The controlled delivery of anticancer drugs is driven by their interaction with carrier molecules. By creating complicated micelle-like complexes, amphiphilic polymers provide an opportunity to load drugs of various kinds. In this work, the interaction of the comb-like PEG-containing polymer poly(VEP-co-GMA)-graft-PEG with the water-soluble antitumor antibiotic doxorubicin and new water-insoluble derivatives of thiozalidinone Les-3883 characterized by a high anticancer efficiency has been studied in aqueous solutions by means of the SAXS, DLS, TEM, and photoluminescence methods. The formation of polymer micelles and their complexes with drugs, as well as their structural changes, is observed. The obtained results give evidence that the mechanism of organization of supramolecular complexes depends on the drug solubility in water. A potential capability of poly(VEP-co-GMA)-graft-PEG to prolong the drug circulation lifetime is confirmed.

The main problems of contemporary chemotherapy are the insufficient efficacy of antitumor drugs and low selectivity of their action, development of multidr

The maleimide derivative 1-(4-chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione (MI-1) was synthesized as inhibitor of several protein kinases, however, its application is hindered by its poor water solubility. In this study, the mechanisms of the antineoplastic action of MI-1 and its MI-1/M5 complex with M5 carrier (poly (PEGMA-co-DMM)) towards human colon carcinoma HCT116 cells were investigated by using the MTT and clonogenic assays, DNA intercalation with methyl green replacement, alkaline DNA comet assay, and Western-blot analysis. MI-1 compound and its MI-1/M5 complex possessed high toxicity towards colon (HCT116), cervical (HeLa) carcinoma cells and melanoma (SK-MEL-28) cells with GI₅₀ value in a range of 0.75–7.22 µg/mL, and demonstrated high selectivity index (SI ˃ 6.9). The p53 status of colon cancer cells did not affect the sensitivity of these cells to the treatment with MI-1 and its MI-1/M5 complex. M5 polymer possessed low toxicity towards studied cells. The MI-1, MI-1/M5, and M5 only slightly inhibited growth of the pseudo-normal HaCaT and Balb/c 3T3 cell lines (GI₅₀ ˃ 50 μg/mL). The MI-1 and its MI-1/M5 complex induced mitochondria-dependent pathway of apoptosis, damage of the DNA, and morphological changes in HCT116 cells, and affected the G2/M transition checkpoint. The MI-1 intercalated into the DNA molecule, while such capability of MI-1/M5 complex and M5 polymer was much lower. Thus, poly (PEGMA-co-DMM) might be a promising carrier for delivery of the maleimide derivative, MI-1, a novel kinase inhibitor, through improving its solubility in aqueous media and enhancing its antiproliferative action towards human tumor cells. Studies are in progress on the treatment of Nemeth-Kellner lymphoma (NK/Ly)-bearing mice with the MI-1 and MI-1/M5 complex.

This study reports a dose-dependent pro-apoptotic action of synthetic cannabimimetic N-stearoylethanolamine (NSE) on diverse cancer cell lines, including multidrug-resistant models. No antioxidant or cytoprotective effects of NSE were found when it was applied together with doxorubicin. A complex of NSE with the polymeric carrier poly(5-(tert-butylperoxy)-5-methyl-1-hexen-3-yn-co-glycidyl methacrylate)-graft-PEG was synthesized. Co-immobilization of NSE and doxorubicin on this carrier led to a 2-10-fold enhancement of the anticancer activity, particularly, against drug-resistant cells overexpressing ABCC1 and ABCB1. This effect might be caused by accelerated nuclear accumulation of doxorubicin in cancer cells, which led to the activation of the caspase cascade, revealed by Western blot analysis. The NSE-containing polymeric carrier was also able to significantly enhance the therapeutic activity of doxorubicin in mice with implanted NK/Ly lymphoma or L1210 leukemia, leading to the complete eradication of these malignancies. Simultaneously, loading to the carrier prevented doxorubicin-induced elevation of AST and ALT as well as leukopenia in healthy Balb/c mice. Thus, a unique bi-functionality of the novel pharmaceutical formulation of NSE was revealed. It enhanced doxorubicin-induced apoptosis in cancer cells in vitro and promoted its anticancer activity against lymphoma and leukemia models in vivo. Simultaneously, it was very well tolerated preventing frequently observed doxorubicin-associated adverse effects.