Abstract
The treatment of brain malignancies with boron neutron capture therapy depends on their ability to cross the blood-brain barrier (BBB). An especially promising class of boron-containing compounds is the rhenacarboranes that, if able to cross the BBB, could act as delivery vehicles as well as a source of boron. Here, we examined the ability of the 3-NO-3,3-κ2-(2,2′-N2C10H6(Me){(CH2)7131I}-4,4′)-closo-3,1,2-ReC2B9H11 (rhenacarborane) labeled with iodine-131 to be taken up into the bloodstream after subcutaneous administration and to cross the BBB. The 131I-rhenacarborane was quickly absorbed from the injection site and reached a steady state in arterial serum of 2.59%/ml of the administered dose. Between 73 and 95% of the radioactivity in serum 6 h after administration represented intact 131I-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratios for brain, lung, and liver showed classic patterns for a lipid-soluble substance with high levels immediately achieved and rapid redistribution. For brain, a steady state of approximately 0.107% of the administered dose/gram-brain was rapidly reached, and 71% of the radioactivity in brain 6 h after subcutaneous administration represented intact 131I-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. 131I-Rhenacarborane was quickly effluxed from brain by a nonsaturable system after its injection into the lateral ventricle of the brain. In conclusion, these results show that a rhenacarborane was enzymatically resistant and able to cross the BBB by transmembrane diffusion and accumulate in brain in substantial amounts. This supports their use as therapeutic agents for targeting the central nervous system.
Footnotes
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This work was supported in part by the Veterans Affairs Merit Review; the National Institutes of Health [Grants R01-NS051334, R01-NS050547, R01-AG029839]; and Beaumont Research Grant.
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doi:10.1124/jpet.108.146878.
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ABBREVIATIONS: BNCT, boron neutron capture therapy; CNS, central nervous system; BBB, blood-brain barrier; THF, tetrahydrofuran; PPh4Br, tetraphenylphosphonium bromide; IR, infrared; TLC, thin layer chromatography; DMSO, dimethyl sulfoxide; %Inj/g, percentage of an intravenous dose taken up per gram of brain; %Inj/brain, residual in brain expressed as a percentage of the dose injected into the lateral ventricle of the brain; vis., visible; PC, partition coefficient; complex 1, 3,3-(CO)2-3-NO-closo-3,1,2-ReC2B9H11; complex 2, PPh4][3-Br-3-CO-3-NO-closo-3,1,2-ReC2B9H11; complex 3, 3-NO-3,3-κ2-(2,2′-N2C10H6(Me){(CH2)7Br}-4,4′)-closo-3,1,2-ReC2B9H11; complex 4, 3-NO-3,3-κ2-(2,2′-N2C10H6(Me)-{(CH2)7131I}-4,4′)-closo-3,1,2-ReC2B9H11.
- Received October 1, 2008.
- Accepted January 28, 2009.
- U.S. Government work not protected by U.S. copyright
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