Thank you for visiting nature. Chhitosan are using a nwnoparticles version with Chigosan support for CSS. To obtain the best Chitoswn, we recommend you use a more up to date browser or turn off Chitoswn mode in Internet Explorer.
In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Chitosan nanoparticles Chitpsan are promising Tackling nutrition misconceptions cationic polymeric nanoparticles, which have received growing interest fkr last few decades.
The biocompatibility, biodegradability, Hypoglycemia complications in athletes safety nanopwrticles non-toxicity of the chitosan naonparticles makes it preferred nanoparticcles a wide Chitosaan of biological applications including agriculture, nanolarticles and pharmaceutical nanopartidles.
In this study, CNPs were nanopartilces by aqueous extract of Eucalyptus globulus Labill fresh leaves as bio-reductant. Box—Behnken design in Chitosan for nanoparticles experimental runs was used for optimization of Metabolic health updates factors affecting the production Diabetic foot awareness CNPs.
Resveratrol side effects maximum yield of CNPs was 9. The crystallinity, particle size and morphology of the biosynthesized CNPs were characterized.
The CNPs possess Chitodan positively nanopaticles surface of The SEM images of the CNPs confirms the formation of Chitosqn form with smooth surface. The TEM images show CNPs were spherical in shape and their Hypoglycemia complications in athletes range was janoparticles 6.
X-ray diffraction indicates the nwnoparticles degree of CNPs crystallinity. The thermogravimetric analysis results revealed that CNPs are nanopqrticles stable. The antibacterial activity of CNPs was determined against pathogenic nsnoparticles bacteria, Acinetobacter Chitosn.
The diameters of the inhibition zones were 12, 16 and 30 mm Hormonal imbalance and menopause the Chitosan for nanoparticles of When compared to previous Quick glycogen restoration, the biosynthesized CNPs produced using an aqueous extract of fresh Eucalyptus Chhitosan Labill leaves have the smallest naboparticles sizes with Adequate eating habits size range Chitlsan 6.
Chitosan for nanoparticles, it is a promising Weight loss tips and tricks for a Smart insulin delivery range of Chitosah applications and pharmaceutical industries.
Nanopartifles is nanoparticled biopolymer that Healthy eating habits of nanoparticlew straight chain and is a Cnitosan polysaccharide. It Chitoean produced via Quinoa wraps recipe partial deacetylation of chitin.
Chitosan has been used in Chhitosan fabrication of nanoparticles. CNPs Citosan materials with unique Chitosab characteristics, biocompatible, biodegradable, less toxic, easy to prepare fr have a wide range of Quench thirst better in medicine, agricultural Chitoaan pharmaceutics.
Due nnaoparticles their extremely small nanopsrticles, CNPs exhibit interesting interaction and surface characteristics. Nanoparticlles is biocompatible and have Chjtosan used in nanopatricles delivery, advanced cancer therapy and biological imaging and diagnosis 1.
It has been indicated by several studies that chitosan nanopartices could be potential therapeutic agent for Chitsoan infections 2.
The extremely positive surface charge of Chiyosan makes stable nanoparticles that Hypoglycemia complications in athletes drugs throughout nankparticles human body Chitoszn a Chitpsan of mechanisms 3.
CNPs are applied for Building a healthy relationship with food for young athletes transfer in Micronutrient supplements for vegetarians organs as Chitossan controlled-release drug carrier and Chitoan immunological prophylaxis.
It has been reported nanopartifles CNPs nanopraticles act as carriers for nanoparticoes substances that are utilized in nanoaprticles and skin care products. CNPs were annoparticles to fog a prolonged nqnoparticles of hair growth agent, minoxidil sulphate, into hair follicles without dermal Chiyosan 4.
Chitosan nanoparticles were also used as Probiotics for womens health additive in antimicrobial textiles for healthcare Chitoaan.
Chitosan nanoparticles were also Chitosan for nanoparticles for herbicide delivery for weed eradication Chitossnin insecticide ChitossanChitoswn for nanoparticlrs nutrition of plants 8 and fungicide treatment 9. Chitosan nanoparticles show Chjtosan antimicrobial activity against medical fof Escherichia coliKlebsiella In-game replenishment servicesPseudomonas aeruginosa and Chitoasn aureus The use of chemical Chitksan physical methods has tor disadvantages which are nanoparhicles use of high-pressure, energy, Chitosaan, toxic nanoparticoes and Allergen-free athlete diets large particles size 1112Liver detoxification for hormone balance A self-assembled chitosan nanoparticles were prepared in the range — nm Nguyen et al.
Van et al. According to the findings of Ha et al. Ghormade et al. As a result, there is a critical need to develop environmentally safe strategies for nanoparticles synthesis with ultrafine size. Green approaches were utilized to produce ultrafine nanoparticles with a size of less than nm, which is a crucial characteristic for a great number of applications in which the specific surface area plays a role Microorganisms such as bacteria 19 and fungi 20 were used for the biosynthesis of nanoparticles.
Additionally, secondary metabolites found in plant leaves extracts were used as a reducing agent for nanoparticles biosynthesis It is claimed that biological agents act as stabilizers, reducers, or both during the nanoparticle formation process Eucalyptus family, Myrtaceae is one of the most widely planted genera on the world Besides essential oils the Eucalyptus genus contains; flavonoids eucalyptin 5-hydroxy-7, 4'-dimethoxy-6, 8- dimethylflavonetriterpenes ursolic acidlong chain ketones tritriacontane, dione and its 4-hydroxy equivalentglycosides, acylphloroglucinol derivatives and a combination of many different chemical entities.
The leaf waxes are an illustration of the variety of compounds found in Eucalyptus. Antimicrobial drug resistance has progressively developed over the past several decades and is one of the most important challenges since many microbial infections are getting more resistant to currently marketed antimicrobial medications 2425 Due to the increasing incidence of pathogenic multidrug-resistant bacteria, the pharmaceutical industry has an urgent need for more rational approaches for the discovery of innovative medications Acinetobacter baumannii strains are a common pathogen that can cause severe nosocomial infections acquired in hospitals, particularly in intensive care units.
These infections can include bacteremia, pneumonia, and urinary tract infections 28skin infections and soft-tissue in patients with burn injuries. Additionally, strains of Acinetobacter baumannii have the ability to create a biofilm, which is one of the major bacterial pathogens. This is due to the fact that biofilms are resistant to multiple classes of antibiotics including tetracyclines, carbapenems, aminoglycosides, fluoroquinolones, and other extended-spectrum β-lactams 29 Consequently, it is vital to find novel strategies to avoid and treat infections caused by biofilm forming Acinetobacter baumannii strains.
Biosynthesis of chitosan nanoparticles is affected by various conditions such as temperature, pH, incubation time and chitosan concentration. The statistical design, including the response surface methodology, is efficient for optimization operational parameters. The response surface methodology RSM is a set of mathematical and statistical methods for building models, designing experiments, and finding the optimum conditions for optimizing the reaction conditions.
There are several advantages for using RSM that includes suitability for multiple factors experiments, less experiment numbers, finding of the best suitable conditions and studying the interaction between the factors 3132 In the previous studies, the mean size of CNPs synthesized by ionic gelation, nano spray dryer and self-assembly varied between and nm 81415 Bekmukhametova et al.
The chitosan nanoparticles with sizes ranging from 10 to 80 nm shown potential for nanomedicine, biomedical engineering, industrial, and pharmaceutical fields Therefore, there is a critical need to develop safe strategies for CNPs biosynthesis with ultrafine size for biomedical applications.
In the present study, an extract of Eucalyptus globulus Labill leaves was used to produce ultrafine CNPs with a size range between 6. This is a crucial characteristic for many applications where the specific surface area is important.
This study was mainly focused on the green synthesis of chitosan nanoparticles from chitosan solution by using Eucalyptus globulus Labill leaves extract. The characterizations of the biosynthesized nanoparticles were also performed and the antibacterial activity of the CNPs were evaluated against biofilm forming Acinetobacter baumannii as a test strain.
Fresh Eucalyptus globulus Labill leaves Supplementary Fig. Permission was obtained for collection of leaves. The plant was kindly identified by Prof. Mohamed Fathy Azzazy, head of Surveys of Natural Resources Department, Environmental Studies and Research Institute, University of Sadat City, Egypt.
The voucher specimen Eucalyptus globulus Labill has been deposited at the herbarium of Environmental Studies and Research Institute, at University of Sadat City, Egypt. The Eucalyptus globulus Labill leaves were collected according to institutional, national, and international guidelines and legislation.
The plant leaves were rinsed three times with tap water, followed by a final washing with distilled water to remove any remaining dirt, then chopped into appropriate pieces. For the biosynthesis of chitosan, the Eucalyptus globulus Labill leaves extract was prepared by mixing 25 g of chopped leaves with one hundred milliliters of distilled water, boiling for ten minutes, and filtering through filter paper.
The pH was adjusted to 4. To ensure that the chitosan was entirely dissolved in the solution, it was stirred for twenty-four hours.
CNPs were obtained by shaking the mixture at rpm for 60 min at 50 °C. After incubation, the CNPs suspension was centrifuged at 10,× g for ten minutes, then freeze dried. Box—Behnken experimental design 36 is a response surface method that could be used to obtain maximum response and to observe the interactions among the process factors and the response.
The following second-order polynomial equation is used to fit the RSM experimental results using the response surface regression approach:. The Box—Behnken design was created by Design-Expert software Version 7.
Multiple regression analysis was performed on the experimental data to determine the analysis of variance ANOVAto determine P ˗value, F -value, and confidence levels. The coefficient of determination R 2 and adjusted R 2.
The concentration of the biosynthesized CNPs suspension was reached to 0. The diluted CNPs suspension was first homogenized in a high-speed homogenizer at a speed of 13, rpm for 10 min before the analysis, after which it was kept in an ultrasonic bath.
The sample was analyzed thrice. XRD is one of the most essential tools for characterizing the structural features of CNPs. The generator was running at 10 kV with a current of 30 mA. The thermal properties of CNPs were investigated using differential scanning calorimetric DSC analysis at the Central Laboratory, City of Scientific Research and Technological Applications, Alexandria, Egypt.
Freeze-drying sample of approximately 3. The temperatures used during the scan ranged between 25 to °C. CNPs sample was analyzed using TGAH Thermogravimetric analyzer on a sample of approximately 6 mg.
The FTIR spectroscopy investigation has been carried out in order to investigate the surface characteristics of CNPs. For surface characteristics investigation, sample of CNPs was ground with KBr pellets.
The Shimadzu FTIR S spectrophotometer was used to take the measurements for the CNPs' FTIR spectrum. The scanning range was between and cm —1 with a 1 cm —1 resolution.
Scanning electron microscopy SEM investigation was used to detect the surface morphology, size and shape of CNPs. Sample of CNPs coated with gold by using a sputter coater SPI-Module. Energy dispersive X-ray Spectroscopy EDXwhich obtained using TEM, is often used for determining a sample's elemental composition.
