Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption.
The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.
Barth
R F
RF
Department of Pathology, The Ohio State University, Columbus 43210, USA.
Yang
W
W
Rotaru
J H
JH
Moeschberger
M L
ML
Joel
D D
DD
Nawrocky
M M
MM
Goodman
J H
JH
Soloway
A H
AH
D000512:Alpha Particles; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001894:Borohydrides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000528:radiation effects; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000528:radiation effects; D016754:Boron Neutron Capture Therapy; D001921:Brain / Q000473:pathology / Q000528:radiation effects; D001932:Brain Neoplasms / Q000532:radiotherapy*; D002339:Carotid Arteries; D005910:Glioma / Q000532:radiotherapy*; D007269:Injections, Intra-Arterial; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000528:radiation effects
D001894:Borohydrides; D001896:Boron Compounds; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate; D008353:Mannitol; D010649:Phenylalanine; C033685:4-boronophenylalanine