Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors

Author： Kawabata Shinji Yang Weilian Barth Rolf Wu Gong Huo Tianyao Binns Peter Riley Kent Ongayi Owendi Gottumukkala Vijay Vicente M.

Publisher： Springer Publishing Company

ISSN： 0167-594X

Source： Journal of Neuro-Oncology, Vol.103, Iss.2, 2011-06, pp. : 175-185

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

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]⁷Li). 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.