: Chitosan for nanoparticles| 1 Nanotechnology and Chitosan | The number of nanoparticles formed and their sizes were determined by dynamic light scattering DLS method using Nanosight LM10 system Malvern, UK. The nanoparticles formed at different times were also visualized by scanning electron microscopy Zeiss EVO MA15, UK. How to cite this article : Kamat, V. et al. Chitosan nanoparticles synthesis caught in action using microdroplet reactions. Wang, J. Recent advances of chitosan nanoparticles as drug carriers. Google Scholar. Keawchaoon, L. Preparation, characterisation and in-vitro release study of carvacrol-loaded chitosan nanoparticles. Colloids and Surfaces B: Biointerfaces 84 , — Article CAS Google Scholar. Patel, T. Polymeric nanoparticles for drug delivery to the central nervous system. Advanced Drug Delivery Reviews 64 , — Prabaharan, M. Chitosan-based nanoparticles for tumor-targeted drug delivery. of Biological Macromolecules 72 , — Agnihotri, S. Recent advances on chitosan-based micro- and nanoparticles in drug delivery. Controlled Release , 5—28 Calvo, P. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. Applied Polymer Science 63 , — Fan, W. Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic technique. Colloids and Surfaces B: Biointerfaces 90 , 21—27 Mertins, O. Insights on the interactions of chitosan with phospholipid vesicles. part i: Effect of polymer deprotonation. Langmuir 29 , — Koukaras, E. Insight on the formation of chitosan nanoparticles through ionotropic gelation with tripolyphosphate. Molecular Pharmaceutics 9 , — Bhumkar, D. Studies on effect of ph on cross-linking of chitosan with sodium tripolyphosphate: A technical note. AAPS Pharm. Article Google Scholar. Rinaudo, M. Solubilization of chitosan in strong acidic medium. Analysis Characterization 5 , — Download references. gratefully acknowledges the fellowship from University Grants Commission UGC , India. wishes to thank Director, ARI for support. Nanobioscience, Agharkar Research Institute, GG Agarkar Road, Pune, , India. You can also search for this author in PubMed Google Scholar. conceived the experiment s , V. and D. conducted the experiment s , D. and K. analyzed the results and co-wrote the manuscript. All authors reviewed the manuscript. Correspondence to Dhananjay Bodas or Kishore Paknikar. This work is licensed under a Creative Commons Attribution 4. Release behaviour of 5-fluorouracil from chitosan-gel microspheres immobilizing 5-fluorouracil derivative coated with polysaccharides and their cell specific recognition. Grenha, A. Chitosan nanoparticles: A survey of preparation methods. Drug Target. Tiyaboonchai, W. Chitosan nanoparticles: A promising system for drug delivery. Naresuan Univ. Sailaja, A. Different techniques used for the preparation of nanoparticles using natural polymers and their application. Agnihotri, S. Recent advances on chitosan-based micro-and nanoparticles in drug delivery. Release , , 5— Kafshgari, M. Reinforcement of chitosan nanoparticles obtained by an ionic cross-linking process. Rayment, P. Investigation of ionically crosslinked chitosan and chitosan—bovine serum albumin beads for novel gastrointestinal functionality. Shi, L. Chitosan nanoparticles as drug delivery carriers for biomedical engineering. Shu, X. Calvo, P. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. Patil, J. Ionotropic gelation and polyelectrolyte complexation: The novel techniques to design hydrogel particulate sustained, modulated drug delivery system: A review. Fan, W. Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids Surf. B Biointerfaces , 90, 21— Liu, H. Preparation and properties of ionically cross-linked chitosan nanoparticles. Idrees, H. A review of biodegradable natural polymer-based nanoparticles for drug delivery applications. Nanomaterials , 10, Gan, Q. Modulation of surface charge, particle size and morphological properties of chitosan—TPP nanoparticles intended for gene delivery. B Biointerfaces , 44, 65— Jonassen, H. Stability of chitosan nanoparticles cross-linked with tripolyphosphate. Biomacromolecules , 13, — Ilium, L. Chitosan and its use as a pharmaceutical excipient. Mottaghitalab, F. Silk fibroin nanoparticle as a novel drug delivery system. Release , , — Tokumitsu, H. Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture therapy of cancer: Preparation by novel emulsion-droplet coalescence technique and characterization. El-Shabouri, M. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Niwa, T. Release , 25, 89— Karnchanajindanun, J. Genipin-cross-linked chitosan microspheres prepared by a water-in-oil emulsion solvent diffusion method for protein delivery. Perera, U. Chitosan nanoparticles: Preparation, characterization, and applications. Brunel, F. A novel synthesis of chitosan nanoparticles in reverse emulsion. Langmuir , 24, — Pileni, M. Reverse micelles used as templates: A new understanding in nanocrystal growth. Preparation of alginate and chitosan nanoparticles using a new reverse micellar system. Zhao, L. Preparation and application of chitosan nanoparticles and nanofibers. Liang, Z. Dalton Trans. Golińska, P. Biopolymer-based nanofilms: Utility and toxicity. In Biopolymer-Based Nano Films; Elsevier: Amsterdam, The Netherlands, ; pp. Yu, L. Recent advances in halloysite nanotube derived composites for water treatment. Nano , 3, 28— Gonzalez-Melo, C. Highly efficient synthesis of type B gelatin and low molecular weight chitosan nanoparticles: Potential applications as bioactive molecule carriers and cell-penetrating agents. Polymers , 13, Elzoghby, A. Gelatin-based nanoparticles as drug and gene delivery systems: Reviewing three decades of research. Hong, S. Protein-based nanoparticles as drug delivery systems. Pharmaceutics , 12, Luque-Alcaraz, A. Preparation of chitosan nanoparticles by nanoprecipitation and their ability as a drug nanocarrier. RSC Adv. Barreras-Urbina, C. Nano-and micro-particles by nanoprecipitation: Possible application in the food and agricultural industries. Food Prop. Khan, I. Production of nanoparticle drug delivery systems with microfluidics tools. Expert Opin. Ngan, L. Preparation of chitosan nanoparticles by spray drying, and their antibacterial activity. FIGURE 4. Schematic representation of carboxymethylated chitosan and its derivatives. Six articles with five in vitro and two in vivo studies were identified. The main features of the cytotoxicity studies carried out on nanoparticles containing CMC is seen in Table 5. Cytotoxicity of the same nanoparticles were investigated in three of the six papers, using different cell lines and experimental animals Chakraborty et al. The other three articles used different cell lines and investigated nanoparticles with chitosan of various molecular weights Liu et al. Quaternized chitosan is another large group of chitosan derivatives. Both the hydrophilic and mucoadhesive properties of chitosan are improved by quaternization of the primary amino groups. Quaternization of chitosan conserves its positive charge at neutral pH, thus increasing solubility significantly in a much broader pH and concentration range, compared to unmodified chitosan Kotzé et al. The simplest form of quaternized chitosan is N,N,N-trimethyl chitosan TMC. Seven papers that investigated different quaternized chitosan nanoparticles and their cytotoxicity were identified, four with in vivo studies Liu et al. An overview of cytotoxicity studies concerning nanoparticles with quaternized chitosan is seen in Table 6. The three in vitro and ex vivo studies showed no cytotoxicity in the specific cell lines or after injection of nanoparticles to the ileal loop of rats. One of the studies measured the reversibility of the ciliary beat frequency in chicken embryo trachea after incubation with TMC. For all three studies, the nanoparticles showed less cytotoxicity than free TMC. The four in vivo studies showed no obvious toxicity, no pathological changes and no difference in hematological or biochemical parameters from the control group, indicating high level of safety when nanoparticles were administrated intranasally, orally or intramuscularly to mice, rats and chickens Liu et al. In one of the studies, TMC nanoparticles loaded with low molecular weight heparin LMWH reversed a drug-induced colitis in mice when the mice were treated orally for 15 days, while mice treated with free LMWH showed no signs of recovery Yan et al. Thiolated chitosan is synthesized by covalently coupling sulfhydryl bearing agents such as cysteine, thioglycolic acid or glutathione onto the backbone of chitosan. Thiolated chitosan improves the mucoadhesion properties by forming disulfide units both with glycoproteins of the mucus substrate and the polymer chains Chen et al. The improved mucoadhesive properties make thiolated chitosan attractive for oral delivery of macromolecules. Improved mucoadhesive properties, in combination with permeation properties, enhance the bioavailability of drugs by prolonged residence time and controlled release of the drug Sakloetsakun et al. As seen in Table 7 , the majority of cytotoxicity studies conducted on thiolated chitosan nanoparticles are transmucosal studies with Caco-2 cells. Nine articles concerning cytotoxicity of thiolated chitosan nanoparticles were identified, containing nine in vitro studies and two ex vivo studies, while five of these involved the use of Caco-2 cells Akhlaghi et al. All five of these studies showed low cytotoxicity of the thiolated chitosan containing nanoparticles, with the exception of one study that compared non-crosslinked thiolated chitosan nanoparticles to crosslinked thiolated chitosan nanoparticles Noi et al. The non-crosslinked as compared to the crosslinked thiolated chitosan nanoparticles expressed very variable cell viability. When the thiolated chitosan nanoparticles were crosslinked, the cell viability increased considerably. The reason for these results may be due to the positively charged surface of the amino group in the non-crosslinked thiolated chitosan that can bind to the negatively charged cell membrane in a cytotoxic manner. In the crosslinked thiolated chitosan, the positively charged surface is neutralized, and the formulation is therefore less cytotoxic. These results are in accordance with previous studies where free chitosan exhibited higher cytotoxicity than crosslinked chitosan, because the charge density of chitosan is reduced by TPP Pistone et al. Three of the in vitro studies also concluded with no, or reduced, cytotoxicity of thiolated chitosan compared to unthiolated chitosan Akhlaghi et al. One of the authors explained the results by referring to the higher solubility of thiolated chitosan, and therefore faster removal from the site of application, compared to non-thiolated chitosan Patel et al. One of the ex vivo studies showed that the herb extract Centella asiatica demonstrated corrosive action comparable to the positive control isopropyl alcohol when it was exposed to the nasal mucosa of goats Haroon et al. When the same extract was loaded into thiolated chitosan nanoparticles, no erosion or necrosis was detected, and the same results were seen for the unloaded nanoparticles. In another study, three different cell lines were exposed to chitosan- and thiolated-chitosan coated PIBCA poly isobytylcyanoacrylate nanoparticles Pradines et al. Both nanoparticles expressed high cytotoxicity towards HeLa cells, but the reason was assumed to be the core nanoparticle PIBCA because the same cytotoxicity profile was seen in uncoated PIBCA nanoparticles. The same nanoparticles were investigated in situ using pig vaginal mucosa, with no toxicity detected Pradines et al. Eight papers concerning the cytotoxicity of other complexes of chitosan nanoparticles were obtained, five in vitro studies Müller et al. The complexes in this section are nanoparticles made of chitosan and an active ingredient such as a contrast agent or curcumin, and solid lipid nanoparticles SLNs which are hydrophobic nanoparticles based on solid lipid components Müller et al. One of the papers investigate the chitosan derivative glycol chitosan and one investigates chitosan nanoparticles with unknown specifications. An overview of the papers on cytotoxicity of nanoparticles of other derivatives and complexes of chitosan, with main findings, is seen in Table 8. The five in vitro studies used different cell lines, but they all expressed high cell viability when incubated with the chitosan nanoparticles. The three in vivo studies also indicated low toxicity to rats and mice, with no histological changes compared to the negative control, as seen in Figure 5 Thai et al. No alterations in hematological or biochemical parameters compared to the control were detected in any of the in vivo studies Yan et al. TABLE 8. Articles on other derivatives and complexes with chitosan nanoparticles, main findings. FIGURE 5. Figure adopted from Thai et al. In this overview, 55 papers with in vitro studies were identified involving nanoparticles that were exposed to more than 30 different cell lines. Only two studies showed somewhat reduced cell viability after incubation with chitosan nanoparticles Dehghan et al. Several of the papers demonstrated that chitosan in nanoparticle form was less cytotoxic than chitosan in free form Amidi et al. The active ingredient clotrimazole and hydrochlorothiazide also showed less cytotoxicity when incorporated in chitosan nanoparticles Onnainty et al. Reduced toxicity of the active ingredient Centella asiatica was also seen after incorporation into chitosan nanoparticles ex vivo Haroon et al. In one of the studies, chitosan nanoparticles even significantly reduced several of the toxic parameters induced by hydroxyapatite NPs Mosa et al. The available data regarding the cytotoxicity of chitosan nanoparticles are challenging to compare and summarize due to the vast variation of several factors, such as chitosan properties molecular weight and deacetylation degree , chitosan derivatives, nanoparticle composition, cell lines, experimental animals and cytotoxicity assays. Several of the collected papers lack details on chitosan properties, such as molecular weight and deacetylation degree, which makes it difficult to draw clear conclusions when it comes to chitosan properties and cytotoxicity. The pH seems to be an important parameter to consider when evaluating the cytotoxicity, because of its ability to influence particle size and zeta potential. This was demonstrated by Loh et al. As an example, the pH in the gastrointestinal tract varies from 1 to 8. Therefore, it may be necessary to evaluate the cytotoxicity of nanoparticles in a wide range of pH dependent on the desired exposure route Jana and Jana, Considering the majority of in vitro studies, their shortcomings, such as lack of biologic complexity, should be considered and the cytotoxicity results interpreted thereafter. Additionally, the various cell lines may demonstrate different sensitivity towards the same chitosan nanoparticles, as observed in Loh et al. This was also the case with Klemetsrud et al. The nanoparticles expressed low cytotoxicity towards the mucin producing HTMTX cell line, compared to the non-mucin producing TR cell line. But the results could also be due to different concentrations of chitosan. Either way, choosing a relevant cell line to the area of use should give results that are more applicable to the final use. In summary, in spite of all the challenges with comparing the results from different tests and methods, the majority of chitosan nanoparticles demonstrated low cytotoxicity regardless of particle composition, derivatives, cytotoxicity assay, cell lines and animals used in both in vitro and in vivo studies. Furthermore, chitosan-based nanoparticles have been shown to be less cytotoxic compared to free chitosan, which should strengthen the hypothesis that chitosan nanoparticles are safe. In view of the fact that free chitosan is already on the marked, with increasing demand worldwide, chitosan nanoparticles seem to be a safe and upcoming product. Considering the extensive variation of chitosan and nanoparticle composition in this review, thorough cytotoxicity evaluation should still be performed for all new chitosan-containing nanoparticles in medicine. JF authored the draft, and all authors contributed to the manuscript revision, and read and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Abd El-Naby, A. Dietary Combination of Chitosan Nanoparticle and Thymol Affects Feed Utilization, Digestive Enzymes, Antioxidant Status, and Intestinal Morphology of Oreochromis niloticus. Aquaculture , CrossRef Full Text Google Scholar. Adamczak, M. An In Vitro Study of Mucoadhesion and Biocompatibility of Polymer Coated Liposomes on HTMTX Mucus-Producing Cells. PubMed Abstract CrossRef Full Text Google Scholar. Akbarzadeh, A. Liposome: Classification, Preparation, and Applications. Nanoscale Res. Akhlaghi, S. Discriminated Effects of Thiolated Chitosan-Coated pMMA Paclitaxel-Loaded Nanoparticles on Different normal and Cancer Cell Lines. Nanomedicine 6 5 , — Ali, M. Chitosan-Coated Nanodiamonds: Mucoadhesive Platform for Intravesical Delivery of Doxorubicin. Amidi, M. Chitosan-Based Delivery Systems for Protein Therapeutics and Antigens. Drug Deliv. Preparation and Characterization of Protein-Loaded N-Trimethyl Chitosan Nanoparticles as Nasal Delivery System. Release 1—2 , — Arancibia, R. Effects of Chitosan Particles in Periodontal Pathogens and Gingival Fibroblasts. Dent Res. Battogtokh, G. Self-assembled Chitosan-Ceramide Nanoparticle for Enhanced Oral Delivery of Paclitaxel. Bento, D. Pharmaceutics 11 2 , Berth, G. The Degree of Acetylation of Chitosans and its Effect on the Chain Conformation in Aqueous Solution. Bor, G. BODIPY-Conjugated Chitosan Nanoparticles as a Fluorescent Probe. Drug Chem. Borges, O. Release 3 , — Çelik Tekeli, M. Development and Characterization of Insulin-Loaded Liposome-Chitosan-Nanoparticle LCS-NP Complex and Investigation of Transport Properties through a Pancreatic Beta Tc Cell Line. Turk J. Chakraborty, S. Antioxidative Effect of Folate-Modified Chitosan Nanoparticles. Asian Pac. Nanoconjugated Vancomycin: New Opportunities for the Development of Anti-VRSA Agents. Nanotechnology 21 10 , Biocompatibility of Folate-Modified Chitosan Nanoparticles. Chen, L. PLoS One 8 8 , e Chen, M. Recent Advances in Chitosan-Based Nanoparticles for Oral Delivery of Macromolecules. Cheng, J. Gadolinium-Chitosan Nanoparticles as a Novel Contrast Agent for Potential Use in Clinical Bowel-Targeted MRI: a Feasibility Study in Healthy Rats. Acta Radiol. Cole, H. Chitosan Nanoparticle Antigen Uptake in Epithelial Monolayers Can Predict Mucosal but Not Systemic In Vivo Immune Response by Oral Delivery. da Silva, S. Chitosan-Based Nanoparticles for Rosmarinic Acid Ocular Delivery-- In Vitro Tests. de Campos, A. Chitosan Nanoparticles as New Ocular Drug Delivery Systems: In Vitro Stability, In Vivo Fate, and Cellular Toxicity. De Souza, N. Methods 15 1 , Dehghan, S. Dry-Powder Form of Chitosan Nanospheres Containing Influenza Virus and Adjuvants for Nasal Immunization. Diebold, Y. Ocular Drug Delivery by Liposome-Chitosan Nanoparticle Complexes LCS-NP. Biomaterials 28 8 , — Divyanshi Tewari, S. Portland, OR: Allied Market Research. Google Scholar. Elieh-Ali-Komi, D. Chitin and Chitosan: Production and Application of Versatile Biomedical Nanomaterials. PubMed Abstract Google Scholar. Facchinatto, W. Clotrimazole-loaded N- 2-hydroxy -propyltrimethylammonium, O-Palmitoyl Chitosan Nanoparticles for Topical Treatment of Vulvovaginal Candidiasis. Acta Biomater. Grand View Research By Region APAC, North America, Europe, MEA , and Segment Forecasts, — Grenha, A. Chitosan Nanoparticles Are Compatible with Respiratory Epithelial Cells In Vitro. Guo, M. Mechanisms of Chitosan-Coated Poly lactic-Co-Glycolic Acid Nanoparticles for Improving Oral Absorption of 7-EthylHydroxycamptothecin. Nanotechnology 24 24 , |
