Preparations based on silybin are used as hepatoprotectors in the treatment of liver lesions of various etiologies. The main disadvantage limiting their use is low bioavailability associated with the low solubility of silybin in water. To solve this problem, numerous delivery systems are created that increase its solubility, including those based on biodegradable polymers. This study presents a method for producing a polymer composition containing silybin (PCS) based on copolymers of lactic and glycolic acids. The content of the active ingredient in the product is 5%, its entrapment efficiency in particles is more than 90%; the Z -average particle size in an aqueous suspension is about 200 nm, the polydispersity index is less than 0.2, and the zeta potential is from ‒1 to ‒5 mV. The high antioxidant activity of silybin in the polymer composition by galvanostatic coulometry, as well as in the reaction of the nonenzymatic autoxidation of adrenaline, is shown. In an in vivo study on a model of acute toxic hepatitis induced by carbon tetrachloride, the more pronounced hepatoprotective effect of PCS is found compared with free silybin.

Modern preparations of milk thistle have been used since 1960−1970s. By their chemical nature, the active substances of milk thistle are flavonoids (flavonolignans). The preparations used are both the milk thistle flavonolignan complex (silymarin) and the most active individual substance (silybin). Preparations based on silymarin and silybin are in demand in clinical practice as hepatoprotectors; however, their serious drawbacks are low water solubility and bioavailability, which significantly reduces their therapeutic potential. In this regard, nano- and microforms of silymarin/silybin are being actively developed. The review provides information on the sources of obtaining, chemical structure, and biological activity of silymarin and silybin. The main known nano- and microforms of silymarin and silybin are considered, and the methods for their obtaining are described. These forms are obtained using one or a combination of several technological methods: dispersion, dissolution in suitable solvents, formation of inclusion complexes and solid dispersions, chemical modification, etc. The developed forms of silymarin/silybin are nanocrystals, solid dispersions, solid lipid systems, inclusion complexes, dendrisomes, liposomes, nano- and microemulsions, polymer particles, and nanocomposites. Each of these forms has a number of advantages, which, in general, include an increase in the solubility and bioavailability of silybin, prolonged/controlled release from nano- and microstructures, and an increase in stability. The development of nano- and microforms of silymarin and silybin made it possible to obtain compositions with improved physicochemical characteristics and biopharmaceutical properties, as well as a higher specific activity (including hepatoprotective, antitumor, antiviral, and antimicrobial activity), which gives grounds for expanding the therapeutic range of ​​application of drugs of this group.

A polymer-containing anastrozole formulation (PAF) in the form of micronized particles based on a copolymer of lactic and glycolic acids with a terminal carboxyl group (PLGA-COOH 50/50) was prepared. The pharmacokinetics and biodistribution of anastrozole in the organs of rats after single intramuscular (i.m.) doses of PAF and anastrozole substance 6.8 mg/kg (in terms of active substance) were studied. The pharmacokinetics of anastrozole were found to be linear over the range 1.7 – 6.8 mg/kg, in terms of AUC(0 – 336) (R2 = 0.99989) and Cmax (R2 = 0.99767) after i.m. administration of the PAF developed here to rats. Use of PAF was found to slow the absorption and elimination of anastrozole in the blood, liver, kidneys, bone, adrenals, fatty tissue, and muscles in rats, as evidenced by increases in the T1/2 and MRT and decreases in Cl, Kel, and Cmax/AUC(0 – 336). Tissue availability of anastrozole (fT) in the adrenals, fatty tissue, and muscles of rats after administration as PAF was 1.12, 1.44, and 1.37 times higher respectively than after administration of anastrozole substance.

The polymeric form ofjosamycin was developed by loading of the antibiotic into spherical submicron particles made of poly(DL- lactide-co-glycolide) (PLGA 50/50) by double emulsion method. The average diameter and zeta-potential of particles synthesized were less than 150 nm and -35 mV respectively. Polymeric form showed antimicrobial activity against gram-positive, gram-negative, and atypical bacteria. The highest antibacterial activity compared to substance (more than 8-fold) was detected against Enterococcus faecalis. The results of in vivo studies of specific activity of drugs on the model of staphylococcal sepsis in mice showed an increase in the efficacy of the studied polymeric form by 1.5-fold compared with the josamycin substance.

