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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 455
Fig. 7 Diagram showing the functionalization of graphene (GR) with chitosan (CTS) connected
to folic acid (FA) and preliminary examinations for two cancer cell models. Reproduced with
permission from ACS [53]
Yang et al. [55] used an electrospinning method to create CTS/PVA/GR
microfibers doped with antimicrobial drugs, such as ciprofloxacin and ciprofloxacin
hydrochloride. The data on medicine release showed a controlled release without
an early spike. The medicine released more quickly after GR was added. The drugloaded nanofibers demonstrated both antibacterial efficacy against Gram-positive
and negative bacteria and cytocompatibility with melanoma cells. An additional
investigation found that the heat resistance of hybridized composite nanofibers was
reduced when the GR content was increased in electrospun antibacterial CTS/PVA/
GR nanofibers [55]. The electrically spun nanofiber web demonstrated excellent
antibacterial properties towards a variety of bacteria, implying that it might be
employed for dressing wounds. Allicin, a naturally occurring garlic extract with
strong antibacterial properties, was incorporated into electrically spun CTS/GR
nanofibers. The study of release demonstrated that the GR concentration may regulate the amount of released allicin. When it came to Staphylococcus aureus,the
drug-loaded nanofibers showed good antibacterial activity, and the ones with GR
performed better than the ones without GR. The drug-loaded nanofibers also demonstrated a high degree of hygroscopicity and moisture retention, indicating potential
uses in tissue engineering and as wound dressings.
5.2 Chitosan/Graphene Aerogels
Because of their large particular area of surface, lack of density, and light weight,
aerogels are widely used. Despite its delicate appearance, it is actually very strong
and resilient, able to withstand pressures hundreds of times its own weight. It can
endure temperatures up to 1200 °C before melting. It has a 39-fold higher insulating
456 R. Priya et al.
capacity than the best glass fibers. Supersonic drying and sol–gel preparation are the
usual methods used to create aerogels [56].
Wet gel is the sol–gel phase. In this stage, the starting material dissolves in solvents
to produce a homogenous dispersion solution. The sol is created through hydrolysis
or alcoholysis. After that, the gel can created through drying and evaporating. The
wet gel’s volume drastically decreases throughout the drying process since it contains
water and basic solvents. Surface tension during regular drying could cause holes
to burst, limiting the amount of pores and surface area. To prevent this, a liquid can
be made into a supercritical fluid by heating and pressurizing it in a pressure vessel.
This process is known as supercritical drying. The liquid’s density and saturation
vapor pressure are equivalent under critical conditions. In this state, in which both
gaseous and liquid stages exist together, so the interface among the gaseous stage and
the liquid state goes away the force of capillary action in the moist gel additionally
goes away holes are unable to disintegration, and a relatively greater pore area and
volume are achieved [56].
Guerrero-Fajardo et al. [57] created GR/CTS an aerogel since excessive stacking
of GR sheets in GR adsorbent affects its pollutant adsorption capacity. However,
after adsorption, an aerogel can be easily removed from the system. The aerogel
absorbed cupric ions well, notably at greater pH, reduced strength of ions, and higher
temperature. As the contamination of the environment worsens, GR/CTS an aerogel
is going to have an increasingly essential role in a variety of industries. Because
most dyes are non-biodegradable, they are difficult to remove. Zhu et al. [58]used
crosslinking and freeze drying to create porous CTS aerogels doped with GR. It is
expected that porous GR/CTS aerogels will find wide use in the chemical, biological,
plastic, paper, paint, and textile sectors, where they could provide a competitive
alternative to color removal.
5.3 Chitosan/Graphene Hydrogels
A smooth, cross-linked polymer gel that dissolves in water is called a hydrogel. It
can keep its shape and absorb an enormous quantity of water without dissolving.
Hydrogel is biodegradable and substance with numerous applications, such as
chemo-mechanical systems, biomimetic materials, and drug delivery networks [59].