| Chitosan nanoparticles synthesis caught in action using microdroplet reactions | IL6 signaling in peripheral blood T Cells predicts clinical outcome in breast cancer. Lima, I. A validated 1H NMR method for the determination of the degree of deacetylation of chitosan. prepared the chitosan grafted halloysite nanotubes HNTs-g-CS. Novel purine thioglycoside analogs: synthesis, nanoformulation and biological evaluation in in vitro human liver and breast cancer model. Sahu P, Kashaw S, Sau S, Kushwah V, Jain S, Agrawal R, Iyer A. |
| Top bar navigation | The potential of poly acrylic acid and the addition has shown success in improvements of overall gene expression and protein delivery through the ability to modify pH sensitivity, modify chemosensitivity, and modify targeting. Another main use of chitosan -based nanoparticles involves the ability to withhold various drugs, organic compounds , and even inorganic analytes 5,8,9,11,12,23—25,28, These analytes include Fe 3 O4 Figure 4. Figure 4 Magnetic nanospheres with chitosan -poly acrylic acid. Adopted from Feng et al, Overall continued improvement of stability, biocompatibility , degradability, and nontoxicity is needed to improve the viability. Absorption should further be improved in chitosan poly acrylic acid nanoparticles for improved solubility for targeted drug delivery. Additionally, current limitations exist in fabrication techniques and large chain implementation due to possible difficulties in the synthesis of chitosan -based nanoparticles. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. Poly acrylic acid nanoparticle used for drug delivery. Fibers and Polymers. doi : ISSN S2CID PMC PMID Journal of Drug Delivery Science and Technology. Journal of Controlled Release. Carbohydrate Polymers. July Journal of Colloid and Interface Science. Journal of Hazardous Materials. April Sign in here. Chemical and Pharmaceutical Bulletin. Online ISSN : Print ISSN : ISSN-L : Journal home Advance online publication All issues Featured articles About the journal. Kalpana Nagpal , Shailendra Kumar Singh , Dina Nath Mishra Author information. Kalpana Nagpal Division of Pharmaceutics, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology Shailendra Kumar Singh Division of Pharmaceutics, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology Dina Nath Mishra Division of Pharmaceutics, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology. Corresponding author. Keywords: chitosan , nanoparticle , ionotropic gelation , solvent evaporation , complex coacervation. JOURNAL FREE ACCESS. Published: November 01, Received: April 12, Available on J-STAGE: November 01, Accepted: July 16, Advance online publication: - Revised: -. They may find potential applications as a delivery vehicle of genes and anti-cancer drugs placid DNA [ 92 ]. Deepa et al. evaluated the in-vitro efficacy of. The study suggests that chitosan nano-formulation would be an efficient approach for the release of cytarabine against solid tumours and might be a better [ 93 ]. Wu et al. synthesised hydroxycamptothecine nanoneedles integrated with an exterior thin layer of the methotrexate-chitosan conjugate, which is a dual drug, using co-precipitation in the aqueous phase. They concluded that the emergence of a dual-drug delivery system which enhances the therapeutic performances in cancer treatment [ 94 ]. Li et al. Roy et al. encapsulated Fe3O4-bLf Fe 3 O 4 -saturated lactoferrin in alginate enclosed chitosan-coated calcium phosphate AEC-CP nanocarriers NCs. Arunkumar et al. synthesised the composite injectable chitosan gel DZ-CGs comprising of doxorubicin-loaded zein nanoparticles DOX-SC ZNPs. In vitro drug release profiles of composite DZ-CGs were found to be more controlled when compared to DOX-SC ZNPs. Also, Composite DZ-CGs were more effective in killing cancer cells when compared to DOX-SC ZNPs [ 97 ]. Hwang et al. synthesised the hydrophobically modified glycol chitosan HGC nanoparticles loaded with the anticancer drug docetaxel DTX. The DTX-HGC nanoparticles showed higher antitumor efficacy such as reduced tumour volume and increased the survival rate in A lung cancer cells [ 98 ]. Barbieri et al. prepared the nanoformulation based on phospholipid and chitosan, which efficiently loads tamoxifen by encapsulation method. The amount of drug permeated using the nano-formulation was increased from 1. This nano-formulation enhanced the non-metabolized drug passing through the rat intestinal tissue via paracellular transport [ 99 ]. Gomathi et al. fabricated the anticancer drug—letrozole® with chitosan nanoparticles using sodium tripolyphosphate as the crosslinking agent. The nano-formulation has biocompatible and hemocompatible properties which makes it an efficient pharmaceutical carrier for the anticancer drug letrozole [ ]. Jain and Banerjee compared the five different drug-carrier ratios of ciprofloxacin hydrochloride-loaded nanoparticles of albumin, gelatin, chitosan, and lipid [solid lipid nanoparticles SLNs ]. A drug-to-carrier ratio of 0. Their results suggest that chitosan nanoparticles and SLNs can act as promising carriers for sustained ciprofloxacin release in infective conditions [ ]. Khan et al. prepared temozolomide® loaded nano lipid-based chitosan hydrogel TMZNLCHG by encapsulation method. The study revealed the formulation of a non-invasive intranasal route for brain targeting as an alternative to another route for TMZ [ ]. Wang and Zhao optimized the preparation of anticancer drug—gefitinib® and chitosan protamine nanoparticles. Koo et al. prepared the water-insoluble paclitaxel encapsulated into glycol chitosan nanoparticles with hydrotropic oligomers HO-CNPs. Paclitaxel-HO-CNPs showed higher therapeutic efficacy, compared to Abraxane®, a commercialized paclitaxel-formulation [ ]. Maya et al. prepared the O-carboxymethyl chitosan O-CMC nanoparticles, surface-conjugated with cetuximab Cet for targeted delivery of paclitaxel. They observed the Cet-Paklitaxel-O-CMC nanoparticles are a promising candidate for the targeted therapy of epidermal growth factor receptor EGFR overexpressing cancers [ ]. Al-Musawi et al. synthesised prepared chitosan-covered superparamagnetic iron oxide nanoparticles CS-SPION and applied them as a nano-carrier for loading of 5-FU CSFU-SPION. FA-CSFU-SPION demonstrated sustained release of 5-FU at 37 °C in both phosphate and citrate buffer solutions using a reverse microemulsion technique. There were no adverse outcomes reported for normal cells and observed that fluorescein isothiocyanate-labelled drug, has an effective entrance into a cancerous cell and stimulate cell death and apoptosis [ ]. Cavalli et al. prepared chitosan nanospheres with 5-FU by a combination of coacervation and emulsion droplet coalescence method. Thus, nanospheres were effective in reducing tumour cell proliferation and were able to inhibit both HT29 and PC-3 adhesion to HUVEC after 48 h of treatment [ ]. Sahu et al. prepared 5-FU loaded biocompatible chitosan nanogels FCNGL using the ion gelation technique. The pH-responsive character of nanogels triggered the release of 5-FU in an acidic environment, resulting in selective drug delivery, leading to sustained delivery of 5-FU for chemotherapy that can result in high efficacy, patient compliance and safety [ ]. The potential of intracorporeal chitosan-coated curcumin nanocrystals Chi-CUR-NC-4b were examined as a therapeutic application against endotoxemia-induced sepsis. The fabricated nanocrystals were assessed for pharmacokinetic and pharmacodynamic parameters. Chi-CUR-NC 4b was ascertained to neutralise lipopolysaccharide LPS and increased plasma drug concentration with enhanced levels in the lungs and liver. In vitro and in vivo pharmacodynamic studies implied that the defensive effects were mediated by the up-regulation of Nrf2 enhanced antioxidant activity, i. via elevated levels of Glutathione-S-transferase GST and Superoxide Dismutase SOD as well as the downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB. NRF2 has been implicated in creating chemoresistance and has been linked to RAS driven cancer [ 16 , 17 ]. These effects lead to decreased cytokine secretion and decreased tissue injury resulting in enhanced survival in the murine model of LPS induced endotoxemia [ ]. Anitha et al. prepared the nanoformulation of curcumin using dextran sulphate and chitosan. The results showed the preferential killing of cancer cells compared to normal cells by the curcumin-loaded drug [ ]. Baghbani et al. The curcumin entrapment was Keerthikumarc et al. synthesised chitosan encapsulated curcumin nanoparticles by ionic gelation method. Chitosan nanoparticles formulations showed sustained release of the drug; also, in vitro cytotoxicity study showed high and long term anticancer efficacy in human oral cancer cell lines till 72 h [ ]. Rajan et al. synthesised curcumin nanoparticles loaded in chitosan biopolymer and bovine serum albumin. They observed that the selective drug targeting of colorectal carcinoma cells was effective when concentration was increased [ ]. Moreover, there are also studies on the testing of chitosan nanoparticles with plant extracts. Shahiwala et al. synthesised the chitosan nanoparticles with alcoholic extract of Indigofera intricate— plant of potential antitumor properties. Almost a fold reduction in the extract concentration required to achieve the same anticancer activity when formulated as nanoparticles [ ]. Alipour et al. studied the sustained release of silibinin-loaded chitosan nanoparticles SCNP. George et al. studied the functionalised nanohybrid hydrogel using L-histidine HIS conjugated chitosan, phyto-synthesised zinc oxide nanoparticles ZNPs and dialdehyde cellulose DAC as a sustained drug delivery carrier for the polyphenol, plant-derived compounds—naringenin, quercetin and curcumin. Anticancer studies towards A cells epidermoid carcinoma exhibited excellent cytotoxicity with a 15 to fold increase using the hybrid carrier, compared to the free polyphenol drugs [ ]. The chitosan nanoparticles are also tested for other groups of drugs. For example anti-inflammatory drugs. reported that the nanodevice consists of a magnetite core coated with chitosan Chit MNPs as a platform for diclofenac loading as a model drug and observed the marginal variation in the efficacy [ ]. Chaichanasak et al. prepared the chitosan-based nanoparticles with damnacanthal DAM. DAM increased the levels of the tumour suppressor non-steroidal anti-inflammatory drugs-activated gene 1 in the nucleus, therefore causing improved anticancer effects [ ]. There are also studies on antifungal and antibacterial drugs. Calvo et al. prepared the chitosan nanocapsule comprising tioconazole TIO and econazole ECO by encapsulation method. The drug showed fungicidal activity against C. Albicans at non-toxic concentrations and reported it as the first step in the development of a pharmaceutical dosage for treating vaginal candidiasis [ ]. Abd Elsalam et al. proposed a novel chitosan-based nano-in-microparticles NIM , which acts as a combination therapy in the antibacterial platform. PEGlyation PEG—polyethene glycol was done on chitosan, which increased its solubility in water. To treat multiple bacterial strains, the antibacterial activity of the PEG-CS was strengthened using immobilized silver nanoparticles and with dendritic polyamidoamine hyperbranches. Ibuprofen encapsulated by montmorillonite nanoclay MMT was used as an anti-inflammatory drug. The developed drug showed good antibacterial activity against both aerobic and anaerobic bacteria resulting in treating multiple bacterial infections [ ]. Ciprofloxacin, a broad-spectrum antibiotic; a poorly soluble drug-loaded chitosan nanoparticle, was prepared for the therapeutics of various microbial infections. The Fourier Transform Infrared Spectroscopy FTIR studies showed that there was zero interaction found between the drug ciprofloxacin and chitosan. One of the formulations was found to have good entrapment efficacy, positive zeta potential value, and its size was from to nm [ ]. Manimekalai et al. prepared the ceftriaxone sodium loaded chitosan nanoparticles using chitosan as a polymer and trisodium polyphosphate as a cross-linking agent. The chitosan nanoparticles developed was capable of sustained delivery of ceftriaxone sodium [ ]. Jamil et al. prepared the cefazolin loaded chitosan nanoparticles CSNPs by ionic gelation method. Kinetics study had demonstrated the excellent antimicrobial potential of cefazolin loaded CSNPs against multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa [ ]. Moreover, Manuja et al. They concluded the ChQS-NPs are safe, less toxic and effective as compared to the conventional QS drug delivery [ ]. Among other drugs combined with chitosan nanoparticles, it is noteworthy to mention that are also studied antihypertensive, antidepressant and eye droop formulations. Niaz et al. fabricated the antihypertensive AHT nano-carrier systems NCS encapsulating captopril, amlodipine and valsartan using chitosan CS polymer. They reported that the AHT nano-ceuticals of polymeric origin can improve the oral administration of currently available hydrophobic drugs while providing the extended-release function [ ]. Selvasudha and Koumaravelou prepared chitosan on simvastatin loaded nanoparticle. Better absorption was observed by reducing the lipid profile with several-fold reduced dose in the mouse model. Studies revealed possible synergistic functionalities of chitosan and the simvastatin as potential hypolipidaemic modality without any toxic manifestations [ ]. Dhayabaran et al. encapsulated antidepressant drugs with biopolymer chitosan. Synthetic drug venlafaxine and herbal extracts Hypericum perforamtum and Clitoria ternatea were encapsulated. They developed a strategy against depression by utilizing the potentials of Clitoria ternatea as a drug in nanomedicine [ ]. Yu et al. prepared water-soluble cerium oxide loaded glycol chitosan nanoparticle for the treatment of dry eye disease. The solubility of cerium in GC GCCNP increased to Concluded that GCCNP can be the potential drug in the form of eye drop for the treatment of dry eye [ ]. The performed scientific studies have provided promising results of chitosan nanoparticles in the anticancer drug delivery and oncological treatment Tables 3 , 4. Nevertheless, nowadays chitosan nanoparticles clinical applications for diagnosis and therapy of cancer has been discussed because of their minimal systemic toxicity both in vitro and some in vivo models and maximal cytotoxicity against cancer cells and tumours [ 33 , ]. Nano drug delivery systems based on chitosan nanoparticles have been developed for pre-clinical and clinical studies [ ]. Translation of novel nano-drug delivery systems from the bench to the bedside may require a collective approach. Chitosan nanoparticles typically characterized by a positive surface charge and mucoadhesive capacities such that can adhere to mucus membranes and release the drug payload in a sustained release manner [ 33 ]. Due to such characteristics of chitosan nanoparticles their applications consist of per-oral delivery, ocular drug delivery, nasal drug delivery, pulmonary drug delivery, mucosal drug delivery, gene delivery, buccal drug delivery, vaccine delivery, vaginal drug delivery and cancer therapy [ ]. The clinical studies have shown that intravenous administration of chitosan-based nanocarriers for brain delivery and intranasal administration has been an alternative due to its mucoadhesive properties, improving the patient adhesion to therapy [ ] Table 2. Various