Chitosan - dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics.

The development of synergistic drug combinations is a promising strategy for effective cancer suppression. Here, we report all-polysaccharide biodegradable polyelectrolyte complex hydrogels (DPCS) based on dextran phosphate carbamate (DP) and chitosan (CS) for controlled co-delivery of the anticancer drug doxorubicin (DOX) and the non-steroidal anti-inflammatory drug indomethacin (IND). IND can induce more apoptosis in tumor cells by reducing the level of multidrug resistance-associated protein 1. Based on calculations using density functional theory and zeta potential analysis data, carriers with high drug loading were obtained. The release profile of both drugs from the hydrogels was tuned by changing the molecular weight and functional groups content of the polysaccharides. The optimized DPCS showed a steady release of DOX both in vitro and in vivo, and a gradual release of IND, which constantly induced the action of DOX. Considering all of these benefits, DOX- and IND-loaded DPCS offer a promising long-acting polysaccharide-based antitumor platform.

Biodegradable polyelectrolyte complexes of chitosan and partially crosslinked dextran phosphate with potential for biomedical applications.

Polyelectrolyte complexes (PECs) are spontaneously formed by mixing oppositely charged polyelectrolyte solutions without the use of organic solvents and chemical crosslinkers are great candidate carriers for drug delivery. Herein, biodegradable antimicrobial polyelectrolyte complexes of chitosan - dextran phosphate (DPCS) containing cefazolin were developed and characterized in order to assess their suitability for biomedical applications. For this purpose, the simultaneous partial crosslinking and functionalization of dextran with phosphoric acid in a urea melt under reduced pressure were studied. The functional group content and molecular weight of dextran phosphate were varied in order to establish their influence on gel fraction yield, thermal properties and morphologies of the hydrogels. The stoichiometric PECs of DPCS showed good in vitro biocompatibility, pH sensitivity and biodegradability depending on the hydrogel composition. The release of drug from cefazolin-loaded DPCS hydrogels was through non-Fickian diffusion and displayed long sustained-release time. The drug-loaded hydrogels showed antimicrobial activity against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The tunable degradation behavior under physiological conditions in combination with biocompatibility of the pristine DPCS and high antibacterial efficacy drug-loaded hydrogels may render the presented materials interesting for biomedical applications.

Fabrication of oxidized bacterial cellulose by nitrogen dioxide in chloroform/cyclohexane as a highly loaded drug carrier for sustained release of cisplatin.

Carboxylated bacterial cellulose (OBC) was fabricated by oxidation with nitrogen dioxide in chloroform/cyclohexane and employed as a carrier for sustained release of antitumor substance cisplatin (CDDP). The influence of removing water method, solvent used in the synthesis, concentration of N2O4, and duration of the oxidation on content of carboxyl groups in reaction products was established. Due to the possibility of nitrogen dioxide to penetrate into cellulose crystallites, the carboxyl group content of the OBC reaches high values up to 4 mmol/g. In vitro degradation of OBC was determined under simulated physiological conditions. The immobilization of CDDP on OBC was studied in detail. The initial burst release of the drug from the polymer was depressed. The cytotoxicity of CDDP-loaded OBC was evaluated with HeLa cells. The unique structure and properties of OBC make it a great candidate as drug delivery carrier.

Biodegradable pH-sensitive prospidine-loaded dextran phosphate based hydrogels for local tumor therapy.

The paper focuses on the development of drug delivery systems based on hydrogels of dextran phosphate (DP) for local cancer therapy. The hydrogels were characterized by physicochemical properties including functional group content, morphology, gel fraction, pH-responsive swelling. The desirable pH-sensitive drug release behavior of these hydrogels was demonstrated by a drug release test with Prospidine-loaded hydrogels (DP-Pr hydrogels) at different pH values. In vitro degradation of the DP-Pr hydrogels was determined under simulated physiological conditions. The cytotoxicity of the blank DP hydrogels and DP-Pr hydrogels with different Pr concentrations was evaluated with HeLa and HЕр-2 cells. Investigations of antitumor efficiency in vivo showed that administration of DP-Pr hydrogels in comparison with an aqueous solution of Pr results in the increase of antitumor activity, prolongation of therapeutic action and growth of a number of animals cured. Therefore, such pH-responsive DP hydrogels could be promising candidates as drug delivery carriers.

Adsorption of zwitterionic drugs onto oxidized cellulose.

Adsorption of zwitterionic drugs (beta-lactam antibiotics and amino acids) onto samples of oxidized cellulose (OC) with various carboxyl contents and structural characteristics from aqueous and water/alcohol solutions was investigated. The adsorption process can be described according to the theory of localized stoichiometric adsorption and represented by Langmuir isotherms. It was established that the constants of interfacial distribution mainly increase with increased relative sorbate hydrophobicity. The dependencies of adsorption on pH of equilibrium drug solution have a maximum at pH 3-3.5, which is caused by peculiarities of dissociation of OC and sorbates. The drug uptake is shown to increase with an increase of alcohol mole fraction in the solution and transfer to the binary water/isopropanol from water/ethanol solutions. The dominant contribution to the increase of uptake is the desolvation of ionic groups of zwitterions in the solution, which increases with increased alcohol content. The degree of crystallinity of the sorbent has no considerable effect on drug adsorption from aqueous solutions. In water/alcohol solutions the adsorption of drugs by OC samples with similar exchange capacity increases with reducted uniformity of carboxylic group distribution in the volume of the polymer, which is connected with increased accessibility of carboxylic groups for sorbate molecules.

Multilayer adsorption of amino acids on oxidized cellulose.

The adsorption of amino acids (AA) (glycine, L-alanine, L-proline) on oxidized cellulose (OC) with various carboxyl contents and degrees of crystallinity from aqueous and water/ethanol solutions was studied. It was found that multilayer adsorption occurs in concentrated solutions of AA. It proceeds according to successive mechanisms via adsorption of AA zwitterions onto carboxyls of already adsorbed AA. This leads to formation of chain AA associates in the OC phase. A sharp increase in swelling accompanies multilayer adsorption. It was established that structural characteristics and degree of polymerization of OC are the main factors that affect multilayer adsorption. The distribution of carboxyls in the OC phase also plays an important role. Multilayer adsorption does not proceed in water/ethanol solutions and in the case of the cationic form of AA.