Chemical modification of hyaluronic acid as a strategy for the development of advanced drug delivery systems.

Hyaluronic acid (HA) has emerged as a promising biopolymer for various biomedical applications due to its biocompatibility, biodegradability, and intrinsic ability to interact with cell surface receptors, making it an attractive candidate for drug delivery systems and tissue engineering. Chemical modification of HA has opened up versatile possibilities to tailor its properties, enabling the development of advanced drug delivery systems and biomaterials with enhanced functionalities and targeted applications. This review analyzes the strategies and applications of chemically modified HA in the field of drug delivery and biomaterial development. The first part of the review focuses on the different methods and functional groups used for the chemical modification of HA, highlighting the impact of these modifications on its physicochemical properties, degradation behavior and interactions with drugs. The second part of the review evaluates the use of chemically modified HA in the development of advanced biomedical materials including nano- and microparticles, hydrogels and mucoadhesive materials with tailored drug release profiles, site-specific targeting and stimuli-responsive behavior. Thus, the review consolidates the current advances and future perspectives in the field of chemical modification of HA, underscoring its immense potential to drive the development of advanced drug delivery systems and biomaterials with diverse biomedical applications.

Biopolymer Drug Delivery Systems for Oromucosal Application: Recent Trends in Pharmaceutical R&D.

Oromucosal drug delivery, both local and transmucosal (buccal), is an effective alternative to traditional oral and parenteral dosage forms because it increases drug bioavailability and reduces systemic drug toxicity. The oral mucosa has a good blood supply, which ensures that drug molecules enter the systemic circulation directly, avoiding drug metabolism during the first passage through the liver. At the same time, the mucosa has a number of barriers, including mucus, epithelium, enzymes, and immunocompetent cells, that are designed to prevent the entry of foreign substances into the body, which also complicates the absorption of drugs. The development of oromucosal drug delivery systems based on mucoadhesive biopolymers and their derivatives (especially thiolated and catecholated derivatives) is a promising strategy for the pharmaceutical development of safe and effective dosage forms. Solid, semi-solid and liquid pharmaceutical formulations based on biopolymers have several advantageous properties, such as prolonged residence time on the mucosa due to high mucoadhesion, unidirectional and modified drug release capabilities, and enhanced drug permeability. Biopolymers are non-toxic, biocompatible, biodegradable and may possess intrinsic bioactivity. A rational approach to the design of oromucosal delivery systems requires an understanding of both the anatomy/physiology of the oral mucosa and the physicochemical and biopharmaceutical properties of the drug molecule/biopolymer, as presented in this review. This review summarizes the advances in the pharmaceutical development of mucoadhesive oromucosal dosage forms (e.g., patches, buccal tablets, and hydrogel systems), including nanotechnology-based biopolymer nanoparticle delivery systems (e.g., solid lipid particles, liposomes, biopolymer polyelectrolyte particles, hybrid nanoparticles, etc.).

Hyaluronan/B12-chitosan polyelectrolyte complex for oral colistin administration.

Polyelectrolyte complexes (PECs) based on polysaccharides, including hyaluronic acid (HA) and chitosan (CS), are promising delivery systems for antimicrobial agents, including oral administration of the peptide antibiotic colistin (CT). Modification of CS with different targeting ligands to improve intestinal permeability is a suitable way to improve the oral bioavailability of polyelectrolyte particles. This study describes the procedure for obtaining CT-containing PECs based on HA and CS modified with cyanocobalamin (vitamin B12). In this case, vitamin B12 is used as a targeting ligand because it is absorbed in the ileum via specific transporter proteins. The resulting PECs had a hydrodynamic size of about 284 nm and a positive ζ-potential of about 26 mV; the encapsulation efficiency was 88.2 % and the CT content was 42.2 µg/mg. The developed systems provided a two-phase drug release: about 50 % of the CT was released in 0.5-1 h, and about 60 % of the antibiotic was cumulatively released in 5 h. The antimicrobial activity of encapsulated CT was maintained at the same level as the pure drug for at least 24 h (minimum inhibitory concentration against Pseudomonas aeruginosa was 2 µg/mL for both). In addition, the apparent permeability coefficient of CT in the PEC formulation was 2.4 × 10-6 cm/s. Thus, the incorporation of CT into HA- and vitamin B12-modified CS-based PECs can be considered as a simple and convenient method to improve the oral delivery of CT.