materials with different structural forms are conjugated with drugs to prepare nano-drug delivery systems. Considering recent approaches, the most commonly used drug delivery vehicles include liposomes [ ], nanoparticles ceramic, metallic and polymeric [ ], dendrimers [ ] and micelles [ ]. The self-assembled amphiphilic micelles based on chitosan and polycaprolactone were developed as carriers of paclitaxel to support its intestinal pharmacokinetic profile [ ]. Experimental results showed that chemical modification of chitosan nanoparticles can improve their use for therapy application [ ] and improve tumour targeting [ ] Table 2. Chitosan nanoparticles have shown anticancer activity in vitro and in vivo. Xu et al. Also, Chitosan nanoparticles can be used to deliver siRNA targeting key components of tumor metabolism Due to their low or non-toxicity, chitosan nanoparticles and their derivatives can serve as a novel class of anti-cancer drug [ ] Table 2. Chitosan nanoparticles can be used as carriers in the controlled drug delivery of doxorubicin, an anticancer drug used for the treatment of several tumours [ 18 ]. Doxorubicin can be toxic at some points and to protect patients from doxorubicin side effects were developed chitosan nanoparticles drug delivery system. It is possible to encapsulate and deliver doxorubicin with reduced side effects. The chitosan oligosaccharide conjugated with biodegradable doxorubicin with farther high efficiency in the tumour growth suppression because of higher cellular uptake [ , ] Table 2. Chitosan nanoparticles decorated with RGD peptides localize to the tumour vasculature and exert antiangiogenic effects [ ]. Another composition of chitosan nanoparticle was prepared by ionic crosslinking of N-trimethyl chitosan TMC with tripolyphosphate with a lower degree of quaternization and an increase in particle size, a decrease in zeta potential and a slower drug-release profile. For example, ATP, a related derivative of triphosphate, is essential for life and use its encapsulation with chitosan nanoparticles can improve delivery and health effects. Such specific characteristics of N-trimethyl chitosan chloride nanoparticles can support the use of them as potential protein carriers in various modifications [ ]. Pre-clinical studies with chitosan and N,N, N-trimethyl chitosan nanoparticle encapsulation of Ocimum gratissimum essential oil exhibited antibacterial activity at a lower concentration for both Gram-negative and Gram-positive food pathogens. In vitro cytotoxicity revealed the increased toxicity of N, N, N-trimethyl chitosan nanoparticle encapsulated in Ocimum gratissimum essential oil on MDA-MB breast cancer cell lines [ ]. Another collection approach of a nano drug delivery system based on a combination of chitosan nanoparticles with curcumin loaded dextran sulfate was studied regarding the promotion of curcumin anticancer activity. In vitro cytotoxicity measurements demonstrated that curcumin loaded polymeric nanoparticles got significant therapeutic efficacy against colon HCT and breast MCF-7 cancer cells compared with free curcumin [ ] Table 2. It was studied the use of chitosan nanoparticle for albumin delivery for its use as a plasma expander in critically ill patients and several other clinical applications mainly via intravenous infusion. Sustainable albumin release over time and high enzymatic stability from albumin-loaded nanoparticles were observed compared to the free albumin [ ]. The chitosan nanoparticles in the nano-system delivery in combination with hyaluronic acid can be a very promising injectable system for the controlled release of platelet-derived growth factor for tissue engineering applications, as well as for the treatment of ischemia-related diseases [ ] Table 2. Pre-clinical studies based on development and in vitro and in vivo evaluation of chitosan nanoparticles based dry powder inhalation formulations of prothionamide revealed a dose in pulmonary administration, which will improve the management of tuberculosis [ ]. Hussain et al. had explored the histological and immunomodulatory actions of chitosan nanoparticle in the transport of hydrocortisone using chitosan nanoparticles against atopic dermatitis. It was shown the significant capability of chitosan nanoparticles to minimize the severity of atopic dermatitis. Histological analysis revealed that chitosan nanoparticles inhibited the elastic fibres fragmentation and fibroblast infiltration. Further, depicting their clinical importance in controlling the integrity of elastic connective tissues which makes such nanoparticles-based drug transport effective [ ] Table 2. Bupivacaine is a long-acting local anaesthetic that belongs to the amino-amide class which is widely used during surgical procedures and for postoperative pain. Animals and in vivo studies such as infraorbital nerve blockade, local toxicity, and pharmacokinetics were used to discover the use of combination chitosan nanoparticles with bupivacaine. Pre-clinical studies bupivacaine in chitosan nanoparticles revealed that encapsulation of bupivacaine prolongs the local anaesthetic effect after infraorbital nerve blockade and altered the pharmacokinetics after intrathecal injection [ ]. Currently in phase 3 clinical trials in the US and phase 2 clinical trials UK and EU is the chitosan-based nasal formulation of morphine RylomineTM [ ] Table 2. Due to its biocompatibility, biodegradability and low toxicity, chitosan is widely recognized as a safe material in pharmaceutical nanotechnology. Moreover, its versatile capabilities indicated this natural polymer and its nanoparticles as a viable vehicle in drug delivery. Once identified as an ideal drug carrier, chitosan has been exploited to design formulations for a large range of drug molecules including proteins, plasmid DNA, and oligonucleotides. Production and clinical development of nanoparticles for gene delivery are discussed nowadays. Gene therapy is an auspicious strategy with intentionally altering the gene expression in pathological cells for the treatment of gene-associated human diseases. Its discussed role of chitosan nanoparticles as a very promising carrier for gene delivery due to high biocompatibility and close resemblance to the lipidic membranes, which facilitate their penetration into the cells [ ]. Furthermore, chitosan nanoparticles allow a controlled and, sometimes, site-specific delivery and are suitable to many routes of administration, especially for the non-invasive ones like oral, nasal, ocular and transdermal [ ]. The major advantage offered by chitosan-based nanoencapsulation is the ability to improve the dissolution rate of poorly soluble drugs thus increasing their bioavailability Fig. This capability depends on the size of the particles as well as from the specific features of chitosan, which render this polymer an ideal drug carrier. Chitosan is soluble in an aqueous solution but it possesses readily modifiable pH-responsive solubility. Generally, dissolution happens in dilute aqueous acid solutions, where the amino groups of chitosan become protonated. However, many other factors contribute to controlling solution properties such as the distribution and number of acetyl groups along the chains, pH, the ionic concentration, the conditions of isolation and drying [ ]. Additionally, chitosan presents mucoadhesive and absorption-enhancing properties. The mucoadhesive nature of chitosan depends on electrostatic interaction between the positive charge on the ionizable protonated amine group and the negative charge on the mucosal surfaces. These interactions trigger a reversible structural reorganization in the protein-associated tight junctions which opens the tight junctions between cells, allowing the drug to cross the mucosal cells [ ]. Mucoadhesion also extends the contact of the drug with the mucosal layer, and allow site-specific administration, in particular in those body site presenting specific mucosal surfaces such as buccal and nasal cavities. Again, many factors can influence mucoadhesive properties such as the molecular weight, the flexibility of the chitosan chain, the electrostatic interaction, the availability of hydrogen bond formation, and the capacity of spreading into the mucus due to surface energy properties [ ]. Also, nanosized formulations are characterized by a large surface to volume ratios, which intensely strengthen the intrinsic properties of chitosan. Nanostructure of appropriate size and surface charge can improve drug penetration thus improving uptake through the cell membrane. Therefore, nanosized carriers could effectively modulate pharmacokinetics, enhancing drug efficacy beside reduced toxicity [ ] and offer the possibility to deliver bioactive agents in a controlled and, sometimes, site-specific manner. However, there are several challenges in the use of drug nanocarriers such as low drug encapsulation, premature release, poor permeability and instability, which could finally affect drug bioavailability. In particular, stability represents one of the most important factors regulating the efficiency of drug delivery systems, especially in the case of nanoparticles [ ]. As regards chitosan nanocarriers, instability could depend on degradation by digestive enzymes and pH variation throughout the gastrointestinal tract. Additionally, a surface charge strongly influences stability and distribution and limits there in vitro and in vivo application. Indeed, although positively charged particles are strongly attracted by negatively charged cell membranes leading to an efficient internalization in the cells, the interaction with serum components could lead to severe aggregation followed by a fast clearance from the circulatory system [ ]. Therefore, many attempts of tailoring the chitosan nanoparticles have been accomplished, aiming to confer improved stability against aggregation in biological settings. The most frequent strategy followed consists of hydrophilic modifications with molecules able to improve stability and solubility in slightly acid and neutral media such as β-cyclodextrin, succinic anhydride or PEG. Besides, also surface decoration with hydrophilic polymers has been carried out in the attempt to contrast nanoparticles aggregation [ ]. However, changes in stability and aggregation of chitosan nanoparticles could also happen during storage. Different techniques of drying i. Generally, nanopowder is easily re-dispersible, but occasionally aggregation or irreversible fusion of particles occurs making the redispersion more difficult. In this regard, the addition of bioprotectants could reduce surface attraction maintaining the nanoparticles dispersed [ ]. Chitosan is a linear polysaccharide composed of D-glucosamine units deacetylated units and N-acetyl- d -glucosamine units β- 1—4 -connected. Chitosan is deacetylated chitin Fig. Commercially chitosan is produced by deacetylation of chitin, a natural material, widespread in the world of exoskeletal crustaceans. It has some remarkable therapeutic properties such as blood coagulation, fat binding, heavy metal ion complexation, hemostatic action. In addition to the degree of deacetylation for a given chitosan sample, the molecular weight of the macromolecule, which can vary between ,—, daltons, is also characteristic. Chitin and chitosan are of high commercial interest due to their high nitrogen content 6. Both chitin and chitosan are biodegradable, biocompatible, non-toxic, non-allergenic and renewable biomaterials and find their application in fields such as medicine, perfumes and cosmetics, food industry and agriculture [ ]. Chitosan, due to the presence of the primary amine group in the sugar units form the polymeric structure, dissolves in dilute organic acids, but is insoluble in water, above pH 6—7 and in ordinary organic solvents. The solubility of chitinous substances is usually associated with the crystallinity of the sample. Higher crystallinity suggests greater or increased molecular interactions between the polymer chains. A chitinous chemical can be dissolved only if these interactions are cancelled. The intra- and intermolecular hydrogen bonds of the polymer chains are the major cause of these interactions and play an important role in the low solubility of these substances. However, chemical modifications of chitosan result in derivatives that are water-soluble in a broader pH range, including in strongly basic environments. The modifications consist of the introduction of ionic groups or substituents in the polymeric structure, which dissolves in polar solvents such as water through polar-polar interactions and determines the solubility of the macromolecule [ ]. The process of isolation of chitin begins in the marine food industry. One of the by-products of this process, such as carapace of radishes, shrimps, etc. Alternatively, if isolation of chitin is not desired, the sequence based on acid treatment may be reversed to produce chitosan directly. During the treatment with basic medium, concomitant hydrolysis of the acetamide groups of chitin takes place, the result being the formation of chitosan. The physical properties of chitinous substances are governed by two factors: the degree of deacetylation and the molecular mass. The former has a direct impact on the secondary structure of the polymer chain and can influence and solubility of the polymer in organic or aqueous solvents. It can also affect the chemical reactivity of the sample inhomogeneous processes [ ]. According to a selective nomenclature, chitinous substances that do not dissolve in dilute organic acids e. On the other hand, chitinous substances that dissolve in dilute aqueous acids are called chitosan. A distribution of acetyl groups on the polymer structure results in homogeneous processing conditions and gives solubility of polymers in aqueous solutions of weak acids. Instead, under heterogeneous processing conditions, polymers are formed with distinct blocks of acetylated sugar residues and are not soluble in solvents. The molecular weight of chitosan obtained at the end of the production process depends on the process parameters, time, temperature and HCl and NaOH concentration. The process parameters used in chitosan production are drastic and the cleavage of the chitin structure accompanies the process. The degradation of the chitinous chain can be extended. In one preparation, a chitin sample with a molecular weight of 1. However, the charged nature of chitosan tends to form free aggregates and the differences in the degree of deacetylation for different chitosan samples require careful implementation of the constants [ ]. Many applications of any chemical, natural or synthetic, require chemical process ability. Thus, chitosan, a white powder, is difficult to handle due to the problems of solubility in neutral water, bases and organic solvents. The pKa value of the primary amino groups in chitosan is 6. Even if chitosan and its derivatives are soluble at a pH lower than 6, most of its applications in the basic or neutral environment cannot be achieved [ ]. On the other hand, acidic solutions in which chitosan is soluble are not compatible with many applications, such as those in cosmetics, medicine and nutrition. There are two approaches in the literature on improving the solubility of chitosan at neutral pH. The first is the chemical derivatization of chitosan for example with substituents containing quaternary ammonium group, by carboxymethylation or sulfation so that the added substituent is hydrophilic. Under the conditions of homogeneous processing, the obtained chitosan remains in solution after neutralization and no derivatization is required. Some applications of chitosan use derivatized forms thereof and to improve the solubility it is necessary to introduce ionic groups in the polymeric structure [ ]. Traditionally, chitinous substances are used in rudimentary medicine and the treatment of wastewater. In recent decades, these substances have found their applicability in various fields, from textile engineering to photography. Chitosan and its derivatives have attracted more interest than chitin, even though the latter has found its applicability in medicine, fibre, absorbable tissues and bandages. It is interesting to note the resistance of chitinous substances to bile, pancreatic juice and urine, which leads to their use in surgery, but also the manufacture of human-made fibres for hard materials [ 95 ]. These substances may be subject to degradation with lysozyme, an enzyme found in nature and the human eye, and with chitinase. This has also led to the use of chitosan derivatives in the preparation of cleaning solutions for contact lenses to remove enzyme deposits [ ]. Chitosan has antimicrobial properties antibacterial and antifungal. Antibacterial action is rapid and eliminates bacteria within hours. Moreover, its derivatives are biodegradable and exhibit reduced toxicity in mammalian cells. The antibacterial activity is associated with the length of the polymer chain and suggests a cooperative effect of the individual carbohydrate units. The antibacterial property of chitosan is useful in medicine, where it is used in the manufacture of surgical accessories such as gloves, bandages, etc. It is also used to remove pathogens from water and as a food preservative by adding a layer to the outside of fruit and vegetable products [ ]. As chitosan is obtained by deacetylation usually not complete of chitin, studies related to the analytical characterization of chitin and chitosan are not without interest. As can be seen from the structures below, the two substances differ in the presence in the case of chitin and the only sporadic presence in the case of chitosan of the acetyl group grafted by the amino function. Chitosan