The homophase oxidation of dextran with sodium metaperiodate in an aqueous solution was studied, and samples of dialdehyde dextran with a degree of substitution of 0.12–1.24 were prepared. The effect of reaction temperature, oxidizing agent concentration, and pH of the reaction medium on the ratio of oxidized units of different chemical composition, molecular weight characteristics of the reaction products, and solubility of dialdehyde dextran samples was studied. The degradation rate of dialdehyde dextran in solutions at various pH values was estimated and it was shown that the hydrolysis rate in solutions with pH 2.0 enhances with increasing the number of aldehyde groups in the samples of oxidized dextran. In a solution with pH 3.5, the lowest degree of hydrolysis of dialdehyde dextran samples is detected, which does not depend on the content of aldehyde groups in their composition.

The composition of carboxymethylcellulose–dioxydine was obtained and its structural, morphological and rheological characteristics in the processes of heat treatment and chemical hydrolysis were studied. Using IR spectroscopy, scanning electron microscopy, and viscometry, it has been established that the introduction of dioxidine into a solution of carboxymethylcellulose sodium salt with different molecular weights leads to partial disordering of hydrogen bonds between macromolecules, promotes thermal destruction of the polysaccharide and a decrease in the dynamic viscosity of solutions. Experimental kinetic curves of carboxymethylcellulose hydrolysis in the presence and absence of dioxidine were obtained, and it was shown that they could be described using a first-order equation. The hydrolysis rate coefficients were calculated, and it was shown that, as a result of heat treatment, as well as in the presence of an active substance, the rate of carboxymethylcellulose hydrolysis increased. The change in the rheological properties of carboxymethylcellulose sodium salt solutions with different degrees of polymerization in the presence of an antimicrobial substance should be taken into account when choosing the composition of viscous prolonged forms of biologically active substances.

The apparent ionization constants have been determined for phosphate groups of phosphorylated starch microgels with particle sizes of 300–500 µm. It has been shown that hydrogen bonds formed by phosphate and carbamate groups play an essential role in the acid-base equilibrium of starch phosphorylated in an orthophosphoric acid−urea system. It has been found that the acidic properties of starch phosphate microgels are almost independent of the ionic strength of a solution (0.05–0.5) and the concentration of phosphate groups (2.0–3.8 mmol/g). The cytostatic activity of starch phosphate microgels has been revealed in vitro using the HeLa cell culture.

The physicochemical and biological properties of hydrogels based on starch, dextran, and cellulose phosphates synthesized in orthophosphoric acid–tributyl phosphate–phosphorus(V) oxide and orthophosphoric acid–urea systems are studied. It is found the apparent first step ionization constants of phosphate groups lie in the range of 2.5–2.9 and are virtually independent of the nature of the initial polysaccharide, the means of esterification, and the concentration of functional groups. It is concluded that the differences between the potentiometric curves of the titration of weakly acidic groups are due to the presence of polysaccharide phosphates. Carbamate groups contribute to the formation of a more cross-linked structure of hydrogels, making it difficult to ionize phosphate groups in the second stage. It is established that gel-forming phosphorylated polysaccharides exhibit antitumor activity.

Gel-forming starch phosphates with a content of acidic phosphate groups ranging from 2.1 to 3.8 mmol/g were obtained in a phosphoric acid-urea system. The rates of starch phosphate degradation in buffer solution in the absence of amylase and in the presence of this enzyme were investigated in vitro. Starch phosphate gels were shown to be prone to enzymatic degradation. However, the rate of biodegradation decreased gradually as the content of phosphate groups increased. The use of microgels with average particle sizes in the range of 7.8–60.1 μm for the production of controlled-release preparations of interferon-alpha 2b has been demonstrated to be possible in principle.