Biopolymers in Drug and Gene Delivery Systems 2.0.

In recent years, significant progress has been made in the design and development of biopolymer-based delivery systems for a wide range of applications, including cancer therapy, gene editing, regenerative medicine, and vaccine delivery [...].

Development and Bioactivity of Zinc Sulfate Cross-Linked Polysaccharide Delivery System of Dexamethasone Phosphate.

Improving the biopharmaceutical properties of glucocorticoids (increasing local bioavailability and reducing systemic toxicity) is an important challenge. The aim of this study was to develop a dexamethasone phosphate (DexP) delivery system based on hyaluronic acid (HA) and a water-soluble cationic chitosan derivative, diethylaminoethyl chitosan (DEAECS). The DexP delivery system was a polyelectrolyte complex (PEC) resulting from interpolymer interactions between the HA polyanion and the DEAECS polycation with simultaneous incorporation of zinc ions as a cross-linking agent into the complex. The developed PECs had a hydrodynamic diameter of 244 nm and a ζ-potential of +24.4 mV; the encapsulation efficiency and DexP content were 75.6% and 45.4 µg/mg, respectively. The designed DexP delivery systems were characterized by both excellent mucoadhesion and prolonged drug release (approximately 70% of DexP was released within 10 h). In vitro experiments showed that encapsulation of DexP in polysaccharide nanocarriers did not reduce its anti-inflammatory activity compared to free DexP.

Biopolymers in Drug and Gene Delivery Systems.

Recent years have seen remarkable advances in the field of drug and gene delivery systems, revolutionizing the way we approach therapeutic treatments [...].

Cyanocobalamin-Modified Colistin-Hyaluronan Conjugates: Synthesis and Bioactivity.

Polymeric drug delivery systems enhance the biopharmaceutical properties of antibiotics by increasing their bioavailability, providing programmable and controlled-release properties, and reducing toxicity. In addition, drug delivery systems are a promising strategy to improve the intestinal permeability of various antimicrobial agents, including colistin (CT). This study describes the modification of conjugates based on CT and hyaluronic acid (HA) with cyanocobalamin (vitamin B12). Vitamin B12 was chosen as a targeting ligand because it has its own absorption pathway in the small intestine. The resulting polysaccharide conjugates contained 95 µg/mg vitamin B12 and the CT content was 335 µg/mg; they consisted of particles of two sizes, 98 and 702 nm, with a ζ-potential of approximately -25 mV. An in vitro release test at pH 7.4 and pH 5.2 showed an ultra-slow release of colistin of approximately 1% after 10 h. The modified B12 conjugates retained their antimicrobial activity at the level of pure CT (minimum inhibitory concentration was 2 µg/mL). The resulting delivery systems also reduced the nephrotoxicity of CT by 30-40% (HEK 293 cell line). In addition, the modification of B12 improved the intestinal permeability of CT, and the apparent permeability coefficient of HA-CT-B12 conjugates was 3.5 × 10-6 cm/s, corresponding to an in vivo intestinal absorption of 50-100%. Thus, vitamin-B12-modified conjugates based on CT and HA may be promising oral delivery systems with improved biopharmaceutical properties.

Carrageenan/Chitin Nanowhiskers Cryogels for Vaginal Delivery of Metronidazole.