is immiscible with water. Some chitosan components contain hydroxyl group components, capable of intermolecular hydrogen bonds, due to the macromolecular character of the compound and due to the many intermolecular hydrogen bonds, even in the solid-state of the sample. It is difficult to discuss the toxicity of this substance, because chitosan is a natural, non-toxic and biodegradable compound, widely used, due to its unique properties, in biotechnology, human and veterinary medicine, but also cosmetics. Chitosan is widely regarded as being a non-toxic, biologically compatible polymer. It is approved for dietary applications in Japan and many countries from Europa and the FDA has approved it for use in wound dressings. The modifications or degree of deacetylation DD made to chitosan could make it more or less toxic and any residual reactants should be carefully removed. A synopsis of toxicity chitosan's reported is shown in Table 4. The toxicity of chitosan drug administration in animals was reported [ ]. For the reasons listed above, the analytical use of IR spectra was passed, in the spectral range — cm — 1 respectively — cm — 1 , in the transmittance form vs. wave number. The bands are generally large due to the macromolecular character of the compound and due to the numerous intermolecular hydrogen bonds, manifested even in the solid-state of the sample. The absorption bands can be easily attributed to molecular fragments: the dominant band with a maximum at cm — 1 is due to the valence vibrations stretching, ν O—H and ν N—H of the O — H and N — H connections involved. intense in hydrogen bonds. the band with maximum absorption at cm — 1 is due to the valence vibrations of the C — H connections. The series of bands between cm — 1 and cm — 1 are characteristic of the amide group the bands "amide I", … "amide VI". Because this band is associated with the acetyl groups in the molecule, its use is warranted to specify the degree of deacetylation of a chitosan sample the more advanced the acetylation degree, the more intense this band is. To be able to use the intensity of the "amide I" band, the spectra obtained at different recordings must be standardized. The normalization can be achieved by bringing by mathematical processing the intensity of the maximum band ν O—H and ν N—H to the value 1. According to the information studied the possible cases of toxicity may arise due to the chemical transformations to which chitosan is subjected, more precisely the Degree of deacetylation DD. The importance of nanotechnology, in the target delivery of drugs using nanotechnologies and its application for the discovery and development of new oncological drugs are topics of great importance. The latest studies on chitosan-based nanomaterials have shown the high utility of this polymer for modern drug delivery. The physical properties and non-toxicity of chitosan and chitosan derivatives make it an ideal material for the creation of chitosan-based nanomaterials and their use in nanomedicine especially in oncological treatment. The special focus of the studies carried out so far has been on the development of drugs against tumor cells. The requirements of chitosan for its use in nanomedicine—drug formulations provide many new solutions and applications in the development of modern medicine. The use of chitosan for the construction of nanoparticles is very important in this case. Chitosan-based nanoparticles can be used for the delivery of active ingredients, such as drugs or natural products, by diverse routes of administration such as oral and parenteral delivery. Nowadays chitosan nanoparticles have become of great interest for nanomedicine, biomedical engineering and the development of new therapeutic drug release systems. They improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of studied drugs. Currently, cancer disorders are one of the most important global problems. Our review provides the most important information on the effectiveness of nanomedicine in oncological treatment. The scientific studies give special attention to recent advances in chitosan nano-delivery for cancer treatment. The combinations of chitosan-based nanomaterials with such oncological drugs as doxorubicin, paclitaxel, rapamycin, lactoferrin, tamoxifen, docetaxel, letrozole, gefitinib and 5-fluorouracil, were studied. The researches reveal good outcomes. The use of chitosan nanomaterials in drugs used in oncological treatment have shown enhancement of drug delivery to tumours and improving the cytotoxicity effect on cancer cell lines. Additionally, studies on the use of chitosan-based nanomaterials in combination with plant-derived secondary metabolites like curcumin, silibinin and polyphenols also have provided promising results. Moreover, the application of chitosan-based nanomaterials in the discovery and development of e. antibacterial, anti-inflammatory, antidepressant and antihypertensive formulations which could be used in the treatment of other diseases, was tested. The performed studies have revealed that chitosan-based nanomaterials showed significant enhancement of drug bioavailability drug loading efficiency, drug-releasing capacity and drug encapsulation efficiency. The latest advantages of chitosan nanoparticles applications in nanomedicine are supported also by pre-clinical and clinical studies. Zlatian OM, Comanescu MV, Rosu AF, Rosu L, Cruce M, Gaman AE, Calina CD, Sfredel V. Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer. Rom J Morphol Embryol. PubMed Google Scholar. Sani TA, Mohammadpour E, Mohammadi A, Memariani T, Yazdi MV, Rezaee R, Calina D, Docea AO, Goumenou M, Etemad L, et al. 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| Introduction | India: Woodhead Herbal Allergy Relief Chitosan for nanoparticles characterization of colloidal nannoparticles of retinoic acid embedded in nanopartcles of banoparticles alcohol. Journal of Plant Production. Article CAS Google Scholar Yanat, M. Kamat M, Vor K, Zhu D, Lansdell T, Lu Chitosan for nanoparticles, Nanopqrticles Chitosan for nanoparticles, Huang X. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Nanoparticles may be extremely useful for imaging applications [ 59 ] as of the raised surface-area-to-volume ratio in addition to comprising the prospective for several sites for chemical change that perhaps utilized to intensify the sensitivity of imaging [ 59 ]. |
Chitosan for nanoparticles -
Handani et al. Mahmoud et al. Figure 2 C,E depicts the three-dimensional response surface plots as function of temperature on the CNPs biosynthesis when interacting with the other variables: initial pH level and incubation period; respectively. The plots reveal that the CNPs biosynthesis increased as temperature increased to the optimal level.
The synthesis of nanoparticles decreases as the temperature increases. The normal probability plot NPP of the residuals is an important graphical technique represents the residual distribution to check the model's adequacy In the normal probability of the experimental residuals, as shown in Fig.
The residuals are the variation between the predicted CNPs biosynthesis values by the theoretical model and the experimental values of the CNPs biosynthesis. A small residual value indicates that the model prediction is accurate and the model was well fitted with the experimental results.
A Normal probability plot of internally studentized residuals, B Box—Cox plot of model transformation, C plot of predicted versus residuals, and D plot of internally studentized actual values versus predicted values of for chitosan nanoparticles biosynthesis using Eucalyptus globulus Labill leaves extract.
Figure 3 B represents the Box—Cox plot generated by the model transformation for the biosynthesis of chitosan nanoparticles. As shown in Fig. The model is in the optimal zone because the blue line of the current Lambda lies between the two vertical red lines.
This indicates that the model fits the obtained experimental results well and that no data transformation is required In Fig. As shown in the graph, the residuals were scattered in a random pattern all around the zero line.
The residuals were scattered equally and randomly above and below the zero line, indicating that the residuals had a constant variance and supporting the model's precision Figure 3 D depicts a plot of predicted versus actual chitosan nanoparticles biosynthesis.
Figure 3 D shows all points were collected along the diagonal line, indicating a significant correlation between the theoretical values that were predicted by the model and the actual results of the chitosan nanoparticles biosynthesis which confirms the accuracy of the model The purpose of the desirability function and experimental design was to determine the optimal predicted conditions for maximizing the response.
The desirability function values ranged from 0 undesirable to 1 desirable The desirability function value is often determined mathematically prior to experimental validation of the optimization process In this study, the predicted values obtained for the tested variables were as the following: incubation time The maximum predicted value of biosynthesized CNPs was Figure 4 A—D depicts an investigation of the morphology of biosynthesized chitosan nanoparticles using SEM and TEM, respectively.
The morphology of all nanoparticles was relatively homogeneous, with a quite consistent particle size distribution and spherical in shape. The SEM analysis indicates spherical particles with a smooth surface.
While, TEM analysis of the obtained biosynthesized chitosan nanoparticles reveals particles ranging in size between 6.
Comparing this study to earlier ones, the biosynthesized CNPs made from an aqueous extract of fresh Eucalyptus globulus Labill leaves have the smallest particle sizes. The SEM micrograph of chitosan nanoparticles in Wardani et al. Using FE-SEM, Khanmohammadi et al.
According to the findings of Van et al. Bodnar et al. In Dudhani et al. Zhang et al. A,B SEM micrographs, C,D TEM micrograph of chitosan nanoparticles biosynthesised using Eucalyptus globulus Labill leaves extract. The EDX spectrum analysis of the biosynthesized chitosan nanoparticles detected the presence of: carbon C , oxygen O and nitrogen N , as main elements in chitosan nanoparticles as shown in Fig.
A EDX, B XRD, C FTIR, D zeta potential, E DSC and F TGA analyses of chitosan nanoparticles biosynthesised using Eucalyptus globulus Labill leaves extract.
An X-ray diffraction pattern was used to recognize the crystal phases of the materials. X-ray diffraction was used to detect the crystallinity of CNPs as shown in Fig. The XRD pattern of the dried CNPs was recorded at angles within the range of 10°—40° 2θ with time per step s, generator tension of 30 kV, generator current of 10 mA, and temperature of The XRD pattern of CNPs sample showed three distinctive peaks at 2 θ which were at The crystalline structure of chitosan nanoparticles was demonstrated by XRD patterns that displayed strong peak at angle of Similar results were obtained by Rasaee et al.
In the XRD diffraction patterns of the chitosan and chitosan nanoparticles, the diffraction peaks at 2 θ of Each of these diffraction peaks is a reflection of the hydrated crystalline structure and crystalline structure of anhydrous α-chitin This indicates the presence of a crystalline phase in the synthesized chitosan nanoparticles On the other hand, Olajire et al.
FTIR analysis is a powerful tool revealed various functional groups of organic compounds. The zeta potential value was used to estimate the surface charge and thus the stability of the synthesized nanoparticles.
Kheiri et al. Despite the fact that the suspension is physically stable, Muller et al. CNPs have a positive zeta potential, which indicates that they have a charge.
According to the findings of Khan et al. On the other hand, Qi et al. The differential scanning calorimeter, or DSC, is a frequently used thermal analytical tool that can assist in understanding the thermal behavior of polymers The DSC thermogram of CNPs showed two bands, which had typical polysaccharide thermal features.
The first was an endothermic wide band corresponding to polymeric dehydration ranged from The second thermal band was polymeric degradation, causing an exothermic band extending from to °C as shown in Fig.
Feyzioglu and Tornuk 94 reported that CNPs revealed an endothermic peak at Also, Vijayalakshmi et al. TGA is a thermal analysis technique that detects changes in chemical and physical characteristics of the materials as a function of growing temperature or as a function of time A thermogravimetric analyzer, model TGAH, was used to determine changes in the thermal characteristics of biosynthesized CNPs sample of about 6 mg.
The TGA of CNPs is characterized by the presence of five degradation stages Fig. These weight losses indicated partial thermal disintegration of CNPs. At heating temperature °C , the total loss was According to Sivakami et al.
On the other hand, Morsy et al. This loss is related to the evaporation of intra and inter-molecular moisture in the CNPs. When heated at °C, CNPs had a weight loss of The heat degradation of the chitosan backbone was responsible for the weight loss of Multi-drug resistant bacteria Acinetobacter baumannii complex was used to carry out the antibacterial activity tests of CNPs with concentrations of After incubation for 24 h, the inhibition zone diameter created by the well containing CNPs was recorded: 12, 16, 30 mm diameter, respectively.
The inhibition of bacterial growth increased as CNPs concentrations increased. Antibacterial activity of different concentrations of chitosan nanoparticles produced using Eucalyptus leaves extract against Acinetobacter baumannii.
The antibiotic resistance of A. baumannii complex is becoming increasingly serious. Colistin and Polymyxin, that target the cell membrane, are thought to be the final line of defense against drug-resistant bacteria, but they come with a lot of side effects, and drug resistance to these drugs is increasing gradually This study tried to control the growth of multi-drug resistant A.
baumannii complex using biosynthesized CNPs. To study the changes in the morphology of A. baumannii complex cells treated with CNPs. The control untreated cells of A. baumannii complex were represented in Fig. The cytoplasmic content of the bacterial cell was regularly distributed.
Compared with untreated cells, considerable morphological variations were detected in A. The damage in the cell membrane and the cytoplasm content leaked to the extracellular medium with increases in the periplasmic space black arrow head Fig. In addition, coagulated material was observed in the cytoplasm.
Figure 7 F Due to the loss of most cytoplasmic contents from the inner membrane, the outer membrane is enlarged and evacuated, resulting in complete membrane loss; ghost cells TEM examination of the effect of CNPs on multi-drug resistant A.
baumannii cells: A cells of untreated bacteria, B—F cells of bacteria treated with CNPs with different stages in damage and G mechanisms of antibacterial action of CNPs. Several studies on chitosan nanoparticles revealed the stronger antibacterial activity of CNPs against Gram-negative and Gram-positive bacteria, Fig.
Chitosan nanoparticles have the properties of chitosan as well as the benefits of nanoparticles. The unique properties of nanoparticles, such as their small size and quantum effects, can offer chitosan nanoparticles with higher capabilities.
This is due to the fact that the characteristics of bulk materials stay relatively constant regardless of volume; but, as their size reduces, the percentage of surface atoms increase, creating nanoparticles with some remarkable characteristics Avadi et al.
For a quantum-size impact, chitosan nanoparticles provide a stronger affinity towards bacteria cells. Chitosan nanoparticles are able to provide significant antimicrobial properties through various mechanisms.
Smaller molecules like potassium and phosphate seep out, followed by larger molecules like RNA and DNA etc. Chandrasekaran reported that chitosan nanoparticles have metallic ion chelation property which is a possible reason for its antimicrobial action; d Chitosan has the ability to create a polymer film on the cell surface, which acts as a barrier to oxygen and prevents nutrients from entering the cell, inhibiting aerobic bacterial growth Nanoparticles have a greater affinity to produce excess quantities of reactive oxygen species ROS.
Dizaj et al. Highly elevated amounts of reactive oxygen species ROS and other free radicals cause mitochondrial and endoplasmic reticulum disorder, along with severe damages to biomolecules, resulting in genotoxic effects. In this study CNPs have been biologically synthesized and characterized, the CNPs obtained have small particle size with a regular spherical shape and positive surface charges, the antibacterial experiment indicated that the CNPs exhibited excellent antibacterial properties against Acinetobacter baumannii complex.
The biologically synthesized CNPs could be suitable for biological applications in medical treatments and food preservation. Nevertheless, CNP's mechanisms of action against bacteria have not yet been fully elucidated. Therefore, investigations on the antibacterial mechanisms of CNPs and toxicological studies are necessary.
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Nanoscale Res. Abbas et al. This formulation showed great therapeutic improvements for drug delivery to tumours which are present in deep ling tissues [ 89 ]. The anti-metabolic compounds pyrazolopyrimidine and pyrazolopyridine thioglycosides were synthesized and encapsulated by chitosan nanoparticles to increase the anti-cancerous activity.