Introduction One of the perspective approaches to the development of anticancer chemotherapy drugs is the use of submicron vectorized delivery systems that increase the selectivity of action and reduce the toxic side effects of chemotherapy. A delivery system of docetaxel (DOC) loaded poly(lactide-co-glycolide) (PLGA) particles modified with folic acid dodecylamide (FAD) was developed (PLGA-DOC-FAD). The aim of the research was a comparative toxicological study of DOC-loaded particles and standard docetaxel solution form in acute and subchronic experiments in mice after intravenous administration. Materials and methods The research was conducted in female C57BL/6 mice. During the study of acute toxicity, drugs were administered in the following dose range: 20, 60, 90, 120, 160 mg/kg. Over 30 days, mortality and body weight were evaluated, pathomorphological studies were performed. The study of toxicity in conditions of subchronic administration of medicine was conducted using three times daily administration in single doses of 11 and 22 mg/kg. Subchronic toxicity of the drugs was studied with three times daily administration in single doses of 11 and 22 mg/kg. The necessary studies were performed within 30 days. Results With a single injection of PLGA-DOC-FAD in doses of 20, 60, 90 mg/kg, the death of animals wasn’t observed; at doses of 120 and 160 mg/kg, the death of animals was detected in 1–4 days. In the case of administration of the DOC substance, the death of animals occurred within a day after the administration of doses of 60, 90, 120, 160 mg/kg. The pattern of intoxication was similar in case of compared drugs and manifested in hypodynamia, impaired movement coordination, hind limbs paresis, though the manifestation degree thereof was more expressed in the groups with the introduction of DOC than in the case of the introduction of PLGA-DOC-FAD. It was detected that the LD 50 for PLGA-DOC-FAD is 140 mg/kg, and for the DOC substance – 112 mg/kg. In case of subchronic administration, the detected toxic properties of drug depend on the size of the dose applied. The administration of a single dose of 22 mg/kg of PLGA - DOC-FAD caused lethal effects (2/10), reversible delay in weight gain and leucopenia in surviving animals, and an increase in the relative mass of the spleen. The use of PLGA-DOC-FAD in a single dose of 11 mg/kg didn’t cause death, was well tolerated and characterized by similar toxicity with the docetaxel substance. Conclusion Based on experimental data, the toxic dose levels of PLGA-DOC-FAD were determined under acute and subchronic administration. The results obtained allowed us to recommend PLGA-DOC-FAD for further examination.

A polymer dosage form of etoposide (PFE) was obtained as submicron particles based on the copolymer of lactic and glycolic acids (PLGA). Pharmacokinetics and biodistributions of etoposide in rat blood and organs after a single i.p. injection of the polymeric form and etoposide drug substance at doses of 10 mg/kg (of active ingredient) were compared and showed that absorption and elimination of etoposide from rat organs slowed if the PFE was used. The increases of T1/2 and MRT and decreases of Kel, Cmax/AUC(0 – 48), and Cl were indicative of this. Liver and lungs had the greatest tissue availability (ft) for the PFE. Etoposide accumulation in tumor tissue was studied after a single i.p. injection of PFE and etoposide drug substance at doses of 25 mg/kg to mice with grafted Ca755 murine breast adenocarcinoma. The etoposide distribution coefficient between blood and tumor tissue after 1 and 24 h was greater for the PFE, indicating the accumulation of etoposide in tumor tissue was greater if the PFE was used.

Silybin (Slb) and ursodeoxycholic acid (UDCA) are hepatoprotectors used in the pathogenetic therapy of liver and biliary tract. However, low bioavailability of these drugs restricts their application. In order to solve this problem, Slb and UDCA were incorporated into polymer carriers based on polylactic acid and poly(lactic-co-glycolic acid) by nanoprecipitation. The polymeric forms obtained according to the developed and optimized method are nanoparticles with a size from 100 to 200 μm. In vitro experiments showed a 1.5–2-fold higher hepatoprotective activity of Slb- and UDCA-containing polymeric nanoparticles compared to free substances.