The development of polymeric carriers based on partially deacetylated chitin nanowhiskers (CNWs) and anionic sulfated polysaccharides is an attractive strategy for improved vaginal delivery with modified drug release profiles. This study focuses on the development of metronidazole (MET)-containing cryogels based on carrageenan (CRG) and CNWs. The desired cryogels were obtained by electrostatic interactions between the amino groups of CNWs and the sulfate groups of CRG and by the formation of additional hydrogen bonds, as well as by entanglement of carrageenan macrochains. It was shown that the introduction of 5% CNWs significantly increased the strength of the initial hydrogel and ensured the formation of a homogeneous cryogel structure, resulting in sustained MET release within 24 h. At the same time, when the CNW content was increased to 10%, the system collapsed with the formation of discrete cryogels, demonstrating MET release within 12 h. The mechanism of prolonged drug release was mediated by polymer swelling and chain relaxation in the polymer matrix and correlated well with the Korsmeyer-Peppas and Peppas-Sahlin models. In vitro tests showed that the developed cryogels had a prolonged (24 h) antiprotozoal effect against Trichomonas, including MET-resistant strains. Thus, the new cryogels with MET may be promising dosage forms for the treatment of vaginal infections.

Chitosan Composites with Bacterial Cellulose Nanofibers Doped with Nanosized Cerium Oxide: Characterization and Cytocompatibility Evaluation.

In this work, new composite films were prepared by incorporating the disintegrated bacterial cellulose (BCd) nanofibers and cerium oxide nanoparticles into chitosan (CS) matrices. The influence of the amount of nanofillers on the structure and properties of the polymer composites and the specific features of the intermolecular interactions in the materials were determined. An increase in film stiffness was observed as a result of reinforcing the CS matrix with BCd nanofibers: the Young's modulus increased from 4.55 to 6.3 GPa with the introduction of 5% BCd. A further increase in Young's modulus of 6.7 GPa and a significant increase in film strength (22% increase in yield stress compared to the CS film) were observed when the BCd concentration was increased to 20%. The amount of nanosized ceria affected the structure of the composite, followed by a change in the hydrophilic properties and texture of the composite films. Increasing the amount of nanoceria to 8% significantly improved the biocompatibility of the films and their adhesion to the culture of mesenchymal stem cells. The obtained nanocomposite films combine a number of favorable properties (good mechanical strength in dry and swollen states, improved biocompatibility in relation to the culture of mesenchymal stem cells), which allows us to recommend them for use as a matrix material for the culture of mesenchymal stem cells and wound dressings.

Nano-Sized Fucoidan Interpolyelectrolyte Complexes: Recent Advances in Design and Prospects for Biomedical Applications.

The marine polysaccharide fucoidan (FUC) is a promising polymer for pharmaceutical research and development of novel drug delivery systems with modified release and targeted delivery. The presence of a sulfate group in the polysaccharide makes FUC an excellent candidate for the formation of interpolyelectrolyte complexes (PECs) with various polycations. However, due to the structural diversity of FUC, the design of FUC-based nanoformulations is challenging. This review describes the main strategies for the use of FUC-based PECs to develop drug delivery systems with improved biopharmaceutical properties, including nanocarriers in the form of FUC-chitosan PECs for pH-sensitive oral delivery, targeted delivery systems, and polymeric nanoparticles for improved hydrophobic drug delivery (e.g., FUC-zein PECs, core-shell structures obtained by the layer-by-layer self-assembly method, and self-assembled hydrophobically modified FUC particles). The importance of a complex study of the FUC structure, and the formation process of PECs based on it for obtaining reproducible polymeric nanoformulations with the desired properties, is also discussed.

Micro-/Nano-Carboxymethyl Cellulose as a Promising Biopolymer with Prospects in the Agriculture Sector: A Review.

