highly efficient transparent conductive
membrane with the potential to replace numerous existing membranes, including
1
Fig. 4 a Hexagonal structure of graphene monolayer, with white (black) circles indicating the
atoms of carbon on A (B) locations, and b monolayer graphene inverse structure. Reproduced with
permission from Springer-Verlag Berlin Heidelberg [31]
450 R. Priya et al.
indium tin oxide and fluorine doped tin oxide. In this industry, applications such
as GR could address difficulties like as fragility, contamination, and limited indium
resources. A GR mediated membranes might be used as a window barrier in solar cells
sensitive to dye and LEDs. Furthermore, after specific modifications, such as doping,
GR can be employed not only as a receiver for electronic products, nevertheless for
an electrode as supercapacitors. Furthermore, when the intensity of the illumination
passes a certain threshold, the absorption of light by GR reaches saturation. This form
of saturation absorption happens in the near-infrared region because to GR’s broad
spectrum of adsorption with zero band gap. This characteristic may be advantageous
in ultrafast photonics applications such as fiber lasers.
4 Chitosan/Graphene Nanocomposites: A Potential Drug
Carrier
The covalent, hydrogen bonding, and electrostatic interactions allow CTS and GR
to easily form composites. These composites outperform the separate components
in terms of performance. According to recent study, the synergistic effects of CTS
and GR yield hybrids in combinations with enhanced thermal endurance, mechanical energy, and photonic qualities [33, 34], and also outstanding in vitro and in vivo
biocompatibility [35], angiogenesis and proliferating cells effects [36], and antibacterial properties [37] among other things. The thermomechanical and antibacterial
activities of packaging materials for food, electrical multidimensional structures,
covering, and nanofiber for tissue regeneration have all benefited from the development of nanocomposites comprising CTS and GR [33]. In light of the multitude
of uses that CTS/GR nanocomposites have demonstrated recently and their bright
future, it is beneficial to examine the most recent accomplishments in order to guide
future investigations and applications (Fig. 5).
Because of their biocompatibility, unusual conjugated structure, vast surface area,
and low cost, GR and its derivatives have sparked renewed interest for healthcare
and biological applications. The in vitro cellular absorption capacity of polyethylene glycol-functionalized nanoscale graphene oxide (GR) as a nanocarrier to load
chemotherapeutic medicines via noncovalent physisorption was examined [38].
Following that, it was demonstrated that PEGylated nanoGR sheets itself have ultrahigh in vivo cancer uptake and efficient photothermal treatment capabilities in mice.
When doxorubicin hydrochloride was packed and released on GR, Jafari et al. [39]
found that the weight proportion of the loaded drug to the GR carrier might be as high
as 200%. In response to these findings, Pal et al. [40] modified GR using sulfonic
acid and folic acid categories, making it physically stable and providing precise
cell-targeting potential. Furthermore, the regulated loading of two chemotherapeutic
medicines, doxorubicin and camptothecin (CPT), into the folic acid-conjugated GR
was investigated using stacking and hydrophobic interactions. The folic acid-GR’s
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 451
Fig. 5 Diagram demonstrating the production of glycidyl methacrylate (GM), glycidyl methacrylate (QCSG), and GM/graphene combination; network diagram demonstrating the uses of QCSG/
GM/graphene hydrogel in wound healing and disinfection. Reproduced with permission from ACS
[41]
codelivery of two drugs showed highly significant cytotoxicity and targeted activity
against MCF-7 cells in contrast to a GR loaded with only DOX or CPT.
The outer layer of GR is inactive because it lacks active groups, and the impact
occurring among the polymer substrate on GR is weak. Because of the difficulty in
processing, GR is changed through oxidation to produce GO. Most hydrophobic polymers, however, are incompatible with GR because to the huge amount of hydrophilic
bonds on its surface. As a result, modifying the surface of GR is a key strategy for
producing high-performance CTS/GR nanocomposites (Fig. 6). The most important
step is dispersing GR into the polymer matrix. Good dispersion can maximize the
physical interface among the polymer substrate and GR, influencing the general efficacy of the nanocomposites. Much effort has been expended to equally disseminate
altered or unmodified GR within the matrix of polymers, with promising results.
So far, the majority of CTS/GR nanocomposites were created using the following
approaches.
