BORONATED NITROIMIDAZOLES FOR NEUTRON CAPTURE THERAPY

BORON NEUTRON CAPTURE THERAPY (BNCT) USING THE (10)B(N, ALPHA)(7) LI REACTION OFFERS PROMISE AS A METHOD FOR SELECTIVE INTERNAL IRRADIATION OF TUMORS. (10)B-SUBSTITUTED AMINO ACIDS, NUCLEOSIDES, AND ANTIBODIES HAVE BEEN DEVELOPED TO TARGET TUMORS. RECENTLY, EXCITING DATA HAS BEEN GENERATED WITH BORONATED PORPHYRINS AND CAGED DODECABORANE SULFHYDRYL COMPOUNDS AS BNCT AGENTS. SINCE EFFECTIVE BNCT MAY ULTIMATELY REQUIRE "COCKTAILS" OF (10)B CARRIERS FOR BEST THERAPEUTIC RESPONSES, THERE IS A NEED FORCONTINUED DEVELOPMENT OF (10)B CARRIERS. IN THIS PHASE I SBIR PROJECT, WE PROPOSE THE DEVELOPMENT OF BORONATED NITROIMIDAZOLES AS BNCT AGENTS. THIS CLASS OF AGENT IS KNOWN TO EFFECTIVELY PENETRATE SOLID TUMORS AT MILLIMOLAR LEVELS NECESSARY FOR BNCT, AND TO UNDERGO REDUCTIVE METABOLISM TO DNA- AND PROTEIN-BOUND FORMS. THIS PROPOSAL IS COMPOSED OF 5 TASKS: 1) SYNTHESIS OF A MONOBORONATED METRONIDAZOLE MIMIC WITH NATURAL ABUNDANCE BORON; 2) SYNTHESIS OF THE MONOBORONATED AGENT WITH (10)B; 3) SYNTHESIS OF A (10)B-DO-DECABORONATED METRONIDAZOLE DERIVATIVE; 4) TESTING OF COMPOUNDS IN 2) AND 3) FOR ACTIVITY IN A V-79 CELL-BASED IN VITRO BNCT PROTOCOL, WHICH INCLUDES EVALUATION OF CELL UPTAKE; 5) PRELIMINARY EVALUATION OF THE UPTAKE AND DISTRIBUTION OF COMPOUNDS IN 1) AND 3) BY C57B1/6 MICE BEARING THE COLON 38 TUMOR MODEL. THESE STUDIES ARE DESIGNED TO EVALUATE THE FEASIBILITY OF BORONATED NITROIMIDAZOLES AS POTENTIAL BNCT AGENTS BASED THE ASSAYS IN 4) AND 5), AND ALSO WILL GIVE AN INDICATION OF THE EFFECTS OF A LOWER LIMIT (MONO) AND AN UPPER LIMIT (DODECA) OF BORONATION ON THE BEHAVIOR OF THIS CLASS OF AGENT.