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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5882_Библиотеки_им_академика_М_И_Перельмана.pdf
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Carbon Nanomaterial-Based Polymeric Nanocomposites for Drug … 175
Fig. 2 Schematic representation of the effect of nanocomposites on the healing of infected wounds. Reproduced with permission from Wiley–VCH [21]

2.5 Fullerene-Based Polymer Nanocomposite

Fullerenes are highly thermally and chemically stable and maintain their structural integrity under extreme conditions. This has led to the wide application of fullerenes in the fields of materials science and chemical engineering. The cavities and func­tional groups of fullerenes provide many chemical reaction sites, making them rich in chemical reaction activity, and the solubility, stability, and interactivity of fullerenes can be tuned through functionalized modifications. In addition, due to their high stability and structural compactness, fullerenes can be used as material enhancers to improve the mechanical, thermal, and optical properties of materials.
Fullerene molecules are composed of polyhedral (i.e. pentagons and hexagons) and have high intensity and electrical conductivity. Common forms of fullerenes are C Buckminsterfullerene. Compared to organic nanoparticles, inorganic nanoparticles are non-toxic, hydrophilic, chemically stable and biocompatible.
Nanocomposites were synthesized by modifying iron oxide nanoparticles (IONP) on C
60
IONP-PEG, which binds the tumor-targeting molecule, folic acid (FA), to C IONP-PEG to obtain active targeting. This multi-purpose nano-platform can also kill
, and C80.C60is the most common fullerene and is also known as
60,C70
while functionalized with polyethylene glycol (PEG2000) to prepare C60-
60
-
176 D. Song and H. Li
Fig. 3 Preparation of C60-IONP-PEG-FA and its function. Reproduced with permission from Elsevier [27]
cancer cells specifically in highly localized regions through superior active tumor targeting and magnetic targeting capabilities (Fig. 3). The study showed that this multifunctional nanoplatform had great potential for application in cancer therapy [27].
together with iron oxide nanoparticles and upconverted nano-phosphorites
C
60
(UCNPs) were loaded into biocompatible n-succinoyl-n ‘-4-(2-nitrobenzyloxy) succinoyl-chitosan micelles (SNSC). Furthermore, the nanocomposites were loaded with the hydrophobic anticancer drug docetaxel (DTX). In vitro and in vivo exper­iments showed that C
Fe3+and UCNPs@DTX@SNSC could act synergistically
60/
to release chemotherapeutic drugs at specific targets and generate reactive oxygen species at 980 nm to kill tumor cells [28]. The C achieved by precipitating gold nanoparticles on C
@Au hybrid nanocomposite was
60
and functionalized by PEG5000
60
with pH cleavable hydrazone bonds to keep the to keep PEG on the surface of the drug delivery system during cycling of C PEG with very efficient drug loading. C
@Au-PEG, and then DOX into the C60@Au-
60
@Au-PEG/DOX has higher anti-tumor
60
efficacy as tumor uptake of DOX is 8.6-fold higher than that of DOX. In addi­tion, it can be used as an X-ray contrast agent [29]. Polyethylene glycol modifies the IONP on the surface of C hematoporphyrin monomethyl ether, is combined with C
, and then a novel photodynamic anticancer drug,
60
-IONP-PEG to form a
60
novel drug delivery system, which has demonstrated excellent magnetic targeting ability in cancer therapy [30].
Carbon Nanomaterial-Based Polymeric Nanocomposites for Drug … 177

2.6 Nanodiamond-Based Polymer Nanocomposite

Nanodiamond (ND) is a crystalline structure composed of carbon atoms. ND is biocompatible with living organisms and does not cause significant toxicity reac­tions, has a high specific surface area, providing more surface active sites and the possibility of functionalization modification, excellent hardness and strength charac­teristics, can withstand extreme conditions such as high temperature, high pressure and friction, excellent optical properties, including a wide range of absorption and emission spectra and high fluorescence brightness, high chemical stability, good tolerance to environmental conditions such as acids and bases, oxidants and high temperatures, and ease of functionalization modification, which allows the i ntroduc­tion of different functional groups by chemical methods to increase their ability to interact with biomolecules. So ND plays a more important role in biomedicine and biotechnology.
Hydrogel materials were prepared from gelatin, chitosan, and NDs to promote wound healing. NDs were complexed with vascular endothelial growth factor (VEGF) and incorporated into the hydrogel network for sustained release of VEGF (Fig. 4)[31]. There are also polyvinylidene fluoride (PVDF) composites with NDs as fillers, and taking advantage of the cell culture properties of the polymers and the potential of NDs fillers for protein functionalisation and drug delivery, NDs/PVDF composites would be a suitable platform for biomedical applications [32].
Although there has been much research into the use of NDs in biomedical appli­cations, ND is more widely used in electronics, energy and optical devices because of its unique properties, so scientists are investigating how nanodiamonds can be used more for drug delivery and surface coatings on medical devices to improve therapeutic efficacy and reduce side effects.
Fig. 4 Synthesis of NDs/VEGF. Reproduced with permission from Elsevier [31]
178 D. Song and H. Li