The increase in the population rate has increased the demand for safe and quality food products. However, the current agricultural system faces many challenges in producing vegetables and fruits. Indiscriminate use of pesticides and fertilizers, deficiency of water resources, short shelf life of products postharvest, and nontargeted delivery of agrochemicals are the main challenges. In this regard, carboxymethyl cellulose (CMC) is one of the most promising materials in the agriculture sector for minimizing these challenges due to its mechanical strength, viscosity, wide availability, and edibility properties. CMC also has high water absorbency; therefore, it can be used for water deficiency (as superabsorbent hydrogels). Due to the many hydroxyl groups on its surface, this substance has high efficacy in removing pollutants, such as pesticides and heavy metals. Enriching CMC coatings with additional substances, such as antimicrobial, antibrowning, antioxidant, and antisoftening materials, can provide further novel formulations with unique advantages. In addition, the encapsulation of bioactive materials or pesticides provides a targeted delivery system. This review presents a comprehensive overview of the use of CMC in agriculture and its applications for preserving fruit and vegetable quality, remediating agricultural pollution, preserving water sources, and encapsulating bioactive molecules for targeted delivery.

Biocomposite films based on chitosan and cerium oxide nanoparticles with promising regenerative potential.

Polymeric nanocomposite materials have great potential in the development of tissue-engineered scaffolds because they affect the structure and properties of polymeric materials and regulate cell proliferation and differentiation. In this work, cerium oxide nanoparticles (CeONPs) were incorporated into a chitosan (CS) film to improve the proliferation of multipotent mesenchymal stem cells (MSCs). The citrate-stabilized CeONPs with a negative ζ-potential (-25.0 mV) were precoated with CS to obtain positively charged particles (+20.3 mV) and to prevent their aggregation in the composite solution. The composite CS-CeONP films were prepared in the salt and basic forms using a dry-cast process. The films obtained in both forms were characterized by a uniform distribution of CeONPs. The incorporation of CeONPs into the salt form of CS increased the stiffness of the CS-CeONP film, while the subsequent conversion of the film to the basic form resulted in a decrease in both the Young's modulus and the yield stress. The redox activity (Ce4+ ⇌ Ce3+) of cerium oxide in the CS-CeONP film was confirmed by thermal oxidative degradation. In vitro culture of MSCs showed that the CS-CeONP film has good biocompatibility, and in vivo experiments demonstrated its substantial regenerative potential.

Patches as Polymeric Systems for Improved Delivery of Topical Corticosteroids: Advances and Future Perspectives.

Mucoadhesive polymer patches are a promising alternative for prolonged and controlled delivery of topical corticosteroids (CS) to improve their biopharmaceutical properties (mainly increasing local bioavailability and reducing systemic toxicity). The main biopharmaceutical advantages of patches compared to traditional oral dosage forms are their excellent bioadhesive properties and their increased drug residence time, modified and unidirectional drug release, improved local bioavailability and safety profile, additional pain receptor protection, and patient friendliness. This review describes the main approaches that can be used for the pharmaceutical R&D of oromucosal patches with improved physicochemical, mechanical, and pharmacological properties. The review mainly focuses on ways to increase the bioadhesion of oromucosal patches and to modify drug release, as well as ways to improve local bioavailability and safety by developing unidirectional -release poly-layer patches. Various techniques for obtaining patches and their influence on the structure and properties of the resulting dosage forms are also presented.

Bacterial Cellulose Composites with Polysaccharides Filled with Nanosized Cerium Oxide: Characterization and Cytocompatibility Assessment.

A new biocompatible nanocomposite film material for cell engineering and other biomedical applications has been prepared. It is based on the composition of natural polysaccharides filled with cerium oxide nanoparticles (CeONPs). The preparative procedure consists of successive impregnations of pressed bacterial cellulose (BC) with a sodium alginate (ALG) solution containing nanoparticles of citrate-stabilized cerium oxide and a chitosan (CS) solution. The presence of CeONPs in the polysaccharide composite matrix and the interaction of the nanoparticles with the polymer, confirmed by IR spectroscopy, change the network architecture of the composite. This leads to noticeable changes in a number of properties of the material in comparison with those of the matrix's polysaccharide composition, viz., an increase in mechanical stiffness, a decrease in the degree of planar orientation of BC macrochains, an increase in hydrophilicity, and the shift of the processes of thermo-oxidative destruction of the material to a low-temperature region. The latter effect is considered to be caused by the redox activity of cerium oxide (reversible transitions between the states Ce4+ and Ce3+) in thermally stimulated processes in the nanocomposite films. In the equilibrium swollen state, the material retains a mechanical strength at the level of ~2 MPa. The results of in vitro tests (cultivation of multipotent mesenchymal stem cells) have demonstrated the good biocompatibility of the BC-ALG(CeONP)-CS film as cell proliferation scaffolds.

pH-Sensitive Drug Delivery System Based on Chitin Nanowhiskers-Sodium Alginate Polyelectrolyte Complex.

