Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of sodium borocaptate with or without blood-brain barrier disruption.
OBJECTIVE
Sodium borocaptate (Na2B12H11SH or BSH) has been used clinically for boron neutron capture therapy (BNCT) of patients with primary brain tumors. The purpose of the present study was to determine if tumor 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
For biodistribution studies 100,000 F98 glioma cells were implanted stereotactically into the brains of Fischer rats, and 12 days later BBB-D was carried out by i.c. infusion of 25% mannitol, followed immediately thereafter by i.c. injection of BSH (30 mg B/kg body weight). Animals were killed 1, 2.5, and 5 h later, and their brains were removed for 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 Laboratory Medical Research Reactor.


RESULTS
The mean tumor boron concentration after i.c. injection with BBB-D was 48.6 +/- 17.2 microg/g at 2.5 h compared with 30.8 +/- 12.2 microg/g after i.c. injection without BBB-D and 12.9 +/- 4.2 microg/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. injected 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-D followed by BNCT (p = 0.003 vs. i.v. injected BSH).


CONCLUSIONS
Intracarotid administration of BSH with or without BBB-D significantly increased tumor uptake of 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 high molecular weight boron compounds to brain tumors. Further studies are in progress to assess this approach with other boron delivery agents.
Yang
W
W
Department of Pathology, The Ohio State University, Columbus 43210, USA.
Barth
R F
RF
Rotaru
J H
JH
Moeschberger
M L
ML
Joel
D D
DD
Nawrocky
M M
MM
Goodman
J H
JH
Soloway
A H
AH
D000818:Animals; D001812:Blood-Brain Barrier; D001894:Borohydrides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000401:mortality / Q000532:radiotherapy; D002339:Carotid Arteries; D005910:Glioma / Q000098:blood supply / Q000378:metabolism* / Q000401:mortality / Q000532:radiotherapy; D007269:Injections, Intra-Arterial; D008297:Male; D009368:Neoplasm Transplantation; D011879:Radiotherapy Dosage; D051381:Rats; D011916:Rats, Inbred F344; D012062:Relative Biological Effectiveness; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D001894:Borohydrides; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate