Ovarian cancer is the leading cause of death from gynecological malignancies in the United States. The NIH panel on ovarian cancer concluded that """"""""innovative approaches for the treatment of advanced primary as well as recurrent cancer must be identified and studied."""""""" Clinical data indicate that the therapeutic use of water-soluble polymer-anticancer drug conjugates appears to be a novel and successful strategy for cancer treatment. The data obtained by the research team to date clearly demonstrated the advantages of macromolecular therapeutics when compared to low molecular weight drugs: increased efficacy, increased maximum tolerated dose, decreased non-specific toxicity, targetability, activity toward mutlidrug resistant cells, increased solubility, enhanced accumulation in solid tumors, enhanced apoptosis induction, and activation of different signaling pathways. Targeted and nontargeted combination chemotherapy and photodynamic therapy (PDT) using macromolecular therapies showed tumor cures that could not be obtained with either chemotherapy of PDT alone. The main aim of the proposed research is to design new, effective macromolecular therapeutics for the treatment of cancer. Water soluble polymeric carriers, based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers will be used. Geldanamycin (GA), 2,5-bis(6-hydroxymethyl-2-thienyl)furan (SOS thiphene), and mesochlorin e6 (Mce6) will be used as anticancer drugs. Novel synthetic pathways will be designed to permit the synthesis of long-circulating conjugates and of targeted conjugates containing antibody fragments and bispecific antibody fragment constructs. Both approaches will further enhance the preferential tumor accumulation of macromolecular therapeutics. The relationship between the detailed structure of the conjugates, namely content of drug, molecular weight distribution, content and specificity of targeting moieties, and the mechanism of action will be evaluated in vitro and in vivo. Based on the detailed analysis of alterations in gene expression profiles, new molecular targets specific to macromolecular therapeutics will be identified. Second-generation conjugates will be designed to match the identified targets, evaluated and optimized. A lead compound will be selected from the second-generation conjugates and its detailed preclinical evaluation will be performed in year five.
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