This proposal addresses the need for the development of suitable molecules for application in a new treatment modality for intractable brain tumors; this need arises from advances in the production and availability of high quality neutron beams. We propose to synthesize and characterize new non-toxic boron containing porphyrins that selectively localize within tumors and which may be used for boron neutron capture therapy (BNCT) of cancer.
Specific aims are: 1) to synthesize novel non-toxic boronated porphyrins, 2) to study their physicochemical and biological properties, 3) to select the most promising candidates for further animal studies, and 4) to determine the mechanisms of selective tumor cell uptake and the chemical features that optimize these pharmacokinetic parameters. Porphyrin-like macrocycles have been shown to selectively localize in a variety of neoplastic tissues, and this property provides the basis for their use in photodynamic therapy (PDT). The U.S. FDA has approved two PDT sensitizers that are porphyrin derivatives: Photofrin and Visudyne. To date, Photofrin has successfully been used to treat thousands of cancer patients worldwide, and is currently being investigated in a Phase II brain tumor trial. BNCT is an emerging therapeutic modality based on a nuclear reaction, which occurs when boron-10 nuclei localized within tumors capture low-energy neutrons to produce high linear energy transfer particles whose cytotoxic effects are confined to the cells in which the drug is retained. Phase 1/11BNCT clinical trials are being pursued in the U.S., Europe, and Japan, for the treatment of patients with glioblastomas and melanomas. We propose to further test the hypothesis that boron-containing porphyrins will retain the low toxicity and tumor localizing properties of porphyrins, and therefore can efficaciously deliver high concentrations of boron-10 to tumor cells. Previous limited tests of this hypothesis were reported in the literature, but only a few poor characterized agents were examined. Our preliminary results however establish that numerous boronated porphyrins are non-toxic tumor localizing agents. We are confident that continued biological studies of our first generation compounds, coupled to new analogues we propose to develop, would provide a platform for further development of even more efficacious drugs. The effectiveness of the new boronated porphyrins for BNCT will be evaluated at the 2 MW TRIGA nuclear reactor at the University of California, Davis McClellan Nuclear Radiation Center.
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