Kobylinska L. Biochemical mechanisms of antitumor action of 4-thiazolidinone derivatives at their delivery to cells by the nanosized polymeric carrier.

This thesis work is devoted to the study of the biochemical mechanisms for enhancing of the antitumor activity of new 4-thiazolidinone derivatives, increasing of their solubility, and reducing negative side effects in vitro and in vivo through the delivery of these derivatives into target cells by a synthetic nanoscale polyethylene glycol-containing polymeric nanocarrier. The Les-3288 derivative has a highly toxic effect towards cells of the rat glioma C6 line and the human glioma U251 line. The Les-3833 compound has high toxicity, close to that of doxorubicin, towards the human melanoma cell lines WM793 and SK-MEL-28. Сomplexes of 4-thiazolidinone derivatives with a nanosized polymeric carrier functionalized with PEG significantly reduced the overall toxic effect of these antitumor compounds in the body. It was established that the immobilization of the water-insoluble 4-thiazolidinone derivatives on this polymeric nanoscale carrier led to the formation of water-soluble complexes with improved stability that penetrate cells more rapidly, retained their biological activity for a longer time, provided accumulation in the target tissue or organ and enhanced cytotoxic action in vitro. The derivatives of 4-thiazolidinones in complexes with the polymeric nanocarrier reduced the viability of mammalian tumor cells in vitro more effectively than the derivatives in free form. It was proved that the created complexes of 4-thiazolidinone derivatives with the polymeric nanocarrier improved the targeting by these antitumor derivatives and reduced the negative side effects, in particular cardio-, hepato- and nephrotoxic effects in the body of laboratory animals. The content of metabolites of free radical oxidation, products of lipoperoxidation, activity of the antioxidant protection system enzymes, as well as the levels of metabolites of nitrosative stress and activities of enzymes of synthesis of nitric oxide synthesis by the derivatives of 4-thiazolidinones and their complexes with the polymeric nanocarrier were determined in vivo. It was proved that the cytotoxic action of 4-thiazolidinone derivatives both in free form and in the complexes with the polymeric nanocarrier is realized by the apoptotic mechanisms, as confirmed by the results of FACS analysis of the presence of pre-G1 cells in rat C6 glioma Annexin V+ cells. The implanted lymphomas were inhibited by Les-3288 and Les-3833 that led to an increased life span of the tumor-bearing mice. Enhanced effectiveness of Les-3833 in combination with the polymeric nanocarrier was demonstrated in the NK/Ly lymphoma model. This effect was accompanied by reduced negative side effects compared to those of the doxorubicin.