Chemotherapy is an important modality in treatment of malignant diseases, however, it is seriously limited by chemoresistance of many tumors. Chemoresistance is very often caused by either intrinsic or acquired multidrug resistance mediated by overexpression of some ABC transporter and P-glycoprotein being the most frequent one. Tumor chemoresistance can be also mediated by constitutive activation of some crucial signaling pathway involved in cell proliferation and survival like that based on STAT3. Here we suggest to employ drug delivery system based on HPMA copolymer conjugates bearing covalently bound cytostatic drug, inhibitor of P-glycoprotein and STAT3 inhibitor. Such conjugates should be capable to overcome chemoresistance of cancer cells by simultaneous delivery of cytostatic drug and inhibitors of molecular targets responsible for insensitivity to these drugs. Moreover, high-molecular-weight polymeric conjugates possess long elimination half-life and passively accumulate within solid tumors via EPR effect thus further improving therapeutic activity of bound drugs in vivo. We plan to design, synthesize and test in vitro and in vivo biological activity of HPMA copolymer conjugates bearing a combination of cytostatic drug, P-glycoprotein inhibitor and STAT3 inhibitor in order to overcome chemorefractory nature of tumors with intrinsic and acquired multidrug resistance.
