The long-term goal of this program is the development of tumor seeking boron compounds for use as radiochemotherapeutic agents for boron capture therapy (BNCT) of cancer. BNCT relies on the selective tumor uptake and retention of a non-toxic boron-containing drug followed by irradiation of the rumor region with a beam of very low energy neutrons. Capture of a neutron by a (10)B nucleus causes a prompt fission reaction in which the boron nucleus splits to form an alpha particle, a lithium nucleus and a gamma ray. These fission products deposit most of their substantial energies within one cell diameter and are considered high linear energy (LET) fragments. Binary therapies such as BNCT have the potential to increase local control of cancer by increasing the radiation dose to cancer cells and simultaneously reducing radiation-induced morbidity to surrounding normal tissue and vasculature. The objective of this proposal is to provide over its five year length one or more boronated porphyrins suitable for clinical BNCT application. This highly translational objective is to be accomplished through an integrated program of directed synthesis and a tier protocol of biological and radiobiological pre-clinical testing. In order to meet this goal, three specific aims, relating to structure-activity/toxicity relationships in these compounds are to be addressed. The Principal Investigator and his team will 1) examine several linkage chemistries for attaching closo carboranes in order to reduce toxicity; 2) attach closo polyhedral borane anions to optimize sensitizer pharmacokinetics; and 3) evaluate methods of attaching more than 40 boron atoms per molecule to maximize tumor boron concentration. Synthetic efforts during the first 2-3 years will focus on the synthesis and characterization of boronated porphyrins from each of five basic structural motifs. Initial biological testing of potential candidates in normal rats will establish maximum tolerated dose and histological profiles and will be followed by biodistribution in athymic nude rats bearing an intracerebral glioma. Successful candidates will be further studied in vitro and in BNCT protocols using an accelerator-produced epithermal beam at the Lawrence Berkeley National Laboratory. The proposed syntheses during the last two years will concentrate on compounds having the most promising structural motif.