Polyelectrolyte complexes (PECs), based on partially deacetylated chitin nanowhiskers (CNWs) and anionic polysaccharides, are characterized by their variability of properties (particle size, ζ-potential, and pH-sensitivity) depending on the preparation conditions, thereby allowing the development of polymeric nanoplatforms with a sustained release profile for active pharmaceutical substances. This study is focused on the development of hydrogels based on PECs of CNWs and sodium alginate (ALG) for potential vaginal administration that provide controlled pH-dependent antibiotic release in an acidic vaginal environment, as well as prolonged pharmacological action due to both the sustained drug release profile and the mucoadhesive properties of the polysaccharides. The desired hydrogels were formed as a result of both electrostatic interactions between CNWs and ALG (PEC formation), and the subsequent molecular entanglement of ALG chains, and the formation of additional hydrogen bonds. Metronidazole (MET) delivery systems with the desired properties were obtained at pH 5.5 and an CNW:ALG ratio of 1:2. The MET-CNW-ALG microparticles in the hydrogel composition had an apparent hydrodynamic diameter of approximately 1.7 µm and a ζ-potential of -43 mV. In vitro release studies showed a prolonged pH-sensitive drug release from the designed hydrogels; 37 and 67% of MET were released within 24 h at pH 7.4 and pH 4.5, respectively. The introduction of CNWs into the MET-ALG system not only prolonged the drug release, but also increased the mucoadhesive properties by about 1.3 times. Thus, novel CNW-ALG hydrogels are promising carriers for pH sensitive drug delivery carriers.

Biophysical Characterization and Cytocompatibility of Cellulose Cryogels Reinforced with Chitin Nanowhiskers.

Polysaccharide-based cryogels are promising materials for producing scaffolds in tissue engineering. In this work, we obtained ultralight (0.046-0.162 g/cm3) and highly porous (88.2-96.7%) cryogels with a complex hierarchical morphology by dissolving cellulose in phosphoric acid, with subsequent regeneration and freeze-drying. The effect of the cellulose dissolution temperature on phosphoric acid and the effect of the freezing time of cellulose hydrogels on the structure and properties of the obtained cryogels were studied. It has been shown that prolonged freezing leads to the formation of denser and stronger cryogels with a network structure. The incorporation of chitin nanowhiskers led to a threefold increase in the strength of the cellulose cryogels. The X-ray diffraction method showed that the regenerated cellulose was mostly amorphous, with a crystallinity of 26.8-28.4% in the structure of cellulose II. Cellulose cryogels with chitin nanowhiskers demonstrated better biocompatibility with mesenchymal stem cells compared to the normal cellulose cryogels.

Hyaluronan-colistin conjugates: Synthesis, characterization, and prospects for medical applications.

The development of nanotechnology-based antibiotic delivery systems (nanoantibiotics) is an important challenge in the effort to combat microbial multidrug resistance. These systems have improved biopharmaceutical characteristics by increasing local bioavailability and reducing systemic toxicity and the number and frequency of drug side effects. Conjugation of low -molecular -weight antibacterial agents with natural polysaccharides is an effective strategy for developing optimal targeted delivery systems with programmed release and reduced cytotoxicity. This study describes the synthesis of conjugates of colistin (CT) and hyaluronic acid (HA) using carbodiimide chemistry to conjugate the amino groups of CT with the carboxyl groups of HA. The obtained polysaccharide carriers had a degree of substitution (DS) with CT molecules of 3-10 %, and the CT content was 129-377 µg/mg. The size of the fabricated particles was 300-600 nm; in addition, there were conjugates in the form of single macromolecules (30-50 nm). The ζ-potential of developed systems was about -20 mV. In vitro release studies at pH 7.4 and pH 5.2 showed slow hydrolysis of amide bonds, with a CT release of 1-5 % after 24 h. The conjugates retained antimicrobial activity depending on the DS: at DS 8 %, the minimum inhibitory concentration (MIC) of the conjugate corresponded to the MIC of free CT. The resulting systems also reduced CT nephrotoxicity by 20-50 %. These new conjugates of CT with HA are promising for the development of nanodrugs for safe and effective antimicrobial therapy.

