There has been increasing interest in the possible use of boronophenylalanine as a capture agent for boron neutron capture therapy of brain tumors. The purpose of the present study was to determine whether the uptake of boronophenylalanine in F98 glioma-bearing rats could be enhanced by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D). Glioma cells (10(5)) were stereotactically implanted into the right cerebral hemisphere of Fischer rats, and 12 days later, BBB-D was performed by infusing 25% mannitol (1.373 mOsmol/ml) into the right carotid artery and then immediately injecting L-boronophenylalanine (300 mg/kg of body weight) intracarotidly. The animals were killed 0.5, 1, 2.5, and 4 hours later, and the brains were removed for boron determination by direct current plasma atomic emission spectroscopy. BBB-D was assessed by the intravenous injection of Evans blue or horseradish peroxidase, and the barrier-disrupted hemispheres and tumors showed intense staining with each. The mean tumor boron concentration after i.c. injection and BBB-D was 34.8 +/- 6.8 micrograms/g at 2.5 hours compared with 20.3 +/- 6.2 micrograms/g after i.c. injection without BBB-D and 10.7 +/- 0.7 micrograms/g after intravenous injection. No significant differences in boron concentration in muscle, skin, and eye were observed among the different groups. Boron concentrations in the ipsilateral, disrupted hemisphere increased transiently but rapidly returned to background levels by 2.5 hours after BBB-D. The tumor:brain and tumor:blood ratios were 5.2 and 5.6, respectively, compared to 3.2 and 2.1 for intravenous injection groups at 2.5 hours. The present study is the first to show that BBB-D combined with i.c. injection can enhance the tumor uptake of boron compounds for boron neutron capture therapy.
When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.
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