Experimental Evaluation and Mathematical Modeling of the Pharmacokinetics of Boronophenylalanine-Fructose (BPA-f) in Murine Tumor Models

With the completion of the fission converter epithermal neutron beam (FCB) at MIT, which has a higher epithermal neutron flux (1.3 x 1010 neutrons/cm 2sec) than the current m-67 beam, future BNCT irradiations conducted by the Harvard-MIT BNCT program could be reduced from approximately 3 hours per beam to just a few minutes. Therefore, it is essential to determine the optimal time after BPA administration to deliver the neutron irradiation, thereby maximizing the dose to tumor and minimizing the dose to the normal tissues. The major goal of this thesis was to gain detailed knowledge of the temporal and spatial distribution of ' 0B in normal tissues and tumors following intravenous BPA-fructose administration, and to use a three-compartment model to study the pharmacokinetics of BPA-f in these tissues. This entailed the investigation of the time-dependent biodistribution of BPA-f in normal brain and in two murine tumor models, GL261 glioma and intracranial B 16 melanoma. From the normal brain study it was shown that there were slight variations in the spatial BPA-f biodistribution in normal brain tissues. The cerebellum and the intracranial nerves consistently showed higher 1 B concentrations than the right cerebrum, the left cerebrum, and the brainstem throughout the whole time course studied. This result, if verified, has important treatment planning implications. It was observed that for GL261 glioma tumor, both the tumor to normal brain ratio and the tumor to blood ratio varied with time, and the best time for neutron irradiation was probably around 60 minutes after the bolus injection. For the B16 intracranial melanoma murine model, the neutron irradiation could be performed during the time frame between 60 and 80 minutes after the bolus injection. The three-compartment pharmacokinetic model parameters (ki through k4) for GL261 tumor were 0.14 ml/g/min, 0.12 min', 0.08 min-1 , and 0.036 min-', respectively, and