3 Drug Delivery Systems Using Carbon Nanomaterial

3.1 Anticancer Drug Delivery

Recently, the incidence and death rate of malignant tumors have been on the rise year by year, which is one of the reasons that threaten the life and health of our nationals. There are many anti-cancer drugs, but the development of anti-cancer drugs has been at a difficult stage due to the fact that most of them are not strongly targeted in vivo, have a short duration of action, and are not biocompatible. Drug carriers can be a good way to improve the deficiencies of drug therapy and this subsection focuses on carbon-based nano-polymers as drug carriers against cancer. Studies have shown that carbon nanomaterials are effective carriers for selective and controlled drug release and therapeutic agents. Synthesis of chitosan/MWCNT composites based on polymer matrices and 5-fluorouracil (5-FU) encapsulated composites. In addition, their 5-FU release characteristics were also evaluated. The encapsulation rate of 5­FU in the nanocomposites was calculated to be 97% with an IC50 value of 60 lg/ml, making the system applicable for the elimination of cancer cells [33].
Nasari et al. also used MWCNTs and 5-FU, but the former was with PCL/PVP to form core–shell nanofibers and the latter as an inner core structure. The MTT assay of the HeLa cell line studied by the authors indicated that the cell toxicity of the 5-FU loaded nanofibers was 35.72% after 50 h. Therefore, it was confirmed that the drug-loaded nanofiber pads were non-toxic and efficacious carriers on cervical cancer cell lines. Therefore, this drug delivery system has demonstrated potential as a postoperative anti-cancer drug delivery system [34].
Murugesan et al. prepared drug-loaded nanocarriers from surface-functionalized MWCNTs and polymers or silver nanoparticles. They concluded that nanocom­posites loaded with Ibrutinib (Ibr) coupled to T-30 oligonucleotides (T-30 ODN) can be used to target prostate-specific membrane antigens that are overexpressed in the prostate. Evaluating the anticancer activity of nanocomposites against prostate cancer, the composites exhibited higher cell killing efficiency compared to free Ibr. Thus, this material could be used as an effective drug delivery system for targeted therapy of prostate cancer disease [35].
Ozgen et al. coupled DOX with two different copolymers, and the synthesized copolymers and FA were encapsulated in CNTs, respectively, resulting in a highly efficient drug delivery platform for dual-targeting of glucose transporter protein and folate receptor in breast cancer. Using characterization methods, the authors demon­strated that the hybrid CNTs were successfully internalized in MCF-7 and MDA­MB-231 human breast cancer cell lines. Therefore, it is feasible to use DOX-coupled carriers for dual-receptor-mediated breast cancer therapy in vitro [36].
Wang et al. successfully fixed fluorescent carbon nanoparticles (FCNPs) in poly (n-isopropylacrylamide-co-acrylamide) [poly (NIPAM-AAm)] nanogel to obtain a hybrid nanogel. This gel can combine the functions of each building block, thereby improving the ability of the nanogel to load curcumin (Cur) drug molecules and regulate the rate of release of anticancer drugs, it is also able to break through the cell
Carbon Nanomaterial-Based Polymeric Nanocomposites for Drug … 179
barrier into the cell and illuminate mouse melanoma B16F10 cells under excitation light. Therefore, the gel can be used as a drug carrier [37]. Xu et al. prepared a simple bio-inspired strategy for the surface PEGylation of CNTs via mussel-inspired and Michael addition reactions, where the anticancer drug adriamycin hydrochloride was used. The experimental results showed that the polyethylene glycolated CNTs were well dispersed in liquid solution and exhibited improved biocompatibility towards cancer cells. Since DOX can be efficiently loaded onto these polyethylene glycolated CNTs, they can be delivered to cells for cancer therapy. This approach is important for the preparation of nanocomposites for multifunctional biomedical applications [38]. Cancer is a major health danger and the fight against cancer has been a major research topic worldwide. Most of the anti-cancer drugs have a large number of deficiencies, so the surface modification of drug carriers to make anti-cancer drugs more effective can solve the shortcomings of anti-cancer drugs for tumor treatment. The development of new anti-cancer drug carriers and new drug delivery systems will certainly contribute to the further development of cancer therapy.
3.2 Lung-Specific Drug Delivery
Lung-specific drug delivery is a method of delivering drugs directly to the lungs to treat respiratory diseases. This approach has many advantages, including direct action at the site of the disease, avoidance of gastrointestinal absorption and first-pass metabolism, and increased local concentration of the drug. In recent years, nanotech­nology has played an important role in lung drug delivery. Nanodrug delivery system can enhance the therapeutic effect by changing the physical and chemical properties of drugs and improve the residence time and penetration ability of drugs in the lungs. For example, carriers such as nanoparticles, nano-micelles or nano-liposomes can be used to encapsulate drugs and achieve precise lung delivery.
Singh et al. formulated chitosan-folate coupled MWCNTs for targeted delivery of lung cancer DOX. The authors show that this targeted drug can be easily internalized into lung cancer cells via folate receptor-mediated endocytosis pathway (Fig. 5)[39].
The surface volume, charge density, and surface polymer coating of CNTs are critical components that determine the effect of f-CNT on the interaction with DNA and peptides and the formation of electrostatic complexes. f-SWCNT compounded with chitosan nanoparticles (NG042) to deliver DNA encoding EGFP reporter proteins or FITC-tagged peptides was used. The cells of bronchoalveolar lavage fluid from mice administered with f-SWCNT showed increased absorption of chitosan by lung cells. Furthermore, f-SWCNT-chitosan was more effective in intracellular delivery of peptides compared to chitosan. Collectively, these findings suggest that f-SWCNT-chitosan dramatically increases the delivery of DNA and peptides into cells [40].
The utilization of chemotherapeutic drugs in the treatment of cancer is often restricted by delivery problems such as non-solubilization, incomplete biodistri­bution efficiency, absence of selectivity, and the failure of drugs to pass through
180 D. Song and H. Li
Fig. 5 Delivery mechanism DTX formulation into human lung cancer cells (A549 cells). Reproduced with permission from Elsevier [39]
the cellular barriers. In order to overcome these limitations, alternative types of drug delivery systems have been investigated, and more recently, CD materials have attracted considerable attention in the field of drug delivery. The authors decorated PEGylated CDs loaded with cisplatin (CDDP) with polyethylene glycolated iRGD peptides (CDs@CDDP-iRGD). Since the nanoparticles effectively destroy cancer cells without destroying non-cancerous cell lines. Therefore, this material has a promising future in specific cancer treatments [41]. Singh et al. prepared a drug delivery system for the loading of anticancer drug Cur based on polysaccharide func­tionalized SWCNTs such as alginate (ALG) and chitosan. Modification of SWCNTs results in high drug loading productivity and sustained drug release, which is neces­sary for drug activity. The researchers used human lung adenocarcinoma cells as a model to demonstrate their anti-cancer potential [42].

