Targeted cancer therapies that selectively destroy malignant cells in the presence of surrounding normal cells are among the most coveted goals of medicinal chemists and oncologists. Boron neutron capture therapy (BNCT) is a form of targeted radiochemotherapy that has the potential to increase local control of cancer by increasing the radiation dose to cancer cells while simultaneously reducing radiation-induced morbidity to surrounding normal tissue and vasculature. This program focuses on the synthesis and testing of boronated porphyrins as potential BNCT agents, making use of the fact that porphyrins are known to localize in solid tumors. The long term goal of the program is to generate sufficient information on one or more candidate compounds to provide a sound basis for a subsequent BNCT clinical trial. This translational objective is to be accomplished by an integrated program of directed synthesis and a tier protocol of in vitro and in vivo biological testing. To achieve our goal of providing at least one suitable clinical candidate for BNCT during the next grant cycle, we propose four specific aims that build on our exisiting work from the current budget period. First, we will synthesize and test boronated porphyrins bearing up to several hundred boron atoms, which willtell us how much boron can be added to a porphyrin without destroying its tumor localizing ability. Second, we will prepare and test new carboranyl meso-porphyrins with carborane cages attached through physiologically stable and non-toxic carbon-carbon bonds. Third, we will investigate the use of peptide nuclear localization sequences to selectively target boronated compounds to the nucleus of cancer cells, the most highly radiation sensitive cellular target. Fourth, we will establish and define the parameters for successful application of convection enhanced delivery (CED) of boronated porphyrins to brain tumors. CED studies to date have provided up to 520 ppm boron in rat brain tumors, a figure ~15 times the generally accepted minimum for successful BNCT therapy. Initial biological testing of potential candidates in normal rats will establish maximum tolerated dose, toxicology and histopathology, and will be followed by biodistribution in athymic rats bearing an intracerebral human glioma, either through systemic or CED compound administration. Successful candidates will be further studied in vitro and in BNCT protocols. A successful outcome could have a major health impact, especially for patients with malignant brain tumors. ? ?