Sodium Alginate-Gelatin Nanoformulations for Encapsulation of Bacillus velezensis and Their Use for Biological Control of Pistachio Gummosis.

Biopolymer-based nanocomposites are favorable materials for the encapsulation of biofertilizers and biocontrol agents. In this research, sodium alginate, a widely used natural polymer, was extracted and purified from Macrocystis pyrifera. Its composition was confirmed using 1H NMR and FTIR analyses, and its molecular weight and mannuronic acid/guluronic acid ratio were obtained. Sodium alginate-gelatin microcapsules enriched with carbon nanotubes and SiO2 nanoparticles were prepared to encapsulate Bacillus velezensis, and the biological effects of this formulation on the control of pistachio gummosis and growth parameters were investigated. Microscopy examination showed that the microcapsules had quite globular shapes. XRD confirmed the occurrence of an electrostatic interaction when sodium alginate was blended with gelatin. The survival rate of the encapsulated bacteria was about 107 CFU/mL and was maintained after one year of storage. The aim of this study was to achieve a unique formulation containing beneficial bacteria and nanoparticles for the synergistic control of Phytophthora drechsleri.

Alginate-Induced Disease Resistance in Plants.

Plants are continuously exposed to a wide range of pathogens, including fungi, bacteria, nematodes, and viruses; therefore, survival under these conditions requires a sophisticated defense system. The activation of defense responses and related signals in plants is regulated mainly by the hormones salicylic acid, jasmonic acid, and ethylene. Resistance to pathogen infection can be induced in plants by various biotic and abiotic agents. For many years, the use of abiotic plant resistance inducers has been considered in integrated disease management programs. Recently, natural inducer compounds, such as alginates, have become a focus of interest due to their environmentally friendly nature and their ability to stimulate plant defense mechanisms and enhance growth. Polysaccharides and the oligosaccharides derived from them are examples of eco-compatible compounds that can enhance plant growth while also inducing plant resistance against pathogens and triggering the expression of the salicylic acid-dependent defense pathway.

Cellulose Cryogels as Promising Materials for Biomedical Applications.

The availability, biocompatibility, non-toxicity, and ease of chemical modification make cellulose a promising natural polymer for the production of biomedical materials. Cryogelation is a relatively new and straightforward technique for producing porous light and super-macroporous cellulose materials. The production stages include dissolution of cellulose in an appropriate solvent, regeneration (coagulation) from the solution, removal of the excessive solvent, and then freezing. Subsequent freeze-drying preserves the micro- and nanostructures of the material formed during the regeneration and freezing steps. Various factors can affect the structure and properties of cellulose cryogels, including the cellulose origin, the dissolution parameters, the solvent type, and the temperature and rate of freezing, as well as the inclusion of different fillers. Adjustment of these parameters can change the morphology and properties of cellulose cryogels to impart the desired characteristics. This review discusses the structure of cellulose and its properties as a biomaterial, the strategies for cellulose dissolution, and the factors affecting the structure and properties of the formed cryogels. We focus on the advantages of the freeze-drying process, highlighting recent studies on the production and application of cellulose cryogels in biomedicine and the main cryogel quality characteristics. Finally, conclusions and prospects are presented regarding the application of cellulose cryogels in wound healing, in the regeneration of various tissues (e.g., damaged cartilage, bone tissue, and nerves), and in controlled-release drug delivery.