3.3 Infectious Disease Drug Delivery

In recent years, there have been increasing numbers of infectious disease outbreaks around the world. The burden on the global economy and public health is consider­able. The use of carbon nanomaterials as antimicrobial agents is an effective solution. Dgo Xuan et al. prepared CNTs-Ag nanoparticles and graphene oxide-silver nanopar­ticles (GO-Ag) nanocomposites by photochemical methods, which could be stably
Carbon Nanomaterial-Based Polymeric Nanocomposites for Drug … 181
dispersed in aqueous solutions. The results showed that the size distribution of the materials was almost uniform and that the materials have high potential as effec­tive and long-term sterilization solutions for the elimination of infectious bacterial pathogens as they exhibited enhanced antibacterial activity against E. coli and S. aureus (Fig. 6)[43]. Banerjee et al. used a modified CNT, porphyrin-coupled multi- walled carbon nanotube (NT-P) to prepare an effective antiviral drug, and NT-P is very effective in dealing with influenza viruses [44].
In summary, carbon nanomaterials have extensive progress and value in infectious disease drug delivery. Through their antimicrobial activity, drug delivery, immune regulation, bioimaging, antibiofilm activity, and other properties, carbon nanoma­terials have the potential to be used in the treatment and prevention of infectious diseases. However, further research and clinical trials are still needed to determine the safety and efficacy of carbon nanomaterials and address the associated technical challenges to achieve their practical application in the field of infectious diseases.
Fig. 6 The synthesis process of materials (up); antibacterial properties of the material (below). Reproduced with permission from Springer [43]
182 D. Song and H. Li

