Polymeric conjugates for deliveryof cytostatic drugs and ABC transporter inhibitors in multi drug resistant tumors.

Significant problem and important cause of failure of the cancer chemotherapy is that even originally very sensitive tumors become resistant to effects of cytostatic drugs. Loss of sensitivity to specific chemotherapeutics agent may not directly cause the loss of sensitivity to other chemotherapeutics. However, it have been described that tumors resistant to one type of chemotherapeutics were found to be resistant to several other anticancer drugs that are different in both structure and mode of action. This phenomenon has been described as multidrug resistance (MDR). MDR can develop in several ways, with the predominant mechanism being the overexpression of ATP- binding cassette (ABC) transporters, such as P-glycoprotein. These transporters acts as energy driven pumps and which, maintain intracellular drug concentration below toxic levels. The aim of this study was to examine the potential of novel polymeric therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing either anticancer drug, inhibitor of ABC transporters or both, for overcoming MDR mediated by P-glycoprotein in doxorubicin (Dox) resistant murine monocytic leukemia cell line P388/MDR. Series of low-molecular weight inhibitors reversin 121 (R121), reversin 205 (R205) and ritonavir (RIT) and their derivatives..