Ovarian cancer is the leading cause of death among gynecological malignancies in the United States. Micronodular and floating tumor colonies cannot be adequately treated by surgery and require extensive chemotherapy. The success of chemotherapy depends on the suppression of anticancer drug cellular resistance and the prevention of adverse drug side effects that typically limit therapies. The LONG-TERM GOAL of the proposed research is to develop a proapoptotic targeted drug delivery system (DDS) that will significantly increase the efficacy of ovarian cancer chemotherapy. The CENTRAL HYPOTHESIS of the proposed research is that targeted proapoptotic anticancer DDSs will significantly increase the efficacy of ovarian cancer treatment by targeting the anticancer drug specifically to ovarian cancer cells with the simultaneous induction of programmed cell death and the suppression of the main antiapoptotic cellular defense mechanisms. Our preliminary experiments demonstrate that (1) luteinizing hormone-releasing hormone (LHRH) can be used as a targeting moiety to deliver an anticancer drug specifically to ovarian cancer cells; (2) synthetic BCL-2 homology 3 (BH3) domain peptide effectively suppresses antiapoptotic defense in ovarian cancer cells and (3) conjugation of BH3 and LHRH to a PEG carrier increased potency over the nonconjugated forms. These exciting preliminary results strongly indicate the feasibility of the proposed approach. The main objective of the proposed research is to develop, synthesize, characterize and evaluate a novel four component targeted proapoptotic anticancer DDS which includes a polyethylene glycol polymer as a permeable carrier; LHRH peptide as a cell surface targeting moiety; the anticancer drug camptothecin (CPT) as an inducer of cell death and synthetic BH3 peptide as a suppressor of antiapoptotic cellular defense. Therefore, the SPECIFIC AIMS of the proposed investigations are: (1) To design, synthesize and characterize novel CPT-PEGLHRH- BH3 bioconjugates with (a) """"""""biodegradable"""""""" or """"""""non-biodegradable"""""""" linkages between PEG carrier and the active components (BH3, CPT) and (b) variable numbers of drug and targeting moiety copies per conjugate. (2) To evaluate drug and component release, cellular uptake and retention, and anticancer effectiveness (i.e. cytotoxicity, apoptosis induction and signaling pathways) of novel drug delivery systems containing a drug carrier (PEG polymer), an anticancer drug (CPT), an inhibitor of antiapoptotic cellular defense (BH3 peptide) and a targeting moiety (LHRH peptide) in human sensitive and multidrug resistant cancer cells. (3) To examine the in vivo release/stability of the DDS, the pharmacokinetics, tumor and organ accumulation and distribution of CPT and the antitumor activity of selected proapoptotic targeted drug delivery systems in well-established animal models. The results of the proposed work will be used to design novel approaches for the treatment of various cancers. The proposed studies will fill important gaps in our understanding of the mechanisms of bioconjugate delivery into cancer cells enabling the development of new two-tier molecular targeting strategies to increase the efficacy of cancer chemotherapy.
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