To address the widespread issue of contamination of water, Jacob et al. [60] created
an environmentally friendly CTS/GR hydrogel for an innovative kind of adsorption
for water supply purification. Organic colorants and ions of heavy metals might
be absorbed by the CTS/GR hydrogel in wastewater. Absorbent CTS/GR is less
expensive and has superior biocompatibility, both of which are crucial in water
treatment. Wang et al. [61] investigated CTS chains with GR nanosheets, where
GR was employed to serve as a two-dimensional bridging agent. By adjusting the
temperature, CTS/GR rate, and GR concentration, they produced a CTS/GR hydrogel
material (Fig. 8). This hydrogel is reversible and self-healing, making it useful for
biological materials, waste disposal, and smart materials.
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 457
Fig. 8 Diagram showing the steps involved in making and using the PC/GO/Met hydrogel. a dihy-
drocaffeic acid and L-arginine-cografted chitosan (CS-DA-LAG), b polyethylene glycol-co-poly
(glycerol sebacic acid) difunctionalized with phenylboronic acid and benzaldehyde (PEGS-PBABA) and c polydopamine-coated rGO (rGO@PDA). Reproduced with permission from ACS
[62]
5.4 Chitosan/Graphene Thin Films
Due to its robust resistance to water and bacteria, as well as its high oxygen permeability, film is another material of choice for wound healing. The most popular
techniques for creating CTS/GR nanocomposite films are moist cast and drying
(often with the use of an oven or infrared drying). Numerous results suggested that
they held promise for wound healing. Wang et al. [61] research is particularly noteworthy. The “brick-and-mortar"-layered tiny structure and stacked and permeable
CTS/GR film biologic materials mimicking a structured permeable lamellar micronscale arrangement were produced by combining vacuum filtration-assisted building
and freeze-drying techniques. The biomaterials’ ideal tensile strength, airflow, and
water absorption characteristics were made possible by their hierarchical microstructure. Additionally,the film demonstrated antibacterial and anticancer activity in vitro.
In vivo methods revealed that the CTS/GR biological materials exhibited adequate
photothermal anticancer effectiveness as well as the ability to repair skin wounds.
458 R. Priya et al.
6 Application of Chitosan/Graphene Nanocomposites
in Drug Delivery
The second and most important field of biomedical applications for CTS and GR
nanocomposites is their usage as possible carriers for the regulated delivery of
medicines and biological macromolecules that include proteins, peptides, and nucleic
acids. Such systems enable medications to be delivered to precisely defined locations in the human body, such as cancer cells, hence increasing the efficacy of the
applied treatment. Numerous scientific articles devoted to study into the feasibility
of employing CTS/GR systems as effective medication carriers have proved this.
Hamghavandi et al. [63] sought to synthesize GR coatings functionalized with CTS
in 2010 due to a lack of previous work on the usage of GR sheets for controlled
dispensing of pharmaceuticals having one aromatic position in their molecular
structure. They employed an anti-inflammatory medicine, ibuprofen, and an anticancer therapeutic, 5-fluorouracil, as model pharmaceuticals in their investigations.
These findings demonstrated that GR sheets functionalized with CTS are a potential
substance for drug delivery applications (Fig. 9).
6.1 Oral Drug Delivery
Oral delivery was a very popular and simple method of administering medication. The
fact that this is a non-invasive treatment makes it much more important to mention.
But this is a drawn-out procedure, and bodily fluids like stomach acid may cause harm
Fig. 9 Oral, mucosal,
transdermal, and parenteral
drug delivery using CTS/GR
nanocomposites are common
modes of administration
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 459
to certain medications. The ideal medication carrier ought to have an arrangement
that creates strong bonds with active chemicals in the gastrointestinal system while
carrying them to target cells and protects them from destruction. Non-toxicity, being
biodegradable and biocompatibility are also required of the carrier, which CTS NPs
meet. The following is a summary of current oral drug delivery studies employing
CTS NPs for a drug carrier.
Complexes such as 10% Channa striata hydrolysate of proteins, CTS-PEG 4000,
and CTS-PEG 6000 NPs for oral delivery were produced, according to Jafernik et al.
[64]. The goal of the produced nanocomplexes was to lower the blood sugar levels of
rats with diabetes. Male Sprague–Dawley rats were used in the experiment. In each
formulation, diabetes was started by a single administration of streptozotocin. It was
discovered that the combination of 10% protein hydrolysate from Channa striata
with PEG6000 was the most efficient in lowering blood glucose levels. The amount
of glucose has also been demonstrated to decrease following 21 days of daily oral
treatment of CTS-PEG 4000 NPs. Blood levels of cholesterol, triglycerides, LDL,
and HDL were also reduced in treated diabetic rats compared to untreated ones [65].