3.4 Topical Drug Delivery

Local administration of chemotherapeutic agents using planted delivery systems is a perspective strategy for the diagnosis and treatment of malignant brain tumors. Regional administration provides high concentrations of local anti­tumor agents, thereby increasing antitumor capacity and reducing the number if system treatments. Shamsipour et al. prepared core–shell-poly (ethylene oxide)­CQDs /carboxymethylcellulose-poly (vinyl alcohol) (CS-PEO-CQDs/CMC-PVA) nanofibers by coaxial electrostatic spinning as temozolomide (TMZ) locally delivered biodegradable polymer implants. The release of TMZ from core–shell nanofibers in vitro showed a biphasic pattern. After the initial burst, continuous release of the drug was observed for nearly 30 days. The antitumor activity of CQDs­TMZ in vitro was higher than that of free drugs. Therefore, this material can be used as a traceable drug delivery agent for local cancer treatments [45, 46]. Qi et al. used MWCNTs to encapsulate the model anti-cancer drug DOX. These were then mixed with a polypropylene-co-ethylene-glycolide (PLGA) polymer solution and electro­statically spun to form drug-carrying composite nanofiber mats. As both the PLGA polymer and MWCNTs are drug carriers, this dual container drug delivery system (PL) facilitates the avoidance of burst releases and enables the sustained release of the anti-tumor drug DOX for 42 days. Therefore, it can be utilized as a therapeutic scaffold material for postoperative local chemotherapy [47].
Injectable thermosensitive hydrogels are commonly used as topical drug delivery systems (DDS). Guo et al. prepared chitosan-functionalized graphene oxide (CS-GO) nanocarriers (DOX/CS-GO) loaded with topical hydrophilic DOX in a polypropylene cross-ester (PLA)-polyethylene glycol (PEG)-PLA thermosensitive hydrogel by pi­pi stacking and hydrophobic interactions. Since the in vitro release of the PLA-PEG­PLA/(CS-GO/DOX) complex lasts >200 h, this injectable composite hydrogel is expected to be utilized as a drug carrier and for clinical applications in situ [48]. Due to the significant mortality rate of female breast cancer patients, the treatment of breast cancer has received much attention worldwide. In order to reduce the risk of body organs being exposed to the high cytotoxicity of ordinary chemotherapeutic agents, local co-delivery of selected chemotherapeutic agents has become a solution. Asgar et al. prepared nano-systems loaded with oxygen-rich nanocarriers paclitaxel (PTX) and Cur, as the drug is sustainably released at neutral ph. Therefore, nanocarrier­encapsulated nanofiber systems represent a novel tunable drug delivery system for local chemotherapy applications [49].

3.5 Brain Drug Delivery

Of the various types of cancer, t he most common in children are pediatric brain tumors and it is also the second leading cause of cancer-related deaths. Commonly used anti-cancer drugs such as DOX can cause serious side effects in patients during
Carbon Nanomaterial-Based Polymeric Nanocomposites for Drug … 183
chemotherapy, especially to children whose bodies are not yet fully developed. These side effects are thought to be a lack of efficiency and targeting selectivity of the delivery system, resulting in severe damage to normal cells. Delivery systems with high efficiency and target selectivity lead to severe damage to normal cells. To improve efficacy and selectivity, transferrin (trans) receptor-mediated endocytosis could be used in drug delivery system design, due to the facts that transferrin is usually highly expressed in brain tumor cells.
Asgari et al. investigated the potential application of carbon point-transferrin— DOX covalent coupling as a drug delivery system for the treatment of childhood brain tumors, with a higher uptake rate for the coupled system compared to DOX alone [50]. Insomnia is a serious sleep problem facing people in today’s society. A nasal gel delivery system supported by SWCNTs was reported to cross the blood–brain barrier by loading zaleplon onto SWCNTs, and to extend its duration of action to enhance the therapeutic effect. The system ameliorates the short half-life of zaleplon, poor sleep maintenance, and low oral availability [51].
Although relevant studies have proved that the effect of treating imaginary diseases is significant, the limitation of the blood–brain barrier is still the biggest obstacle to imaginary drug delivery and treatment.