Aims and objectives. During regional intraperitoneal chemotherapy cytostatics in prolonged dosage form, in particular, on the basis of various biodegradable hydrogels, such as dextran phosphate are applied. Aim of the study - a comparative evaluation of the antitumor activity ofcisplatin and cisplatin in prolonged dextran phosphate hydrogel form on Zajdel ascites hepatoma. Materials and methods. On 49 white no inbreed rats (n = 7) with implanted intraperitoneal Zajdel ascites hepatoma the antitumor activity of cisplatin in prolonged dextran phosphate hydrogel form with single intraperitoneal injection of the dosage from 3 to 8 mg/kg (≈ maximum tolerated dose, MTD) was evaluated in comparison with officinal cisplatin. The treatment efficacy was assessed by a statistically significant standard criteria: the absence of ascites by 32nd day of the experiment (complete remission) and an increase in life span of rats with ascites (T/C >_125 %, «treatment/control») in comparison with the rats without treatment (tumor growth control, where T/C = 100 %) or treated with officinal cisplatin. Macroscopic, pathomorphological and statistical analysis of the results were used. Results. It has been shown that hydrogel form of cisplatin compared to cisplatin was significantly more effective: complete remission 4/7-6/7 vs 0/7, T/C = 140-188 % vs 91-101 %, the volume of ascites 13,6 ± 6,6 ml vs 50,0 ± 7,9 ml (p = 0,004) because of a better tolerance. Regression analysis confirms that hydrogel form of cisplatin in used dose range significantly improves the rats survival with Zajdel ascites hepatoma, reducing the risk of death from tumor in 7-35 times and the relative risk with the dose of 5,5 mg/kg in 36 times (95 % CI3,86 + 327,60) (p = 0,002-0,005). Conclusions. The data obtained allow considering the hydrogel form of cisplatin as a promising prolonged this drug form of cisplatin by the intraperitoneal therapy and recommending it to preclinical study.

Исследовано межмолекулярное взаимодействие проспидина с гелеобразующими фосфатами декстрана и крахмала. Изучены сорбционные равновесия этого цитостатика и биодеградируемых гидрогелей фосфатов полисахаридов. Рассчитаны концентрационные коэффициенты равновесия ионного обмена и коэффициенты распределения проспидина при разной степени заполнения фазы микрогелей цитостатиком, показана их связь со степенью набухания гидрогелей. Определены величины ионнообменной и необменной составляющих сорбции. Анализ коэффициентов распределения свидетельствует о том, что концентрация необменно сорбированного проспидина превышает его концентрацию во внешнем растворе, что объясняется наличием ван-дер-ваальсовых взаимодействий между катионами проспидина и макромолекулами фосфатов полисахаридов. Оптимальным носителем проспидина является Na-форма фосфатов полисахаридов, которая характеризуется более высокой плотностью отрицательного суммарного заряда по сравнению с их Н-формой.

The intermolecular interaction of prospidinum with gel-forming dextran and starch phosphates has been studied. The sorption equilibria have been studied for cytostatic and the biodegradable hydrogels of polysaccharide phosphates. The concentration coefficients of ion exchange equilibrium and distribution coefficients of prospidinum have been calculated at different degrees of microgel phase filling with the cytostatic, and the relations between the coefficients and the degree of hydrogel swelling have been determined. The ion-exchange and nonexchange contributions to sorption values have been found. The analysis of the distribution coefficients has demonstrated that the concentration of prospidinum sorbed through the nonexchange mechanism is higher than its concentration in an external solution due to the van der Waals interactions between prospidinum cations and macromolecules of polysaccharide phosphates. The Na form of polysaccharide phosphates is the optimal carrier for prospidinum, because this form has a higher density of the total negative charge than their H form has.

A new, long-acting form of prospidine was formulated by immobilization of the cytostatic agent on biodegradable dextran phosphate. Results from in vitro and in vivo studies of the antitumor activity of the long-acting prospidine formulation are presented. In vitro experiments established that the rate of release of prospidine from the hydrogel slowed with increases in the polymer:carrier mass ratio. Experiments using a Zaidel's hepatoma model showed an increase in the antitumor activity of the long-acting prospidine formulation as compared with native substance.

A new prolonged form of prospidine has been obtained by immobilization of this cytostatic agent on a biodegradable dextran phosphate. Results of in vitro and in vivo evaluation of the antitumor activity of the prolonged form of prospidine are presented. In vitro studies showed that the prospidine release from hydrogels slowed down with increasing polymer carrier/cytostatic agent mass ratio. Tests in vivo on a Seidel hepatoma model showed that the antitumor activity of the prolonged form of prospidine is increased as compared to the parent drug substance.