Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors.
Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by Alzet™ osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) ± standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 ± 4 and 44 ± 10 days, compared to 23 ± 3 and 27 ± 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5× higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be used as delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of synthesizing and evaluating carboranylporphyrins that could have enhanced cellular uptake and improved therapeutic efficacy.
Kawabata
Shinji
S
Department of Neurosurgery, Osaka Medical College, Takatsuki City, Osaka, Japan.
Yang
Weilian
W
Barth
Rolf F
RF
Wu
Gong
G
Huo
Tianyao
T
Binns
Peter J
PJ
Riley
Kent J
KJ
Ongayi
Owendi
O
Gottumukkala
Vijay
V
Vicente
M Graça H
MG
D000818:Animals; D001894:Borohydrides / Q000008:administration & dosage*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000532:radiotherapy*; D018481:Convection; D005260:Female; D005910:Glioma / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011166:Porphyrins / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
D001894:Borohydrides; D011166:Porphyrins