Boron Neutron Capture Therapy (BNCT) using theboron-hthium m(hoisotope reaction offers promise as a method forselective internal irradiation of tumors. Substituted amino acids,nucleosides, and antibodies have been developed to WW tumors- Especially promising data have recently been generated withboronated porphyrins and caged dodecaborane sulfhydryl compounds asBNCR agents. Because effective BNCR may ultimately require"cocktails" of 'OB carriers for best therapeutic responses,continued development of 'OB carriers is needed. In Phase I thedevelopment of borortated nitroimidazoles as BNCT agents is p This class of agent is known to effectively te solid tumorsat mdhnkolar levels necessary for BN'-T, and to undergo reductivemetabolism to DNA- and protein-bound forms. Phase I consists of 5tasks: (1) synthesis of a n-*onoboronated nietronidazole min-dcwith natural abundance boron; (2) synthesis of the nwnoboronatedagent with 'OB; (3) synthesis of a ll"odecaboronated metronidazolederivative; (4) testing of compounds in tasks (2) and (3) foractivity in a V-79 cell-based in-vitro BNCR protocol, whichincludes evaluation of cell uptake; and (5) preliminary evaluationof the uptake and distribution of compounds in tasks (1) and (3) byC57Bl /6 n-dce bearing the Colon 38 tumor model. These tasks aredesigned to evaluate the feasibility of boronated nitroimidazolesas potential BNCT agents based on the assays in tasks (4) and (5),these tasks also will give an indication of the effects of a lowerlimit (mono) and an upper @t (dodeca) of Coronation on the behaviorof this class of agent.Anticipated Results/Potential Commercial Applications as described by the awardee:Successful completion of Phase I will establishthe feasibility of developing nitroimidazoles as agents for BNCT,based on an in-vitro BNCT protocol and based on evaluation ofpenetration of "B into a tumor in an in-vivo model. If successful,this research will lead to development of c@taining drugs that willbe important therapeutic tools in the management of cancer. Drugsdeveloped under this program will have worldwide commercial valueand will make a significant impact on cancer therapy.
