Improved survival after boron neutron capture therapy of brain tumors by cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine

OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been pre viously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediat ed opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophe nylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral im plants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/ kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 mu g/kg b .w. of Cereport. For therapy studies, BNCT was initiated 14 days after intr acerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BP A (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 mu g/g with Cereport versus 33.6 +/- 3.9 mu g/g without Cereport at 2.5 hours after i.c. infusion of BPA, an d concentrations were 29.4 +/- 9.9 mu g/g with Cereport versus 15.4 +/- 3.5 mu g/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0 .6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administra tion of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, a nd 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusio n of Cereport and then BPA, and an 86% increase in lifespan in rats that re ceived i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cere port can not only increase tumor uptake of BRA, but also enhance the effica cy of BNCT.