Ovarian cancer is the leading cause of death from gynecological malignancies in the United States despite the fact that it rarely disseminates from the peritoneal cavity. While the primary and larger tumor nodules may be removed surgically, micronodular disease and floating tumor colonies remain. pharmacological modelling studies have suggested a major pharmacokinetic advantage of intraperitoneally (ip) administered drugs to an ip tumor. Binding of anticancer drugs to water soluble polymeric carriers results in the decrease of their peritoneal permeability and sustained exposure of tumor cells to high concentrations of cytotoxic agents with lower nonspecific toxicity. In addition, due to the different (compared to low molecular weight drugs) mechanism of cellular uptake, polymer bound drugs have the potential to overcome the P-glycoprotein dependent multidrug resistance. The fact, that the intracellular trafficking of polymer-drug conjugates occurs in membrane limited organelles should render the P- glycoprotein efflux pump ineffective. A new HPMA copolymer based drug delivery system for the combination chemotherapy and photodynamic therapy of ovarian cancer is proposed. This delivery system will be targeted with the monoclonal OV-TL16 antibody (Ab) (or its Fab' fragment) that recognizes a common antigen (Ag) both on a human ovarian cancer model (OVCAR-3) and on human ovarian tumors of different types. Our-preliminary studies demonstrated that: 1) Novel synthetic routes are available to synthesize tailor- made HPMA copolymer - anticancer drug - OV-TL16 Ab (or Fab' fragment) conjugates; 2) The Ab (fragment) containing conjugates are biorecognizable by an Ag present on OVCAR-3 cells. This nonshedding Ag is present on the majority of human ovarian cancer cells; 3) It appears that HPMA copolymer - drug conjugates can avoid the ATP driven P-glycoprotein efflux pump on multidrug resistant human ovarian cancer cells (A2780/AD); 4) Combination chemotherapy and photodynamic therapy with nontargeted HPMA copolymer bound anticancer drugs on two tumor models (human ovarian carcinoma xenografts, Neuro 2A neuroblastoma) showed cures which could not be achieved by either chemotherapy or photodynamic therapy alone; 5) Phase I clinical trials (27 patients to date) with the HPMA copolymer - ADR conjugate demonstrated the low nonspecific toxicity of polymer drug conjugates. A detailed correlation of physicochemical and biological properties of targeted HPMA copolymer conjugates as well as the study of their antitumor activity on human ovarian cancer models, including multidrug resistant ones is planned. The results will provide a new therapeutic method for the treatment of ovarian cancer.
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