SELECTIVITY OF BORON CARRIERS FOR BORON NEUTRON-CAPTURE THERAPY - PHARMACOLOGICAL STUDIES WITH BOROCAPTATE SODIUM, L-BORONOPHENYLALANINE AND BORIC-ACID IN MURINE TUMORS

Borocaptate sodium (BSH) and L-boronophenylalanine (L-BPA) are two bor on carriers used for boron neutron capture therapy (BNCT) in the treat ment of glioblastoma and melanoma, respectively. The suitability of th ese two compounds was evaluated on the basis of pharmacokinetic studie s aiming at characterizing their biodistribution, tumor uptake and tum or selectivity. Boric acid was also used as a reference compound since it is nonselective and relatively freely diffusible. The compounds we re investigated in two tumor models, a B16 pigmented melanoma and the RIF1 sarcoma. Mice were sacrificed after different boron doses at vari ous post-injection times and tissue and plasma levels measured using i nductively coupled plasma atomic emission spectroscopy (ICP-AES). The proposed minimum effective tumor boron concentration of 15 ppm was ach ieved in both tumor models for the three compounds tested, although on ly for L-BPA in the melanoma was this achieved when tumor-plasma ratio s were above 1. In the RIF1 model, maximum tumor concentrations of 44 and 31 ppm B were reached after administration of 50 mug B/g body weig ht for boric acid and BSH, respectively. After administration of 12.5 mug B/g Of L-BPA, maximum concentrations of 15 and 21 ppm were found i n the RIF1 and B16 models, respectively. Tumor-plasma ratios (TPR) for BSH remained close to or below unity at all times studied in both tum ors. Brain levels of BSH were very low, however, leading to tumor-brai n ratios markedly greater than 1 at all times. L-BPA and boric acid sh owed TPR values above unity in both tumor models, reaching 3.2 in B16. Tissue-plasma ratios after L-BPA reached maxima of 1.3 and 3.1 for br ain and muscle, in contrast to the low values for BSH. In conclusion, the study showed only modest selectivity for tumor type for the boron compounds tested, although L-BPA showed significant selectivity for th e melanoma and would appear to better than BSH for this tumor type. Al though tumor-plasma ratios were lower for BSH than L-BPA, the very low normal brain concentrations with BSH would favor this compound for tu mors such as glioblastoma. Data on intracellular distributions, both f or tumor and relevant normal tissue subpopulations, will be needed to supplement gross tissue boron data for accurate assessment of potentia l for BNCT.