SOLUBILIZATION AND SUSTAINED DELIVERY OF ANTITUMOR AGENTS

THE OVERALL OBJECTIVE IS TO PROVIDE A NEW DRUG DELIVERY SYSTEM AND TO ENHANCE THE SOLUBILITY OF EXISTING COMPOUNDS THAT EXHIBIT EXCELLENT ANTITUMOR PROPERTIES BUT ARE INSOLUBLE IN WATER. AQUEOUS SOLUBILITY IS ESSENTIAL FOR I.V. ADMINISTRATION OF ANTITUMOR DRUGS. PHASE I RESEARCH WILL SOLUBILIZE DIAMMINEPLATINUMHYDROXYMALONATE AND (TRANS-1,2-DIAMINOCYCLOHEXANE) PLATINUMHYDROXYMALONATE COMPLEXES BY CONJUGATING THEM TO THE HYDROPHILIC AND BIODEGRADABLE POLYMERIC LIGAND, CARBOXYDEXTRAN, AND TO THE MONOMERIC GLUCOPYRANOSE LIGAND. THESE COMPLEXES ARE SPARINGLY SOLUBLE BUT STABLE IN AQUEOUS SOLUTION, AND THEY EXHIBIT DIFFERENT SPECTRA OF ANTITUMOR ACTIVITY THAN CISPLATIN. CONJUGATION OF THESE COMPLEXES TO CARBOXYDEXTRAN MAY PROVIDE A MECHANISM FOR THE SUSTAINED DELIVERY OF ANTITUMOR AGENTS. THE MERITS OF CONJUGATING POLYMERIC OR MONOMERIC LIGANDS WILL BE ASSESSED FROM THE ANTITUMOR DATA OF THE CONJUGATES. INITIAL SCREENING OF THE NEW CONJUGATES WILL BE DONE AGAINST L1210. THE TUMOR WILL BE INJECTED I.P., AND THE TREATMENT WILL BE I.V. SELECTED CANDIDATES WILL ALSO BE SCREENED AGAINST A PANEL OF SOLID TUMORS. PRELIMINARY NEPHROTOXICITY AND HEPATOTOXICITY STUDIES WILL ALSO BE UNDERTAKEN. THE SUCCESS OF THIS PROGRAM WILL PROVIDE EXPANDED USE OF PLATINUM COMPLEXES IN CANCER CHEMOTHERAPY, AND THIS APPROACH WILL BE EXTENDED TO THE SOLUBILIZATION OF OTHER INSOLUBLE ANTITUMOR PLATINUM AND ORGANIC DRUGS IN PHASE II RESEARCH.