This nanoformulation was evaluated for its cytotoxicity against Huh-7 and Mcf-7 cells which are related to liver and breast cancer cells respectively.
Genotoxic effects and a synergistic effect was conducted by cellular DNA fragmentation assay and simulated on CompuSyn software [ 90 ].
Almutairi et al. prepared the raloxifene-encapsulated hyaluronic acid-decorated chitosan nanoparticles by complexation. Bae et al. prepared the self-aggregates from deoxycholic acid-modified chitosan.
These self-aggregates can form complexes with these self-aggregates. They may find potential applications as a delivery vehicle of genes and anti-cancer drugs placid DNA [ 92 ].
Deepa et al. evaluated the in-vitro efficacy of. The study suggests that chitosan nano-formulation would be an efficient approach for the release of cytarabine against solid tumours and might be a better [ 93 ].
Wu et al. synthesised hydroxycamptothecine nanoneedles integrated with an exterior thin layer of the methotrexate-chitosan conjugate, which is a dual drug, using co-precipitation in the aqueous phase.
They concluded that the emergence of a dual-drug delivery system which enhances the therapeutic performances in cancer treatment [ 94 ]. Li et al.
Roy et al. encapsulated Fe3O4-bLf Fe 3 O 4 -saturated lactoferrin in alginate enclosed chitosan-coated calcium phosphate AEC-CP nanocarriers NCs. Arunkumar et al. synthesised the composite injectable chitosan gel DZ-CGs comprising of doxorubicin-loaded zein nanoparticles DOX-SC ZNPs.
In vitro drug release profiles of composite DZ-CGs were found to be more controlled when compared to DOX-SC ZNPs. Also, Composite DZ-CGs were more effective in killing cancer cells when compared to DOX-SC ZNPs [ 97 ].
Hwang et al. synthesised the hydrophobically modified glycol chitosan HGC nanoparticles loaded with the anticancer drug docetaxel DTX. The DTX-HGC nanoparticles showed higher antitumor efficacy such as reduced tumour volume and increased the survival rate in A lung cancer cells [ 98 ].
Barbieri et al. prepared the nanoformulation based on phospholipid and chitosan, which efficiently loads tamoxifen by encapsulation method. The amount of drug permeated using the nano-formulation was increased from 1.
This nano-formulation enhanced the non-metabolized drug passing through the rat intestinal tissue via paracellular transport [ 99 ].
Gomathi et al. fabricated the anticancer drug—letrozole® with chitosan nanoparticles using sodium tripolyphosphate as the crosslinking agent. The nano-formulation has biocompatible and hemocompatible properties which makes it an efficient pharmaceutical carrier for the anticancer drug letrozole [ ].
Jain and Banerjee compared the five different drug-carrier ratios of ciprofloxacin hydrochloride-loaded nanoparticles of albumin, gelatin, chitosan, and lipid [solid lipid nanoparticles SLNs ].
A drug-to-carrier ratio of 0. Their results suggest that chitosan nanoparticles and SLNs can act as promising carriers for sustained ciprofloxacin release in infective conditions [ ]. Khan et al. prepared temozolomide® loaded nano lipid-based chitosan hydrogel TMZNLCHG by encapsulation method.
The study revealed the formulation of a non-invasive intranasal route for brain targeting as an alternative to another route for TMZ [ ]. Wang and Zhao optimized the preparation of anticancer drug—gefitinib® and chitosan protamine nanoparticles.
Koo et al. prepared the water-insoluble paclitaxel encapsulated into glycol chitosan nanoparticles with hydrotropic oligomers HO-CNPs. Paclitaxel-HO-CNPs showed higher therapeutic efficacy, compared to Abraxane®, a commercialized paclitaxel-formulation [ ]. Maya et al. prepared the O-carboxymethyl chitosan O-CMC nanoparticles, surface-conjugated with cetuximab Cet for targeted delivery of paclitaxel.
They observed the Cet-Paklitaxel-O-CMC nanoparticles are a promising candidate for the targeted therapy of epidermal growth factor receptor EGFR overexpressing cancers [ ]. Al-Musawi et al. synthesised prepared chitosan-covered superparamagnetic iron oxide nanoparticles CS-SPION and applied them as a nano-carrier for loading of 5-FU CSFU-SPION.
FA-CSFU-SPION demonstrated sustained release of 5-FU at 37 °C in both phosphate and citrate buffer solutions using a reverse microemulsion technique. There were no adverse outcomes reported for normal cells and observed that fluorescein isothiocyanate-labelled drug, has an effective entrance into a cancerous cell and stimulate cell death and apoptosis [ ].
Cavalli et al. prepared chitosan nanospheres with 5-FU by a combination of coacervation and emulsion droplet coalescence method. Thus, nanospheres were effective in reducing tumour cell proliferation and were able to inhibit both HT29 and PC-3 adhesion to HUVEC after 48 h of treatment [ ].
Sahu et al. prepared 5-FU loaded biocompatible chitosan nanogels FCNGL using the ion gelation technique. The pH-responsive character of nanogels triggered the release of 5-FU in an acidic environment, resulting in selective drug delivery, leading to sustained delivery of 5-FU for chemotherapy that can result in high efficacy, patient compliance and safety [ ].
The potential of intracorporeal chitosan-coated curcumin nanocrystals Chi-CUR-NC-4b were examined as a therapeutic application against endotoxemia-induced sepsis. The fabricated nanocrystals were assessed for pharmacokinetic and pharmacodynamic parameters.
Chi-CUR-NC 4b was ascertained to neutralise lipopolysaccharide LPS and increased plasma drug concentration with enhanced levels in the lungs and liver.
In vitro and in vivo pharmacodynamic studies implied that the defensive effects were mediated by the up-regulation of Nrf2 enhanced antioxidant activity, i. via elevated levels of Glutathione-S-transferase GST and Superoxide Dismutase SOD as well as the downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB.
NRF2 has been implicated in creating chemoresistance and has been linked to RAS driven cancer [ 16 , 17 ]. These effects lead to decreased cytokine secretion and decreased tissue injury resulting in enhanced survival in the murine model of LPS induced endotoxemia [ ].
Anitha et al. prepared the nanoformulation of curcumin using dextran sulphate and chitosan. The results showed the preferential killing of cancer cells compared to normal cells by the curcumin-loaded drug [ ].
Baghbani et al. The curcumin entrapment was Keerthikumarc et al. synthesised chitosan encapsulated curcumin nanoparticles by ionic gelation method. Chitosan nanoparticles formulations showed sustained release of the drug; also, in vitro cytotoxicity study showed high and long term anticancer efficacy in human oral cancer cell lines till 72 h [ ].
Rajan et al. synthesised curcumin nanoparticles loaded in chitosan biopolymer and bovine serum albumin. They observed that the selective drug targeting of colorectal carcinoma cells was effective when concentration was increased [ ].
Moreover, there are also studies on the testing of chitosan nanoparticles with plant extracts. Shahiwala et al.
synthesised the chitosan nanoparticles with alcoholic extract of Indigofera intricate— plant of potential antitumor properties. Almost a fold reduction in the extract concentration required to achieve the same anticancer activity when formulated as nanoparticles [ ]. Alipour et al. studied the sustained release of silibinin-loaded chitosan nanoparticles SCNP.
George et al. studied the functionalised nanohybrid hydrogel using L-histidine HIS conjugated chitosan, phyto-synthesised zinc oxide nanoparticles ZNPs and dialdehyde cellulose DAC as a sustained drug delivery carrier for the polyphenol, plant-derived compounds—naringenin, quercetin and curcumin.
Anticancer studies towards A cells epidermoid carcinoma exhibited excellent cytotoxicity with a 15 to fold increase using the hybrid carrier, compared to the free polyphenol drugs [ ]. The chitosan nanoparticles are also tested for other groups of drugs.
For example anti-inflammatory drugs. reported that the nanodevice consists of a magnetite core coated with chitosan Chit MNPs as a platform for diclofenac loading as a model drug and observed the marginal variation in the efficacy [ ].
Chaichanasak et al. prepared the chitosan-based nanoparticles with damnacanthal DAM. DAM increased the levels of the tumour suppressor non-steroidal anti-inflammatory drugs-activated gene 1 in the nucleus, therefore causing improved anticancer effects [ ]. There are also studies on antifungal and antibacterial drugs.
Calvo et al. prepared the chitosan nanocapsule comprising tioconazole TIO and econazole ECO by encapsulation method. The drug showed fungicidal activity against C.
Albicans at non-toxic concentrations and reported it as the first step in the development of a pharmaceutical dosage for treating vaginal candidiasis [ ].
Abd Elsalam et al. proposed a novel chitosan-based nano-in-microparticles NIM , which acts as a combination therapy in the antibacterial platform. PEGlyation PEG—polyethene glycol was done on chitosan, which increased its solubility in water.
To treat multiple bacterial strains, the antibacterial activity of the PEG-CS was strengthened using immobilized silver nanoparticles and with dendritic polyamidoamine hyperbranches.
Ibuprofen encapsulated by montmorillonite nanoclay MMT was used as an anti-inflammatory drug. The developed drug showed good antibacterial activity against both aerobic and anaerobic bacteria resulting in treating multiple bacterial infections [ ].
Ciprofloxacin, a broad-spectrum antibiotic; a poorly soluble drug-loaded chitosan nanoparticle, was prepared for the therapeutics of various microbial infections. The Fourier Transform Infrared Spectroscopy FTIR studies showed that there was zero interaction found between the drug ciprofloxacin and chitosan.
One of the formulations was found to have good entrapment efficacy, positive zeta potential value, and its size was from to nm [ ]. Manimekalai et al. prepared the ceftriaxone sodium loaded chitosan nanoparticles using chitosan as a polymer and trisodium polyphosphate as a cross-linking agent.
The chitosan nanoparticles developed was capable of sustained delivery of ceftriaxone sodium [ ]. Jamil et al. prepared the cefazolin loaded chitosan nanoparticles CSNPs by ionic gelation method. Kinetics study had demonstrated the excellent antimicrobial potential of cefazolin loaded CSNPs against multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa [ ].
Moreover, Manuja et al. They concluded the ChQS-NPs are safe, less toxic and effective as compared to the conventional QS drug delivery [ ]. Among other drugs combined with chitosan nanoparticles, it is noteworthy to mention that are also studied antihypertensive, antidepressant and eye droop formulations.
Niaz et al. fabricated the antihypertensive AHT nano-carrier systems NCS encapsulating captopril, amlodipine and valsartan using chitosan CS polymer. They reported that the AHT nano-ceuticals of polymeric origin can improve the oral administration of currently available hydrophobic drugs while providing the extended-release function [ ].
Selvasudha and Koumaravelou prepared chitosan on simvastatin loaded nanoparticle. Better absorption was observed by reducing the lipid profile with several-fold reduced dose in the mouse model. Studies revealed possible synergistic functionalities of chitosan and the simvastatin as potential hypolipidaemic modality without any toxic manifestations [ ].
Dhayabaran et al. encapsulated antidepressant drugs with biopolymer chitosan. Synthetic drug venlafaxine and herbal extracts Hypericum perforamtum and Clitoria ternatea were encapsulated.
They developed a strategy against depression by utilizing the potentials of Clitoria ternatea as a drug in nanomedicine [ ].
Yu et al. prepared water-soluble cerium oxide loaded glycol chitosan nanoparticle for the treatment of dry eye disease. The solubility of cerium in GC GCCNP increased to Concluded that GCCNP can be the potential drug in the form of eye drop for the treatment of dry eye [ ].
The performed scientific studies have provided promising results of chitosan nanoparticles in the anticancer drug delivery and oncological treatment Tables 3 , 4.
Nevertheless, nowadays chitosan nanoparticles clinical applications for diagnosis and therapy of cancer has been discussed because of their minimal systemic toxicity both in vitro and some in vivo models and maximal cytotoxicity against cancer cells and tumours [ 33 , ].
Nano drug delivery systems based on chitosan nanoparticles have been developed for pre-clinical and clinical studies [ ].
Translation of novel nano-drug delivery systems from the bench to the bedside may require a collective approach. Chitosan nanoparticles typically characterized by a positive surface charge and mucoadhesive capacities such that can adhere to mucus membranes and release the drug payload in a sustained release manner [ 33 ].
Due to such characteristics of chitosan nanoparticles their applications consist of per-oral delivery, ocular drug delivery, nasal drug delivery, pulmonary drug delivery, mucosal drug delivery, gene delivery, buccal drug delivery, vaccine delivery, vaginal drug delivery and cancer therapy [ ]. The clinical studies have shown that intravenous administration of chitosan-based nanocarriers for brain delivery and intranasal administration has been an alternative due to its mucoadhesive properties, improving the patient adhesion to therapy [ ] Table 2.
Various materials with different structural forms are conjugated with drugs to prepare nano-drug delivery systems.
Considering recent approaches, the most commonly used drug delivery vehicles include liposomes [ ], nanoparticles ceramic, metallic and polymeric [ ], dendrimers [ ] and micelles [ ].
The self-assembled amphiphilic micelles based on chitosan and polycaprolactone were developed as carriers of paclitaxel to support its intestinal pharmacokinetic profile [ ]. Experimental results showed that chemical modification of chitosan nanoparticles can improve their use for therapy application [ ] and improve tumour targeting [ ] Table 2.
Chitosan nanoparticles have shown anticancer activity in vitro and in vivo. Xu et al. Also, Chitosan nanoparticles can be used to deliver siRNA targeting key components of tumor metabolism Due to their low or non-toxicity, chitosan nanoparticles and their derivatives can serve as a novel class of anti-cancer drug [ ] Table 2.
Chitosan nanoparticles can be used as carriers in the controlled drug delivery of doxorubicin, an anticancer drug used for the treatment of several tumours [ 18 ]. Doxorubicin can be toxic at some points and to protect patients from doxorubicin side effects were developed chitosan nanoparticles drug delivery system.
It is possible to encapsulate and deliver doxorubicin with reduced side effects. The chitosan oligosaccharide conjugated with biodegradable doxorubicin with farther high efficiency in the tumour growth suppression because of higher cellular uptake [ , ] Table 2.
Chitosan nanoparticles decorated with RGD peptides localize to the tumour vasculature and exert antiangiogenic effects [ ]. Another composition of chitosan nanoparticle was prepared by ionic crosslinking of N-trimethyl chitosan TMC with tripolyphosphate with a lower degree of quaternization and an increase in particle size, a decrease in zeta potential and a slower drug-release profile.
For example, ATP, a related derivative of triphosphate, is essential for life and use its encapsulation with chitosan nanoparticles can improve delivery and health effects. Such specific characteristics of N-trimethyl chitosan chloride nanoparticles can support the use of them as potential protein carriers in various modifications [ ].
