Journal
JOURNAL OF NEURO-ONCOLOGY
Volume 103, Issue 2, Pages 175-185Publisher
SPRINGER
DOI: 10.1007/s11060-010-0376-5
Keywords
Convection enhanced delivery; Carboranylporphyrins; Boron neutron capture therapy; F98 rat glioma
Categories
Funding
- N.I.H. [R01 CA098902, R01 CA098945]
- United States Department of Energy through Innovations in Nuclear Infrastructure and Education, Office of Nuclear Energy, Science and Technology [DE-FG07-02ID14420DE-FG07-02, K14420]
- Office of Environmental and Biological Research [DE-FG02-02ER63358]
- Ohio State University Department of Pathology
- Grants-in-Aid for Scientific Research [23592146] Funding Source: KAKEN
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Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive B-10 is irradiated with low energy thermal neutrons to produce alpha-particles (B-10[n,alpha]Li-7). 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 (TM) 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 +/- A 4 and 44 +/- A 10 days, compared to 23 +/- A 3 and 27 +/- A 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5x 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.
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