Method for the synthesis of polymeric nanoparticles (NP) with encapsulated daunorubicin (DNR) was developed on the basis of double emulsion solvent evaporation technique using biodegradable poly(lactide-co-glycolide) (PLGA), which is aimed at customization of pharmacokinetic properties of the preparation, enhanced accumulation of DNR in tumor cells and prolongation of its action. The obtained polymer nanoparticles (DNR-PLGA) had average size ranging around 138±36 nm, with zeta-potential of –25.3 mV and the polydispersity index (PDI) of 0.072. The release kinetics of DNR from polymer nanoparticles at pH 7.4 and 5.0 has been studied. In vitro studies showed similar specific activity of DNR- PLGA in K562 and MCF-7 cancer cell lines together with an increase in activity in K562 Adr and MCF-7 Adr cell lines, which are anthracycline resistant, by 1.6 and 3.4 times. The study demonstrated the efficacy of the developed PLGA-based DNR delivery system in the improvement of antitumor effect of DNR, overcoming multidrug resistance in cancer cells, and also in the decrease in nonspecific toxicity of the preparation.

A new pharmaceutical form of the antitumor drug docetaxel (Dtx) has been developed based on a biodegradable copolymer of lactic and glycolic acids (PLGA 50/50). This form was constituted of polymeric particles (250 to 300 nm in size) and was highly active against mouse mammary adenocarcinoma (Ca755) and human breast adenocarcinoma (MCF-7 Wt ) cell lines. The results of the in vivo studies carried out on the C 57 Bl/6 female mice line showed an increase in the life span of the animals treated with the polymeric particles. Furthermore, the polymeric drug at a dose of 10 mg/kg and the drug substance at a dose of 20 mg/kg manifested a similar effect. At the same time, the acute toxicity of the Dtx polymeric form was 2.3 times lower than that of the drug substance.

The present work relates to the field of pharmacology and medicine, in particular, to a new generation of anticancer drugs based on biocompatible polymers containing etoposide as the drug substance. A polymeric composition containing a surfactant and cryoprotective agent in addition to polymer and drug substance was designed. The optimum formulation of the polymeric composition and process conditions for its preparation were selected. The samples of etoposide polymeric forms were found to exhibit in vitro cytotoxic activity against two human tumor cell lines, viz., MCF-7 breast adenocarcinoma and K562 myeloleukemia cell lines, which was either identical or higher than the activity of free etoposide. The samples of the PLGA-based polymeric form of etoposide exhibited the highest activity.

Biodegradable polymeric nanoparticles conjugated with targeting vector molecules have become prospective agents to improve the effectiveness of chemotherapeutic cancer treatment. This approach reduces the systemic toxicity of the drugs and increases the specificity of their uptake by cancer cells. A method has been developed to obtain complex nanoparticles loaded with the antitumor drug paclitaxel and a C-terminal fragment of recombinant oncofetal alpha-fetoprotein serving as a vector molecule, the in vitro cytotoxic activity of complex nanoparticles for MCF-7 human breast adenocarcinoma cells and resistant MDR1 + cells of the MCF-7 Adr subline was shown to be higher than the cytotoxicity of the free drug and drug-loaded nanoparticles without the vector molecule. Moreover, the toxicity of complex paclitaxel-loaded nanoparticles against lymphocytes was low, which confirmed the selectivity of nanoparticle action. In summary, these results demonstrate that the strategy of active targeting of nanoparticles can efficiently enhance the antitumor activity of paclitaxel and it can solve the problem of reversing the multidrug resistance (MDR) of tumor cells.

A new chimeric gene ApE1 encoding the receptor-binding domain of the human alpha-fetoprotein fused to a sequence of 22 glutamic acid residues was constructed. A new bacterial producer strain E. coli SHExT7 ApE1 was selected for ApE1 production in a soluble state. A simplified method was developed to purify ApE1 from bacterial biomass. It was shown that the new vector protein selectively interacts with AFP receptors on the tumor cell surface and can be efficiently accumulated in tumor cells. In addition, ApE1 was shown to be stable in storage and during its chemical modification. An increased number of carboxyl groups in the molecule allows the production of cytotoxic compound conjugates with higher drug-loading capacity and enhanced tumor targeting potential.