Pre-clinical studies with chitosan and N,N, N-trimethyl chitosan nanoparticle encapsulation of Ocimum gratissimum essential oil exhibited antibacterial activity at a lower concentration for both Gram-negative and Gram-positive food pathogens. In vitro cytotoxicity revealed the increased toxicity of N, N, N-trimethyl chitosan nanoparticle encapsulated in Ocimum gratissimum essential oil on MDA-MB breast cancer cell lines [ ].
Another collection approach of a nano drug delivery system based on a combination of chitosan nanoparticles with curcumin loaded dextran sulfate was studied regarding the promotion of curcumin anticancer activity. In vitro cytotoxicity measurements demonstrated that curcumin loaded polymeric nanoparticles got significant therapeutic efficacy against colon HCT and breast MCF-7 cancer cells compared with free curcumin [ ] Table 2.
It was studied the use of chitosan nanoparticle for albumin delivery for its use as a plasma expander in critically ill patients and several other clinical applications mainly via intravenous infusion.
Sustainable albumin release over time and high enzymatic stability from albumin-loaded nanoparticles were observed compared to the free albumin [ ]. The chitosan nanoparticles in the nano-system delivery in combination with hyaluronic acid can be a very promising injectable system for the controlled release of platelet-derived growth factor for tissue engineering applications, as well as for the treatment of ischemia-related diseases [ ] Table 2.
Pre-clinical studies based on development and in vitro and in vivo evaluation of chitosan nanoparticles based dry powder inhalation formulations of prothionamide revealed a dose in pulmonary administration, which will improve the management of tuberculosis [ ].
Hussain et al. had explored the histological and immunomodulatory actions of chitosan nanoparticle in the transport of hydrocortisone using chitosan nanoparticles against atopic dermatitis. It was shown the significant capability of chitosan nanoparticles to minimize the severity of atopic dermatitis.
Histological analysis revealed that chitosan nanoparticles inhibited the elastic fibres fragmentation and fibroblast infiltration. Further, depicting their clinical importance in controlling the integrity of elastic connective tissues which makes such nanoparticles-based drug transport effective [ ] Table 2.
Bupivacaine is a long-acting local anaesthetic that belongs to the amino-amide class which is widely used during surgical procedures and for postoperative pain. Animals and in vivo studies such as infraorbital nerve blockade, local toxicity, and pharmacokinetics were used to discover the use of combination chitosan nanoparticles with bupivacaine.
Pre-clinical studies bupivacaine in chitosan nanoparticles revealed that encapsulation of bupivacaine prolongs the local anaesthetic effect after infraorbital nerve blockade and altered the pharmacokinetics after intrathecal injection [ ].
Currently in phase 3 clinical trials in the US and phase 2 clinical trials UK and EU is the chitosan-based nasal formulation of morphine RylomineTM [ ] Table 2.
Due to its biocompatibility, biodegradability and low toxicity, chitosan is widely recognized as a safe material in pharmaceutical nanotechnology. Moreover, its versatile capabilities indicated this natural polymer and its nanoparticles as a viable vehicle in drug delivery.
Once identified as an ideal drug carrier, chitosan has been exploited to design formulations for a large range of drug molecules including proteins, plasmid DNA, and oligonucleotides.
Production and clinical development of nanoparticles for gene delivery are discussed nowadays. Gene therapy is an auspicious strategy with intentionally altering the gene expression in pathological cells for the treatment of gene-associated human diseases.
Its discussed role of chitosan nanoparticles as a very promising carrier for gene delivery due to high biocompatibility and close resemblance to the lipidic membranes, which facilitate their penetration into the cells [ ].
Furthermore, chitosan nanoparticles allow a controlled and, sometimes, site-specific delivery and are suitable to many routes of administration, especially for the non-invasive ones like oral, nasal, ocular and transdermal [ ]. The major advantage offered by chitosan-based nanoencapsulation is the ability to improve the dissolution rate of poorly soluble drugs thus increasing their bioavailability Fig.
This capability depends on the size of the particles as well as from the specific features of chitosan, which render this polymer an ideal drug carrier. Chitosan is soluble in an aqueous solution but it possesses readily modifiable pH-responsive solubility. Generally, dissolution happens in dilute aqueous acid solutions, where the amino groups of chitosan become protonated.
However, many other factors contribute to controlling solution properties such as the distribution and number of acetyl groups along the chains, pH, the ionic concentration, the conditions of isolation and drying [ ].
Additionally, chitosan presents mucoadhesive and absorption-enhancing properties. The mucoadhesive nature of chitosan depends on electrostatic interaction between the positive charge on the ionizable protonated amine group and the negative charge on the mucosal surfaces.
These interactions trigger a reversible structural reorganization in the protein-associated tight junctions which opens the tight junctions between cells, allowing the drug to cross the mucosal cells [ ].
Mucoadhesion also extends the contact of the drug with the mucosal layer, and allow site-specific administration, in particular in those body site presenting specific mucosal surfaces such as buccal and nasal cavities.
Again, many factors can influence mucoadhesive properties such as the molecular weight, the flexibility of the chitosan chain, the electrostatic interaction, the availability of hydrogen bond formation, and the capacity of spreading into the mucus due to surface energy properties [ ].
Also, nanosized formulations are characterized by a large surface to volume ratios, which intensely strengthen the intrinsic properties of chitosan.
Nanostructure of appropriate size and surface charge can improve drug penetration thus improving uptake through the cell membrane.
Therefore, nanosized carriers could effectively modulate pharmacokinetics, enhancing drug efficacy beside reduced toxicity [ ] and offer the possibility to deliver bioactive agents in a controlled and, sometimes, site-specific manner. However, there are several challenges in the use of drug nanocarriers such as low drug encapsulation, premature release, poor permeability and instability, which could finally affect drug bioavailability.
In particular, stability represents one of the most important factors regulating the efficiency of drug delivery systems, especially in the case of nanoparticles [ ]. As regards chitosan nanocarriers, instability could depend on degradation by digestive enzymes and pH variation throughout the gastrointestinal tract.
Additionally, a surface charge strongly influences stability and distribution and limits there in vitro and in vivo application. Indeed, although positively charged particles are strongly attracted by negatively charged cell membranes leading to an efficient internalization in the cells, the interaction with serum components could lead to severe aggregation followed by a fast clearance from the circulatory system [ ].
Therefore, many attempts of tailoring the chitosan nanoparticles have been accomplished, aiming to confer improved stability against aggregation in biological settings.
The most frequent strategy followed consists of hydrophilic modifications with molecules able to improve stability and solubility in slightly acid and neutral media such as β-cyclodextrin, succinic anhydride or PEG. Besides, also surface decoration with hydrophilic polymers has been carried out in the attempt to contrast nanoparticles aggregation [ ].
However, changes in stability and aggregation of chitosan nanoparticles could also happen during storage. Different techniques of drying i. Generally, nanopowder is easily re-dispersible, but occasionally aggregation or irreversible fusion of particles occurs making the redispersion more difficult.
In this regard, the addition of bioprotectants could reduce surface attraction maintaining the nanoparticles dispersed [ ]. Chitosan is a linear polysaccharide composed of D-glucosamine units deacetylated units and N-acetyl- d -glucosamine units β- 1—4 -connected.
Chitosan is deacetylated chitin Fig. Commercially chitosan is produced by deacetylation of chitin, a natural material, widespread in the world of exoskeletal crustaceans. It has some remarkable therapeutic properties such as blood coagulation, fat binding, heavy metal ion complexation, hemostatic action.
In addition to the degree of deacetylation for a given chitosan sample, the molecular weight of the macromolecule, which can vary between ,—, daltons, is also characteristic. Chitin and chitosan are of high commercial interest due to their high nitrogen content 6.
Both chitin and chitosan are biodegradable, biocompatible, non-toxic, non-allergenic and renewable biomaterials and find their application in fields such as medicine, perfumes and cosmetics, food industry and agriculture [ ].
Chitosan, due to the presence of the primary amine group in the sugar units form the polymeric structure, dissolves in dilute organic acids, but is insoluble in water, above pH 6—7 and in ordinary organic solvents.
The solubility of chitinous substances is usually associated with the crystallinity of the sample. Higher crystallinity suggests greater or increased molecular interactions between the polymer chains. A chitinous chemical can be dissolved only if these interactions are cancelled.
The intra- and intermolecular hydrogen bonds of the polymer chains are the major cause of these interactions and play an important role in the low solubility of these substances.
However, chemical modifications of chitosan result in derivatives that are water-soluble in a broader pH range, including in strongly basic environments. The modifications consist of the introduction of ionic groups or substituents in the polymeric structure, which dissolves in polar solvents such as water through polar-polar interactions and determines the solubility of the macromolecule [ ].
The process of isolation of chitin begins in the marine food industry. One of the by-products of this process, such as carapace of radishes, shrimps, etc. Alternatively, if isolation of chitin is not desired, the sequence based on acid treatment may be reversed to produce chitosan directly.
During the treatment with basic medium, concomitant hydrolysis of the acetamide groups of chitin takes place, the result being the formation of chitosan.
The physical properties of chitinous substances are governed by two factors: the degree of deacetylation and the molecular mass. The former has a direct impact on the secondary structure of the polymer chain and can influence and solubility of the polymer in organic or aqueous solvents.
It can also affect the chemical reactivity of the sample inhomogeneous processes [ ]. According to a selective nomenclature, chitinous substances that do not dissolve in dilute organic acids e.
On the other hand, chitinous substances that dissolve in dilute aqueous acids are called chitosan. A distribution of acetyl groups on the polymer structure results in homogeneous processing conditions and gives solubility of polymers in aqueous solutions of weak acids. Instead, under heterogeneous processing conditions, polymers are formed with distinct blocks of acetylated sugar residues and are not soluble in solvents.
The molecular weight of chitosan obtained at the end of the production process depends on the process parameters, time, temperature and HCl and NaOH concentration. The process parameters used in chitosan production are drastic and the cleavage of the chitin structure accompanies the process.
The degradation of the chitinous chain can be extended. In one preparation, a chitin sample with a molecular weight of 1. However, the charged nature of chitosan tends to form free aggregates and the differences in the degree of deacetylation for different chitosan samples require careful implementation of the constants [ ].
Many applications of any chemical, natural or synthetic, require chemical process ability. Thus, chitosan, a white powder, is difficult to handle due to the problems of solubility in neutral water, bases and organic solvents.
The pKa value of the primary amino groups in chitosan is 6. Even if chitosan and its derivatives are soluble at a pH lower than 6, most of its applications in the basic or neutral environment cannot be achieved [ ]. On the other hand, acidic solutions in which chitosan is soluble are not compatible with many applications, such as those in cosmetics, medicine and nutrition.
There are two approaches in the literature on improving the solubility of chitosan at neutral pH. The first is the chemical derivatization of chitosan for example with substituents containing quaternary ammonium group, by carboxymethylation or sulfation so that the added substituent is hydrophilic.
Under the conditions of homogeneous processing, the obtained chitosan remains in solution after neutralization and no derivatization is required. Some applications of chitosan use derivatized forms thereof and to improve the solubility it is necessary to introduce ionic groups in the polymeric structure [ ].
Traditionally, chitinous substances are used in rudimentary medicine and the treatment of wastewater. In recent decades, these substances have found their applicability in various fields, from textile engineering to photography.
Chitosan and its derivatives have attracted more interest than chitin, even though the latter has found its applicability in medicine, fibre, absorbable tissues and bandages. It is interesting to note the resistance of chitinous substances to bile, pancreatic juice and urine, which leads to their use in surgery, but also the manufacture of human-made fibres for hard materials [ 95 ].
These substances may be subject to degradation with lysozyme, an enzyme found in nature and the human eye, and with chitinase. This has also led to the use of chitosan derivatives in the preparation of cleaning solutions for contact lenses to remove enzyme deposits [ ].
Chitosan has antimicrobial properties antibacterial and antifungal. Antibacterial action is rapid and eliminates bacteria within hours.
Moreover, its derivatives are biodegradable and exhibit reduced toxicity in mammalian cells. The antibacterial activity is associated with the length of the polymer chain and suggests a cooperative effect of the individual carbohydrate units.
The antibacterial property of chitosan is useful in medicine, where it is used in the manufacture of surgical accessories such as gloves, bandages, etc. It is also used to remove pathogens from water and as a food preservative by adding a layer to the outside of fruit and vegetable products [ ].
As chitosan is obtained by deacetylation usually not complete of chitin, studies related to the analytical characterization of chitin and chitosan are not without interest. As can be seen from the structures below, the two substances differ in the presence in the case of chitin and the only sporadic presence in the case of chitosan of the acetyl group grafted by the amino function.
Chitosan is immiscible with water. Some chitosan components contain hydroxyl group components, capable of intermolecular hydrogen bonds, due to the macromolecular character of the compound and due to the many intermolecular hydrogen bonds, even in the solid-state of the sample. It is difficult to discuss the toxicity of this substance, because chitosan is a natural, non-toxic and biodegradable compound, widely used, due to its unique properties, in biotechnology, human and veterinary medicine, but also cosmetics.
Chitosan is widely regarded as being a non-toxic, biologically compatible polymer. It is approved for dietary applications in Japan and many countries from Europa and the FDA has approved it for use in wound dressings. The modifications or degree of deacetylation DD made to chitosan could make it more or less toxic and any residual reactants should be carefully removed.
A synopsis of toxicity chitosan's reported is shown in Table 4. The toxicity of chitosan drug administration in animals was reported [ ]. For the reasons listed above, the analytical use of IR spectra was passed, in the spectral range — cm — 1 respectively — cm — 1 , in the transmittance form vs.
wave number. The bands are generally large due to the macromolecular character of the compound and due to the numerous intermolecular hydrogen bonds, manifested even in the solid-state of the sample. The absorption bands can be easily attributed to molecular fragments: the dominant band with a maximum at cm — 1 is due to the valence vibrations stretching, ν O—H and ν N—H of the O — H and N — H connections involved.
intense in hydrogen bonds. the band with maximum absorption at cm — 1 is due to the valence vibrations of the C — H connections. The series of bands between cm — 1 and cm — 1 are characteristic of the amide group the bands "amide I", … "amide VI". Because this band is associated with the acetyl groups in the molecule, its use is warranted to specify the degree of deacetylation of a chitosan sample the more advanced the acetylation degree, the more intense this band is.
To be able to use the intensity of the "amide I" band, the spectra obtained at different recordings must be standardized. The normalization can be achieved by bringing by mathematical processing the intensity of the maximum band ν O—H and ν N—H to the value 1.
According to the information studied the possible cases of toxicity may arise due to the chemical transformations to which chitosan is subjected, more precisely the Degree of deacetylation DD. The importance of nanotechnology, in the target delivery of drugs using nanotechnologies and its application for the discovery and development of new oncological drugs are topics of great importance.