Jafernik et al. [64] also interested in diabetes therapy. They created a new formulation that combined oral administration of CTS NPs using polytadine, which
increased polytadine’s therapeutic potential. The produced complex considerably
outperformed polytadine alone in diabetic rats in in vivo trials, suggesting that CTS
NPs may be useful as polytadine carriers in the treatment of diabetes of the type 2
variety [66]. In recent years, ibuprofen and 5-fluorouracil have been delivered via
CTS-functionalized GR. The mechanism of drug loading is primarily facilitated by
hydrophobic contacts and π–π stacking. In fact, implementing such non-covalent
interactions can stop the fundamental structure and physical characteristics of the
loaded agent from being altered or destroyed. The DOX-GR-CTS–folic acid nanohybrid combination is one such carrier that allows for a significantly larger release rate
of DOX at acidic pH (5.3) than at physiological pH (7.4) [67].
6.2 Mucosal Drug Delivery
Over the past few decades, numerous studies investigating novel and more efficient methods of drug administration have identified the mucosal route as a viable
non-invasive therapeutic channel for systemic drug administration. Because mucosal
delivery is non-invasive, painless, and has several advantages over parenteral administration—including easy access, rapid onset of action, removal of the hepatic firstpass effect, high bioavailability, low cost, self-administration, and good patient adherence—it is an exciting and feasible substitute for parenteral administration [68].
Additionally, mucosal delivery offers a variety of absorptive surfaces, including the
mucosa of the buccal, nasal, ocular, vaginal, and rectal regions. This presents a multitude of opportunities for both regional and institutional dosing of various chemicals,
enabling the possible of achieving high “in situ” concentrations and targeting specific
tissue (Fig. 10). In addition, mucosal delivery offers a variety of absorptive surfaces,
460 R. Priya et al.
Fig. 10 Internal mucosal
surfaces. Human body
schematic (left) and
representations of certain
mucosal tissues (right)
showing the variation in the
mucus layer’s thickness and
composition (blue) and the
underlying mucosa’s
thickness (yellow).
Reproduced with permission
from ACS [70]
including the mucosa of the buccal, nasal, ocular, vaginal, and rectal regions. These
surfaces offer a plethora of options for the systemic and regional dosing of various
chemicals. These options allow for the reduction of systemic side effects in local
disease therapy as well as the ability to target a specific tissue and achieve high
“in situ” concentrations of medications [69, 70]. Mucosal drug delivery can also
be achieved by oral administration of appropriate mucoadhesive delivery systems,
which utilize the mucosa lining of the intestinal tract [71].
Concurrent with the growing interest in mucosal delivery, polymers with mucoadhesive properties became more and more attractive as a basis for developing mucosal
delivery systems [68, 69], with CTS being a key player [72]. While CTS has been
proposed for application in numerous drug delivery method, it is indisputable that
mucosal drug delivery is currently the main focus of CTS-based systems. This is
because of the unique biological properties of CTS, which are especially well-suited
to promote and enhance mucosal delivery—as we will discuss later—or the growing
significance of the mucous pathway as an effective substitute form of administration.
Therefore, this section will briefly discuss the key characteristics that make CTS a
base component in mucosal delivery formulations. After that, several related examples that demonstrate the special advantages of this specific polymer for managing
the challenging issues and overcoming the inherent limitations presented by each of
these various drug administration sites will be provided, along with an illustration
of its applications in buccal, nasal, ocular, rectal, vaginal, and oral delivery.
