Immunopharmacological Properties of Methacrylic Acid Polymers as Potential Polymeric Carrier Constituents of Anticancer Drugs

Abstract

Cytostatic chemotherapeutics provide a classical means to treat cancer, but conventional treatments have not increased in efficacy in the past years, warranting a search for new approaches to therapy. The aim of the study was, therefore, to obtain methacrylic acid (MAA) (co)polymers and to study their immunopharmacological properties. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid (CDSPA) and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT) were used as reversible chain transfer agents. Experiments were carried out in Wistar rats. The MTT assay was used to evaluate the cytotoxic effect of the polymeric systems on peritoneal macrophages. An experimental tumor model was obtained by grafting RMK-1 breast cancer cells. Serum cytokine levels of tumor-bearing rats were analyzed. The chain transfer agents employed in classical radical polymerization substantially reduced the molecular weight of the resulting polymers, but a narrow molecular weight distribution was achieved only with CDSPA and high CPDT concentrations. Toxicity was not observed when incubating peritoneal macrophages with polymeric systems. In tumor-bearing rats, the IL-10 concentration was 1.7 times higher and the IL-17 concentration was less than half that of intact rats. Polymeric systems decreased the IL-10 concentration and normalized the IL-17 concentration in tumor-bearing rats. The maximum effect was observed for a MAA homopolymer with a high molecular weight. The anion-active polymers proposed as carrier constituents are promising for further studies and designs of carrier constituents of drug derivatives.

Keywords: (co)polymers of methacrylic acid; cytokines; immune system; interleukins; molecular weight characteristics of (co)polymers.

Figure 1

Metabolic activity measured in the MTT assay for peritoneal macrophages incubated with the polymers for 4 h. Data presented are the mean ± SD of eight independent experiments each performed in triplicate. System 1, polyMAA (M_n∙10³ = 16.0 Da, M_w/M_n = 1.47); system 2, polyMAA (M_n∙10³ = 99.2 Da, M_w/M_n = 1.57); system 3, polyMAA (M_n∙10³ = 19.0 Da, M_w/M_n = 1.45); system 4, TBMA–MAA copolymer (M_n∙10³ = 21.5 Da, M_w/M_n = 1.33); system 5, TBMA–MAA copolymer (M_n∙10³ = 13.8 Da, M_w/M_n = 1.13).

Figure 2

Changes in IL-10 concentration in response to administration of the polymeric systems. Rats were administered i.p. with 9 mg/kg polymeric system (System 2 or System 5) once on the 10th day, which corresponded to the beginning of oncogenesis and formation of tumor nodes, and the activation of the immune system. Control rats received PBS. Results are representative of four independent assays and show the Median (Me) with interquartile range (25th percentile; 75th percentile) of triplicate determinations for one of four experiments. Differences from (*) intact rats were significant at p < 0.05.

Figure 3

Changes in IL-17 concentration in response to administration of the polymeric systems. Rats were administered i.p. with 9 mg/kg polymeric system (System 2 or System 5) once on the 10th day, which corresponded to the beginning of oncogenesis and formation of tumor nodes, and the activation of the immune system. Control rats received PBS. Results are representative of four independent assays and show the Median (Me) with interquartile range (25th percentile; 75th percentile) of triplicate determinations for one of four experiments. Differences from (*) intact rats or (**) control tumor-bearing rats were significant at p < 0.05.

Figure 4

Roles that IL-10 and IL-17 play in the tumor process. MDSCs: myeloid-derived suppressor cells. Treg (regulatory T cells: T-regulatory cells, T suppressors) are central regulators of the immune response.