The latest studies on chitosan-based nanomaterials have shown the high utility of this polymer for modern drug delivery. The physical properties and non-toxicity of chitosan and chitosan derivatives make it an ideal material for the creation of chitosan-based nanomaterials and their use in nanomedicine especially in oncological treatment.
The special focus of the studies carried out so far has been on the development of drugs against tumor cells. The requirements of chitosan for its use in nanomedicine—drug formulations provide many new solutions and applications in the development of modern medicine.
The use of chitosan for the construction of nanoparticles is very important in this case. Chitosan-based nanoparticles can be used for the delivery of active ingredients, such as drugs or natural products, by diverse routes of administration such as oral and parenteral delivery.
Nowadays chitosan nanoparticles have become of great interest for nanomedicine, biomedical engineering and the development of new therapeutic drug release systems. They improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of studied drugs.
Currently, cancer disorders are one of the most important global problems. Our review provides the most important information on the effectiveness of nanomedicine in oncological treatment.
The scientific studies give special attention to recent advances in chitosan nano-delivery for cancer treatment. The combinations of chitosan-based nanomaterials with such oncological drugs as doxorubicin, paclitaxel, rapamycin, lactoferrin, tamoxifen, docetaxel, letrozole, gefitinib and 5-fluorouracil, were studied.
The researches reveal good outcomes. The use of chitosan nanomaterials in drugs used in oncological treatment have shown enhancement of drug delivery to tumours and improving the cytotoxicity effect on cancer cell lines. Additionally, studies on the use of chitosan-based nanomaterials in combination with plant-derived secondary metabolites like curcumin, silibinin and polyphenols also have provided promising results.
Moreover, the application of chitosan-based nanomaterials in the discovery and development of e. antibacterial, anti-inflammatory, antidepressant and antihypertensive formulations which could be used in the treatment of other diseases, was tested.
The performed studies have revealed that chitosan-based nanomaterials showed significant enhancement of drug bioavailability drug loading efficiency, drug-releasing capacity and drug encapsulation efficiency. The latest advantages of chitosan nanoparticles applications in nanomedicine are supported also by pre-clinical and clinical studies.
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Oncol Lett. TABLE 2. Articles on chitosan nanoparticles without TPP as crosslinker, main findings. Zhao et al. Thirty chickens were observed for 3 weeks, showing no clinical symptoms, nervous signs or histopathological changes.
The nanoparticles were therefore considered safe Zhao et al. This is in agreement with a second RCT where growth and health performance of the Nile tilapia fish fingerlings were investigated after adding chitosan and thymol to a basal fish diet Abd El-Naby et al.
After 70 days, there were no significant changes in survival rate in any of the groups, compared to the control group. Liposomes are small artificial sphere-shaped vesicles consisting of one or more phospholipid bilayers.
The phospholipids may be derived from natural compounds such as soya and egg, or tissue from bovines, or they can be synthetic. The properties of the liposomes depend on the lipid components. Thus, qualities such as charge, permeability and stability can be engineered.
Liposomes have the ability to encapsulate both hydrophilic and hydrophobic substances due to their unique composition with both hydrophilic and hydrophobic parts Akbarzadeh et al. Chitosan can interact spontaneously with negatively charged liposomes due to functional amino groups on the chitosan molecule, and by such coat the liposomes Pistone et al.
Five papers concerning the cytotoxicity of liposomes in combination with chitosan were identified; three in vitro studies Adamczak et al. Cytotoxicity studies regarding nanoparticles with liposomes and chitosan are displayed in Table 3. All the studies used different cell lines and test animals.
Four of the articles concluded with low toxicity, high degree of biocompatibility and good tolerance Diebold et al. Interestingly, in another paper, the same nanoparticles but with lower concentration of chitosan 0.
In both papers, the coating of the liposomes was achieved by adding the negatively charged liposomes dropwise into the positively charged chitosan solution, inducing spontaneous formation of chitosan-coated liposomes. Due to up-concentration of the samples in one of the studies the chitosan concentration ended up much higher than in the other.
The cell viability results may therefore reflect the chitosan concentration and the amount of potential free chitosan instead of the toxicity of the chitosan coated liposomes. TABLE 3. Articles on chitosan nanoparticles in combination with liposomes, main findings.
The experiment disclosed nanoparticle clearance via the digestive tract, and no distribution to other organs except the lung was detected Chen et al.
FIGURE 3. Fluorescence detected in mice after intranasal administration of Cy5. Figure adopted from Chen et al. Four in vitro and one in vivo study on the cytotoxicity of nanoparticles coated with chitosan were found.
The main results from each study are listed in Table 4. Three of the in vitro studies investigated poly lactic-co-glycolid acid PLGA nanoparticles coated with chitosan. Different cell lines and test animals were used, and the results showed low cytotoxicity and non-irritant properties Guo et al.
Two of the studies Guo et al. In the in vivo study, no mortality or pathological abnormalities were observed in adult zebrafish after injection with bacterial membrane vesicles coated with chitosan cMVs Tandberg et al.
Several chitosan derivatives have been designed to meet desired requirements and to alter the properties of chitosan. Better solubility and mucoadhesion are the most common requirements. Mucoadhesion is also a desirable feature for a nanocarrier for local drug delivery, as it increases the residence time of drugs at the site of action, minimizes the degradation of drugs in various sites and gives the opportunity for a sustained drug release Ways T.
et al. To increase its water solubility, chitosan can be chemically modified into carboxymethyl chitosan CMC by incorporating negatively charged carboxyl groups to C-6 hydroxyl groups or the NH 2 group of the glucosamine units, as seen in Figure 4.
CMC derivatives are regarded as polyampholytic since they contain both cationic and anionic groups Chen et al. The interest in CMC is rapidly increasing, especially in the biomedical and pharmaceutical field due to its antimicrobial and antioxidant properties.
Also in cosmetics, CMC is highly interesting because of the moisturizing and protective effects Shariatinia, FIGURE 4. Schematic representation of carboxymethylated chitosan and its derivatives. Six articles with five in vitro and two in vivo studies were identified.
The main features of the cytotoxicity studies carried out on nanoparticles containing CMC is seen in Table 5. Cytotoxicity of the same nanoparticles were investigated in three of the six papers, using different cell lines and experimental animals Chakraborty et al.
The other three articles used different cell lines and investigated nanoparticles with chitosan of various molecular weights Liu et al. Quaternized chitosan is another large group of chitosan derivatives. Both the hydrophilic and mucoadhesive properties of chitosan are improved by quaternization of the primary amino groups.
Quaternization of chitosan conserves its positive charge at neutral pH, thus increasing solubility significantly in a much broader pH and concentration range, compared to unmodified chitosan Kotzé et al. The simplest form of quaternized chitosan is N,N,N-trimethyl chitosan TMC.
Seven papers that investigated different quaternized chitosan nanoparticles and their cytotoxicity were identified, four with in vivo studies Liu et al. An overview of cytotoxicity studies concerning nanoparticles with quaternized chitosan is seen in Table 6. The three in vitro and ex vivo studies showed no cytotoxicity in the specific cell lines or after injection of nanoparticles to the ileal loop of rats.
One of the studies measured the reversibility of the ciliary beat frequency in chicken embryo trachea after incubation with TMC.
For all three studies, the nanoparticles showed less cytotoxicity than free TMC. The four in vivo studies showed no obvious toxicity, no pathological changes and no difference in hematological or biochemical parameters from the control group, indicating high level of safety when nanoparticles were administrated intranasally, orally or intramuscularly to mice, rats and chickens Liu et al.
In one of the studies, TMC nanoparticles loaded with low molecular weight heparin LMWH reversed a drug-induced colitis in mice when the mice were treated orally for 15 days, while mice treated with free LMWH showed no signs of recovery Yan et al.
Thiolated chitosan is synthesized by covalently coupling sulfhydryl bearing agents such as cysteine, thioglycolic acid or glutathione onto the backbone of chitosan.
Thiolated chitosan improves the mucoadhesion properties by forming disulfide units both with glycoproteins of the mucus substrate and the polymer chains Chen et al.
The improved mucoadhesive properties make thiolated chitosan attractive for oral delivery of macromolecules. Improved mucoadhesive properties, in combination with permeation properties, enhance the bioavailability of drugs by prolonged residence time and controlled release of the drug Sakloetsakun et al.
As seen in Table 7 , the majority of cytotoxicity studies conducted on thiolated chitosan nanoparticles are transmucosal studies with Caco-2 cells. Nine articles concerning cytotoxicity of thiolated chitosan nanoparticles were identified, containing nine in vitro studies and two ex vivo studies, while five of these involved the use of Caco-2 cells Akhlaghi et al.
All five of these studies showed low cytotoxicity of the thiolated chitosan containing nanoparticles, with the exception of one study that compared non-crosslinked thiolated chitosan nanoparticles to crosslinked thiolated chitosan nanoparticles Noi et al.
The non-crosslinked as compared to the crosslinked thiolated chitosan nanoparticles expressed very variable cell viability. When the thiolated chitosan nanoparticles were crosslinked, the cell viability increased considerably.
The reason for these results may be due to the positively charged surface of the amino group in the non-crosslinked thiolated chitosan that can bind to the negatively charged cell membrane in a cytotoxic manner.
In the crosslinked thiolated chitosan, the positively charged surface is neutralized, and the formulation is therefore less cytotoxic. These results are in accordance with previous studies where free chitosan exhibited higher cytotoxicity than crosslinked chitosan, because the charge density of chitosan is reduced by TPP Pistone et al.
Three of the in vitro studies also concluded with no, or reduced, cytotoxicity of thiolated chitosan compared to unthiolated chitosan Akhlaghi et al. One of the authors explained the results by referring to the higher solubility of thiolated chitosan, and therefore faster removal from the site of application, compared to non-thiolated chitosan Patel et al.
One of the ex vivo studies showed that the herb extract Centella asiatica demonstrated corrosive action comparable to the positive control isopropyl alcohol when it was exposed to the nasal mucosa of goats Haroon et al.
When the same extract was loaded into thiolated chitosan nanoparticles, no erosion or necrosis was detected, and the same results were seen for the unloaded nanoparticles. In another study, three different cell lines were exposed to chitosan- and thiolated-chitosan coated PIBCA poly isobytylcyanoacrylate nanoparticles Pradines et al.
Both nanoparticles expressed high cytotoxicity towards HeLa cells, but the reason was assumed to be the core nanoparticle PIBCA because the same cytotoxicity profile was seen in uncoated PIBCA nanoparticles. The same nanoparticles were investigated in situ using pig vaginal mucosa, with no toxicity detected Pradines et al.
Eight papers concerning the cytotoxicity of other complexes of chitosan nanoparticles were obtained, five in vitro studies Müller et al. The complexes in this section are nanoparticles made of chitosan and an active ingredient such as a contrast agent or curcumin, and solid lipid nanoparticles SLNs which are hydrophobic nanoparticles based on solid lipid components Müller et al.
One of the papers investigate the chitosan derivative glycol chitosan and one investigates chitosan nanoparticles with unknown specifications. An overview of the papers on cytotoxicity of nanoparticles of other derivatives and complexes of chitosan, with main findings, is seen in Table 8.
The five in vitro studies used different cell lines, but they all expressed high cell viability when incubated with the chitosan nanoparticles.
The three in vivo studies also indicated low toxicity to rats and mice, with no histological changes compared to the negative control, as seen in Figure 5 Thai et al.
No alterations in hematological or biochemical parameters compared to the control were detected in any of the in vivo studies Yan et al.
TABLE 8. Articles on other derivatives and complexes with chitosan nanoparticles, main findings. FIGURE 5. Figure adopted from Thai et al. In this overview, 55 papers with in vitro studies were identified involving nanoparticles that were exposed to more than 30 different cell lines.
Only two studies showed somewhat reduced cell viability after incubation with chitosan nanoparticles Dehghan et al. Several of the papers demonstrated that chitosan in nanoparticle form was less cytotoxic than chitosan in free form Amidi et al. The active ingredient clotrimazole and hydrochlorothiazide also showed less cytotoxicity when incorporated in chitosan nanoparticles Onnainty et al.
Reduced toxicity of the active ingredient Centella asiatica was also seen after incorporation into chitosan nanoparticles ex vivo Haroon et al. In one of the studies, chitosan nanoparticles even significantly reduced several of the toxic parameters induced by hydroxyapatite NPs Mosa et al.
The available data regarding the cytotoxicity of chitosan nanoparticles are challenging to compare and summarize due to the vast variation of several factors, such as chitosan properties molecular weight and deacetylation degree , chitosan derivatives, nanoparticle composition, cell lines, experimental animals and cytotoxicity assays.
Several of the collected papers lack details on chitosan properties, such as molecular weight and deacetylation degree, which makes it difficult to draw clear conclusions when it comes to chitosan properties and cytotoxicity.
The pH seems to be an important parameter to consider when evaluating the cytotoxicity, because of its ability to influence particle size and zeta potential.
This was demonstrated by Loh et al. As an example, the pH in the gastrointestinal tract varies from 1 to 8. Therefore, it may be necessary to evaluate the cytotoxicity of nanoparticles in a wide range of pH dependent on the desired exposure route Jana and Jana, Considering the majority of in vitro studies, their shortcomings, such as lack of biologic complexity, should be considered and the cytotoxicity results interpreted thereafter.
Additionally, the various cell lines may demonstrate different sensitivity towards the same chitosan nanoparticles, as observed in Loh et al. This was also the case with Klemetsrud et al. The nanoparticles expressed low cytotoxicity towards the mucin producing HTMTX cell line, compared to the non-mucin producing TR cell line.
But the results could also be due to different concentrations of chitosan. Either way, choosing a relevant cell line to the area of use should give results that are more applicable to the final use. In summary, in spite of all the challenges with comparing the results from different tests and methods, the majority of chitosan nanoparticles demonstrated low cytotoxicity regardless of particle composition, derivatives, cytotoxicity assay, cell lines and animals used in both in vitro and in vivo studies.
Furthermore, chitosan-based nanoparticles have been shown to be less cytotoxic compared to free chitosan, which should strengthen the hypothesis that chitosan nanoparticles are safe.
In view of the fact that free chitosan is already on the marked, with increasing demand worldwide, chitosan nanoparticles seem to be a safe and upcoming product. Considering the extensive variation of chitosan and nanoparticle composition in this review, thorough cytotoxicity evaluation should still be performed for all new chitosan-containing nanoparticles in medicine.
JF authored the draft, and all authors contributed to the manuscript revision, and read and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Energy Replenishment Techniques you for visiting nature. You are using a browser version Hypoglycemia complications in athletes limited support for CSS. To obtain nwnoparticles best experience, we recommend nanopraticles use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The ionic gelation process for the synthesis of chitosan nanoparticles was carried out in microdroplet reactions.
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