BORON NEUTRON-CAPTURE THERAPY OF BRAIN-TUMORS - ENHANCED SURVIVAL FOLLOWING INTRACAROTID INJECTION OF SODIUM BOROCAPTATE WITH OR WITHOUT BLOOD-BRAIN-BARRIER DISRUPTION

Purpose: Sodium borocaptate (Na2B12H11SH or BSH) has been used clinica lly for boron neutron capture therapy (BNCT) of patients with primary brain tumors. The purpose of the present study was to determine if tum or uptake of BSH and efficacy of BNCT could be enhanced in F98 glioma- bearing rats by intracarotid (i.c.) injection of the compound with or without blood-brain barrier disruption (BBB-D). Methods and Materials: For biodistribution studies 100,000 F98 glioma cells were implanted s tereotactically into the brains of Fischer rats, and 12 days later BBB -D was carried out by i.c. infusion of 25% mannitol, followed immediat ely thereafter by i.c. injection of BSH (30 mg B/kg body weight). Anim als were killed 1, 2.5, and 5 h later, and their brains were removed f or boron determination. For BNCT experiments, which were initiated 14 days after intracerebral implantation of 1000 F98 cells, BSH (30 mg B/ kg b.wt. was administered intravenously (i.v.) without BBB-D, or i.c. with or without BBB-D. The animals were irradiated 2.5 h later with a collimated beam of thermal neutrons at the Brookhaven National Laborat ory Medical Research Reactor. Results: The mean tumor boron concentrat ion after i.c. injection with BBB-D was 48.6 +/- 17.2 mu g/g at 2.5 h compared with 30.8 +/- 12.2 mu g/g after i.c. injection without BBB-D and 12.9 +/- 4.2 mu g/g after i.v. injection. The best composite tumor to normal tissue ratios were observed at 2.5 h after BBB-D, at which time the tumor:blood (T:B1) ratio was 5.0, and the tumor: brain (T:Br) ratio was 12.3, compared to 1.1 and 4.6, respectively, in i.v. inject ed rats. The mean survival time for untreated control rats was 24 +/- 3 days, 29 +/- 4 days for irradiated controls, 33 +/- 6 days for those receiving i.v. injection of BSH, 40 +/- 8 days for rats receiving i.c . BSH without BBB-D, and 52 +/- 13 days for BBB-B followed by BNCT (p = 0.003 vs. i.v. injected BSH). Conclusions: Intracarotid administrati on of BSH with or without BBB-D significantly increased tumor uptake o f BSH and enhanced survival of F98 glioma-bearing rats following BNCT. BBB-D may be a useful way to enhance the delivery of both low and hig h molecular weight boron compounds to brain tumors. Further studies ar e in progress to assess this approach with other boron delivery agents . (C) 1997 Elsevier Science Inc.