3.6 Oral Drug Delivery

Oral administration is considered to be the most common mode of drug delivery. The oral route of drug delivery is widely used and accepted because of the ease of oral administration. However, it is susceptible to the effects of gastrointestinal function and gastrointestinal contents, and some drugs can also cause adverse gastrointestinal irritation, while others have poor solubility, permeability and stability in the gastroin­testinal environment, resulting in slow and irregular absorption of the drug effect. Therefore, the ideal drug carrier for oral administration should have a high drug loading capacity and good biocompatibility.
Lu et al. modified the surface of mesoporous carbon nanoparticles with chitosan, an inert hydrophilic material as the coating layer, and then loaded probucol (PB) into the nanocore. The drug effectively overcomes many gastrointestinal absorp­tion disorders and has an oral bioavailability nearly 3 times higher than that of commercially available preparations [52]. Jiang et al. constructed ZR-based MOF for the first time and encased anionic drugs in it. The results showed that it had high negative ion loading (>1%) and was more suitable for oral administration [53]. Enteropathy caused by radiation therapy is a major clinical challenge of radiation therapy. Resveratrol has shown beneficial pharmacological activity, but low oral bioavailability limits its effectiveness. Ali et al. prepared a system for controlling the release of resveratrol that, when taken orally, is more effective than free resveratrol in restoring the colon DOX state and regulating various hormone levels in the body [54]. The researchers cross-linked GQDs with chitosan hybrid bio-nanocomposite beads in which sodium salicylate (SS) was used as a model drug, while loading
184 D. Song and H. Li
SS protected by pH-sensitive biopolymer carboxymethyl cellulose (CMC) hydrogel beads (CS-GQD/SS). The authors performed in vitro drug delivery assays under simulated gastrointestinal conditions and showed that the biocomposite nanocom­posite beads showed low toxicity to human colon adenocarcinoma HT29 cells. Thus, the prepared hydrogel beads can be used as a safe carrier for oral drug delivery [55].
Diabetes has many complications that can eventually lead to death and is one of the leading causes of death worldwide. Currently, insulin injection and oral hypo­glycemic drugs are the main ways to maintain normal blood sugar. Camlik et al. used fluorescent composite CQDs (N-doped) prepared using L-cysteine, treated with insulin and then decorated with polyethylene glycol 3350 and methylcellulose for oral drug delivery. Since the authors administered the drug orally to diabetic animals, their blood glucose was reduced by about 5% within 60 h, thus oral administration has an anti-hyperglycemic effect [56]. Patients with low disease duration and mild diabetes mostly use oral drugs to maintain stable blood sugar, but long-term oral drugs have a great impact on intestinal organs and other body organs. Research and development with the main purpose of rapid glucose reduction accounts for the majority, and it is hoped that relevant researchers can develop oral drugs with small side effects on the body, and give diabetes patients a better future.

4 Challenge and Future Perspectives

Carbon nanopolymeric materials are novel nanomaterials with good biocompati­bility, biodegradability, and drug loading ability. Therefore, it has a wide range of application prospects in drug delivery. Firstly, carbon nanopolymeric materials can be used as drug carriers to encapsulate drugs on their surfaces or inside, and by regulating their size, shape and surface properties, they can improve the stability and solubility of drugs, prolong the time of blood circulation of drugs, and reduce the toxic side effects of drugs. Secondly, carbon nanopolymeric materials have a large specific surface area and rich surface functional groups, which can realize efficient loading and controlled release of drugs, enhance the targeting and bioavail­ability of drugs, and reduce the number of frequent drug administration. In addition, carbon nanopolymeric materials can also achieve targeted release and tissue-specific delivery of drugs by changing their surface properties and functionalized modifi­cations, improve the absorption and transport efficiency of drugs in target cells or tissues, and enhance the therapeutic effects of drugs.

5 Conclusion

Carbon nanopolymeric materials have great potential in drug delivery and can bring new breakthroughs and innovations in drug research and clinical treatment.
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