This Phase I proposal details the rationale and the research plan for the synthesis and characterization of a polymeric delivery system that will deliver two anticancer drugs with diverse mechanisms of action simultaneously into ovarian cancer cells. The delivery system will be composed of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer as the backbone. It is a well characterized, water-soluble, biocompatible, non-immunogenic and non-toxic synthetic polymeric drug carrier. Attached to the backbone will be a geldanamycin analog which has a well known dual mode of action (antiangiogenic and antitumor) and docetaxel, an FDA approved antineoplastic agent which acts by stabilizing microtubules. The drugs will be attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity; and (3) a cyclic tripeptide containing ligand that will target the HPMA conjugates to tumor-associated receptors. The novelty of this approach is that the geldanamycin analog and docetaxel, with their different mechanisms of action, will be attached to the same polymer backbone containing a targeting moiety, thereby ensuring the delivery of both the drugs simultaneously to the cancer cells. The aims are three fold: (1) synthesize and physiochemically characterize HPMA copolymers with the geldanamycin analog, docetaxel and the targeting tripeptide in the side chains; (2) characterize the stability and release profile of the HPMA conjugates; and (3) characterize the binding and cytotoxicity of the HPMA conjugates by biological methods in ovarian cancer cell lines. The ultimate goal of this project is the development of an effective and marketable drug combination with novel drug delivery systems for the treatment of ovarian cancer where the drugs are localized at the site of the tumor, adverse effects of chemotherapy are minimized and efficacy maximized.
Public Health Relevance: This Phase I proposal details the rationale and the research plan for the synthesis and characterization of a polymeric delivery system that will deliver two anticancer drugs with diverse mechanisms of action simultaneously into ovarian cancer cells. This combination therapy will minimize the adverse effects of chemotherapy and maximize efficacy, thereby improving significantly the five year survival rate for ovarian cancer patients.
Thesaurus Terms: Acute; Adverse Effects; Aminoacetic Acid; Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenesis Inhibitors; Angiogenetic Antagonists; Angiogenic Antagonists; Angiostatic Agents; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antiangiogenesis Agents; Antiangiogenic Agents; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Arginine; Arginine, L-Isomer; Aspartate; Binding; Binding (Molecular Function); Biocompatible; Biological; Blood; Blood Serum; Buffers; Calibration; Cancer Drug; Cancer Patient; Cancer Cell Line; Cancer Of The Ovary; Chemotherapeutic Agents, Neoplastic Disease; Chronic; Combined Modality Therapy; Conduct Clinical Trials; Development; Dose; Drug Carriers; Drug Combinations; Drug Delivery; Drug Delivery Systems; Drug Evaluation; Drug Targeting; Drug Targetings; Drugs; Ensure; Enzymes; Evaluation; Evaluation Studies, Drug; Fda Approved; Geldanamycin; Geldanamycin Analogue; Glycine; Goals; Human; Human, General; Hydrogen Oxide; In Vitro; Inhibitors, Angiogenetic; Inhibitors, Angiogenic; L-Arginine; L-Aspartate; L-Leucine; L-Phenylalanine; Leucine; Leucine, L-Isomer; Ligands; Lysosomes; Lytotoxicity; Malignant Cell; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor Of The Ovary; Malignant Neoplasm Of Ovary; Man (Taxonomy); Man, Modern; Medication; Methods; Micro-Tubule; Microtubules; Molecular Interaction; Molecular Weight; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; N-Debenzoyl-N-(Tert-Butoxycarbonyl)-10-Deacetyltaxol; Neovascularization Inhibitors; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phenylalanine; Phenylalanine, L-Isomer; Physiologic; Physiological; Polymers; Preparation; Receptor Protein; Research; Reticuloendothelial System, Blood; Sttr; Series; Serum; Side; Site; Small Business Technology Transfer Research; Spinal Column; Spine; Survival Rate; System; System, Loinc Axis 4; Taxotere; Time; Toxic Effect; Toxicities; Treatment Side Effects; Tumor-Specific Treatment Agents; Vertebral Column; Water; Antiangiogenic; Anticancer Agent; Anticancer Drug; Backbone; Cancer Cell; Chemotherapy; Combination Therapy; Combined Modality Treatment; Combined Treatment; Copolymer; Cytotoxicity; Docetaxel; Docetaxol; Drug/Agent; Geldanomycin; Immunogenic; Improved; In Vivo; Methacrylamide; Multimodality Therapy; Novel; Ovarian Cancer; Phase 2 Study; Preclinical Study; Public Health Relevance; Receptor; Side Effect; Therapy Adverse Effect; Treatment Adverse Effect; Tumor