6.3 Transdermal Drug Delivery
The dermis, epidermis, and subcutaneous tissues are the three layers that make up
the skin from the outside in. Transparent, granular, spinous, and basal layers make up
the stratum corneum, which is the layer of the epidermis that is organized from the
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 461
outside inward [73]. The stratum corneum, a layer of dead keratinocytes, is located
on the shallowest part of the skin. It contains moisturizing, anti-friction, and antiinvasion properties, and inhibiting the migration of fluid from tissues from the body
and the spread of chemicals and germs [74]. Designing the best delivery pathway for
drugs has always been a priority in the area of drug delivery studies. Since skin is the
largest and most mass-producing tissue in the human body, it is unquestionably the
greatest organ to deliver a wide variety of medications [75]. In comparison with other
methods of administration including intravenous and consumption, skin distribution
has the advantages of minimizing the first-pass impact, having a lengthy administration interval, maintaining a steady blood concentration, achieving local or widespread
administration. However, skin problems indicated by the stratum corneum severely
impede many medications’ percutaneous absorption. As a result, the key difficulty for
researchers is determining how to ensure efficient transdermal medication delivery
in order to produce greater therapeutic benefits.
Patches, lotions, spreads, sprays, and other similar transdermal treatments are
currently available [76]. These medicines are commonly used to treat skin diseases.
Laser devices operating in fraction form have been suggested as well to improve
medicine transdermal delivery [77]. They have though several disadvantages,
including poor patient compliance, low bioavailability, low transdermal absorption
of medications, and unpleasant side effects such localized skin stimulation [78, 79].
To get around the aforementioned problems, researchers are searching for novel
supplemental materials. Because of their remarkable durability and adhesion capabilities, some manufactured high-molecular-weight polymers, like PLA and PEG,
are being employed for drug delivery through the skin [78, 79]. But there are issues
related to such artificial polymers with high molecular weights that still need to be
addressed, such as immunogenicity, cytotoxicity, inertness, and disintegration. For
these reasons, researchers prefer to use naturally occurring high-molecular-weight
polymers like polysaccharides. This process, or the hydrolysis of several monounsaturated molecules, yields polysaccharides. These are large molecules of carbohydrates with an intricate molecular structure. One of the many physiological benefits of
partially reducing the acetyl of the organic polysaccharides chitin is CTS, which can
suppress bacteria, improve immunity, reduce blood fat, and resist cancer [28, 80, 81].
6.4 Parenteral Drug Delivery
Chemotherapeutic drugs administered parenterally through intravenous (IV) or intraarterial methods have low selection, poor biodistribution, rapid removal, and systemic
toxicity, particularly at large doses [82]. Furthermore, parenteral delivery of anticancer medicines frequently fails to give a clinically efficient amount of treatment
that is required for solid tumor elimination. For example, when delivered via an
intravenous drip for the therapy of lung cancer, a maximum of 0.5 percent of the
entire dosage of paclitaxel is accessible at the cancerous site [83]. This could be
because huge solid tumors are difficult for chemotherapy and/or immunotherapy
462 R. Priya et al.
medications to deeply penetrate because of their chaotic structure and insufficient
blood flow. When cancerous cells are repeatedly exposed to less-than-lethal amounts
of chemotherapy, they may acquire resistance to the anticancer treatments [84, 85].
7 Challenges and Future Perspectives
Right now, one of the most fascinating areas of research is nanomedicine. Extensive
study on this topic over the past 20 years has led to the completion of countless
clinical studies and the filing of 1500 patents [86]. As was discussed in the sections
prior to this one, cancer seems to be the most prominent instance of a disease where
nonmedical innovation has benefited in both detection and therapy. Research and
development into the application of nanomedicine and nano-drug devices for delivery
will surely continue in this rapidly developing field for many years to come. CTS/GR
nanocomposites are used to ensure that a specific amount of drug is delivered to the
affected cells, such as cancer/tumor cells, without interfering with the physiological
functions of the normal cells.
More study would be conducted on composites with greater uniformity as well
as the loading of drugs and release capacity. This chapter also discusses significant
advancements in the use of polymer-based nanocomposites for diagnostic purposes.
More studies on the use of these polymers, in particular CTS in treatment and diagnostics, could open the door to a greater variety of nanomedicine uses. In this arena,
CTS/GR nanocomposites are an interesting source of interest since they seem to be
effectively absorbed in sensitive tumor tissues, enabling heat therapy-based radiation
to target and eradicate the tumor specifically.
