A New Polymer-Drug Combination Therapy for Targeting Ovarian Cancer

Executive summary – Nov 2011 Polymer drug conjugates have been considered as promising carriers for the treatment of cancer. Their use facilitates the uptake and transport of therapeutic agents into target tissues and creates a dose-differentiation between the treatment target and the rest of the body due to the fact that macromolecules can accumulate passively in solid tumor tissue by the phenomenon called “enhanced permeability and retention (EPR) effect”. To achieve a high local concentration of polymer-drug conjugate in tumor tissues a targeting moiety can be further incorporated into the polymeric backbone to actively guide the therapeutic agents to antigens or receptors uniquely expressed or over-expressed on the target cells relative to normal tissues. This project aims at the design and preparation of polymer drug conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, carrying either the Fab OV-TL 16 antibody fragment or low molecular weight (MW) oligomers of hyaluronic acid (HA) as the targeting ligand for OA-3 surface antigen and CD44 receptor, respectively, to improve the selectively of chemotherapy for ovarian tumors. A monoclonal antibody (mAb) to P-glycoprotein (Pgp), UIC2, was further utilized as a targeting moiety for HPMA-drug conjugates. The above targeting ligands were exploited to navigate the delivery of two anticancer agents: Paclitaxel (PTX) and Doxorubicin (DOX) to ovarian cancer cells. The binding specificity and the cytotoxicity of the targeted polymer-drug conjugates towards the CD44 and Pgp over-expressing human ovarian carcinoma cells was investigated. Polymer conjugates bearing HA fragments at the size of 10 oligosaccharides and above (HA10-14) bind actively and profoundly to CD44-overexpressing ovarian cancer cells (SK-OV-3) and internalize to the greatest extent relative to HA-polymer conjugates of 8 oligomers and below (HA4-8). HPMA-(HA)34-PTX copolymer conjugate exhibited 50-times higher cytotoxicity towards CD44-overexpressing cells relative to the control, non-targeted, HPMA-PTX copolymer. UIC2 targeted HPMA copolymer-drug conjugates showed a higher IC50 dose than non-targeted HPMA copolymer-drug conjugates for the A2780 cell line, demonstrating specificity. The decreased cytotoxicity of UIC2 targeted HPMA copolymer-drug conjugates for A2780 cells and generally increased cytotoxicity in A2780/AD cells supports antigen specific enhancement of cytotoxicity. Altogether, PTX and DOX can be selectively delivered into ovarian cancer cells over-expressing the CD44 and Pgp.