452 R. Priya et al.
Fig. 6 A straightforward method based on the synergetic electrostatic interaction and hydrogen
bonding in aqueous medium was used to produce CTS/GR hybrid films
4.1 Electrospinning Method
A relatively new method of creating fibers is called electrospinning, which involvesjet
spinning polymer melts or mixes using an electrical force. Spherical droplets within
a needle form cones under an electric field, and fibrous filaments extend through the
center of the cone tip. A modern, easy-to-use, and widely accessible technique for
creating nanofibers is called electrospinning. In this process, a polymer liquid that
has been dispersed by static electricity is pushed far before it eventually expands
into fiber [42]. Fathollahipour et al. [43] used aqueous electrospinning to successfully prepare polyvinyl alcohol/CTS/GR biological composite nanofibers, and they
were the first to synthesis CTS nanofibers using nontoxic, solution-based GR. The
addition of GR considerably improved the mechanical characteristics, hydrophilicity,
and antibacterial activity of PVA/CTS fibers. These fibers might be useful in tissue
engineering, medication delivery, and wound healing. A polyoxyethylene/CTS/GR
nanofiber scaffold with the ability to regulate adriamycin release was developed by
Zuo et al. [44]. In addition to exhibiting strong stability and proving drug delivery,
the electrospun nanofibers resolved previous issues with electrospun CTS, including
low mechanical qualities, limited solubility, and instability.Moreover, π–π
*
allowed for the strong coupling of adriamycin, and π–π
stacking was helpful in regulating drug release. Polyethylene oxide/CTS/GR are good materials for delivering
anti-cancer medications since they have no negative impacts on normal cells and
tissues. The World Health Organization estimates that billions of people worldwide
do not have access to clean consuming water annually. Conversely, excessive pressure and membranes are required by water filtration systems in order to eliminate
heavy metal ions and parvovirus infection. An electrospun hybrid fiber composed
of CTS and GR may be able to absorb membraneless viruses and eliminate bacteria
and viruses from water, based on the research by Fahimirad et al. [45]. As a result,
*
bonding
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 453
this finding is significant for locations where fresh water is scarce and filtration
membranes are not possible to use.
4.2 Sol–gel Method
The following processes are often included in the sol–gel process: hydrolysis; particle
development; accumulation of polymeric nanostructures; condensation and conversion of monomers into chains; and network construction. Making a sol is the first
step. The catalyst and initiator are combined and dissolved in the solvent at the proper
temperatures to create the sol. When the condensation processes and hydrolysis start,
the viscosity rises along the condensation reaction’s route to produce a colloidal sol.
At or close to the conclusion of these reactions, the coating process can begin. The
gel-colloid system is made up of a fluid distribution encased in a spatial grid with
particles scattered throughout. The sol–gel formation then becomes a freeze gel,
which is quickly followed by a phase involving air drying and/or thermal treatment.
Gel reinforcing and sol stabilization, if necessary, can both be carried out [46].
After applying the coating to the surface, the top most layer of coating may
be created through thermal annealing. Particles start to form cross-structures when
they group together to initiate the gelation process. The gel is made up of different
organic frameworks and solvents; while being liquid, it looks solid. Consequently,
this structure’s solvents are removed in order to collect the aerogel [47]. The sol–
gel mechanism is influenced by multiple factors, such as the type of substance to be
used, together with the solvents and precursors. Other important factors that influence
the length of the gelation process and the structure of the solution include the pH
and temperature of the solution, composition, stabilizing agents, and drying control
chemical additives [48].
Nassar et al. [46] used this technology for the very first time to create GRbased aerogels. The authors proposed combining resorcinol and formaldehyde using
sodium carbonate in an aqueous solution of GR. Danks et al. [49] used the sol–gel
process to create a GR aerogel with a high nitrogen concentration. The product was
created by freeze-drying a GR/melamine–formaldehyde hydrogel and then thermally
treating it. The findings showed that as GR concentration increased, the CTS were
more equally loaded into the GA owing to a permeable separation effect.
4.3 Solution Mixing Method
Solution mixing is the process of combining GR and another component in order
that the additional material can be incorporated into the GR through a solvent that is
used. The composite is then created using a stabilizing substance. Prior to building
a magnetic CTS/GR composite with unique properties, Szabó et al. [50] created
454 R. Priya et al.
cationic active hexa-alkylguanidinium ionic liquids and anionic operational tetraalkylguanidinium ionic liquids. Bovine serum albumin, ovalbumin, lysozyme, and
trypsin were all extracted satisfactorily. A variety of biomolecules will be processed
using the readily recyclable CTS/GR-functional guanidinium ionic solution. Yuan
et al. [51] created a CTS/GR ionic solution composite and observed that it could
swiftly and efficiently remove Cr
and environmentally friendly.
3+
. It also offers the advantages of being economical
4.4 In-situ Polymerization Method
GR and monomers undergo in-situ polymerization, and monomers agglomerate
between GR layers through an initiator. Theory to practice must ultimately be
adapted through the exploration and discovery of novel materials. Velusamy et al. [52]
discarded previous methods of GR reduction and developed a technique aimed at the
vat dye industry in which GR decreased using sodium dithionite as the catalyst and
CTS/GR composites created using in-situ polymerization. According to the study,
when GR is evenly distributed throughout the polymer matrix, it may effectively
convert GR to graphite and greatly enhance its physical and electrical properties.
5 Types of Chitosan/Graphene Nanocomposites-Based
Nanocarriers
Research on the use of biopolymers enhanced with nanoparticles has advanced significantly over the past 10 years, as shown by a number of reports on the potential
medical uses of CTS/GR nanocomposites. The next section of the chapter conducted
a brief discussion of types of CTS/GR nanocomposites based nanocarriers work on
the subject, concentrating mostly on presenting the most innovative application area
of drug delivery (Fig. 7).
5.1 Chitosan/Graphene Nanofibers
Electrically spun materials resemble the extracellular matrix structurally; they may
improve cellular adhesion, proliferation, and migration. This makes them a promising
alternative for use in wound dressing applications. They have the ability to keep open
wounds free from external microbial contamination and to hold onto surface moisture
to promote wound healing. Due to their huge surface area, electrospun nanofibers
are well suited for use in drug delivery systems [54].