Despite widespread recognition of the future potential of nanotechnology in
medicine including nano-drug delivery systems, its actual influence in the healthcare
system, including cancer therapy/diagnosis, remains quite restricted. This is because
there has only been two decades of real research on the topic, making the field a
young one with numerous important basic characteristics still unknown. One major
future field of research will be the fundamental indicators of sick tissues, including
crucial biological indicators which enable absolute targeting without affecting the
normal cellular process. Finally, the use of nanomedicine will grow when we gain a
better understanding of diseases at the molecular level or that reflects a nanomaterialsubcellular scale similar biomarker recognition to open up new pathways for new
diagnosis. As a result, understanding illness molecular fingerprints will lead to breakthroughs in nanomedicine applications in the future. Additional study beyond what
we have detailed in this review using existing nanoprobes and nanotheragnostics
items would be critical for the broader use of nanomedicine.
The concept of precisely administering specific medications to susceptible areas
still needs improvement, as does the technology for assessing these incidents,
drug activity at the tissue or cellular level, and theoretically mathematical prediction models. Biomaterials and formulation research seem to be the early stages of
Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 463
biomedicine applications, and so are the subject of many nanomedicine investigations. Extensive time and resource-intensive transdisciplinary research and animal
investigationswill yield important data for potential drug therapy and diagnosis trials.
The global trend toward more accurate diagnosis and medication looks to be pointing
toward a promising future for nanomedicine and nano-drug delivery technologies.
There has been a lot of excitement about the fabrication of nanodevices which
assist in tissue diagnosis and repair processes and have full external control mechanisms. This is still far from reality and continues a futurist research project that
humanity may be able to achieve in a matter of years. Further study is needed to
fully understand the threats that nanomedicines may pose to people and the environment as a whole. Consequently, a comprehensive evaluation of the potential negative
either immediate or lasting impacts of novel composites for people and the environment is required. As nanomedicines gain prominence, a different field of research
that requires additional attention is their cost. Finally, as discussed in the preceding
section, the laws governing the use of nanomedicines will evolve in tandem with
technological developments in nanomedicine applications.
8 Concluding Remarks
By combining CTS with GR, nanocomposites with outstanding physical efficiency,
bioactivity, and biocompatibility can be successfully created. This has resulted in
an increase in the number of academic articles on the application of CTS and GR
nanocomposites in numerous sectors, most notably biological materials. CTS/GR
hybrid systems have a substantial specific area and a large number of amino and
functional groups that contain oxygen, which make them desirable choices for the
delivery of medications and biomolecules. The constructed delivery systems may
additionally be targeted by engaging with targeting ligands or magnetic nanoparticles
while having an excellent drug loading ability and a slow release rate. Due to their
capacity to promote electron transport when fixed into electrodes, which yields great
sensitivity and selectivity, they also form good biosensor substrates. The issue is that,
in comparison with previously described frameworks, CTS/GR composites possess
insufficient electron transport.
Moreover, the CTS/GR composite can offer an environment that is favorable
for cell migration, proliferation, and differentiation. They all have very significant
osteoinductive activity. For this reason, CTS/GR nanocomposites are essential in
tissue engineering, particularly in bone regrowth. Furthermore, it is thought that CTS/
GR nanocomposites having strong antibacterial properties towards gram-negative
and positive bacteria play an important role in wound dressings. However, current
related studies have primarily concentrated on leveraging the functionalities of each
of the bioactive components alone, ignoring the need of building distinct micro and
nano-topographies. Special surface texture can significantly improve bone formation or antibacterial properties. The haemostasis impact of the covering is a crucial
factor in wound healing that is often overlooked. Overall, greater emphasis should
464 R. Priya et al.
be placed in the future on developing CTS/GR nanocomposite having topographic
features. It is also promising to integrate several different features at the same time.
It should be mentioned that when used in biosensors, enhancing the electron transfer
performance of CTS/GR nanocomposite remains difficult. Furthermore, comprehensive biological research for possible biotoxicity should be conducted before implementing nanocomposites constructed using CTS and GR in regular clinical practice.
What happens to the CTS/GR nanocomposites once they are implanted in the body is
also concerning. Furthermore, the breakdown rate of the manufactured biomaterials
should be matched to the duration of tissue regeneration. We are confident that the
CTS/GR nanocomposites will have improved performance and a broader range of
biological fields.
Acknowledgements This work was supported by the Basic Science Research Program through the
National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future
Planning (NRF-2022R1I1A1A01069472).
Conflict of Interest The authors declare that there is no conflict of interest in publishing this
article.
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