Permeability of the Blood-Brain Barrier to a Rhenacarborane
Permeability of the Blood-Brain Barrier to a Rhenacarborane
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DOI：
10.1124/jpet.108.146878
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Banks, William A.
中科院分区：
文献类型：
--
作者：
Hawkins, Patrick M.;Jelliss, Paul A.;Banks, William A.
硼中子捕获疗法治疗脑恶性肿瘤取决于其穿越血脑屏障（BBB）的能力。一种特别有前途的含硼化合物是烯碳硼烷，如果能够穿过血脑屏障，它不仅可以作为硼的来源，还可以作为运载工具。在这里，我们检测了碘-131标记的3- no -3,3-kappa(2)-(2,2'- n 2C10H6(Me){(CH2)(7)I-131}-4,4')- closo3,1,2 - rec2b9h11 （rhenacarborane）在皮下给药后进入血液并穿过血脑屏障的能力。i -131-萘卡硼烷从注射部位迅速被吸收，并在动脉血清中达到稳定状态，为给药剂量的2.59%/ml。给药后6小时血清中有73% ~ 95%的放射性代表完整的i -131-壬卡硼烷。辛醇/缓冲液分配系数为1.74，具有亲脂性。脑、肺和肝脏的组织/血清比率显示脂溶性物质的典型模式，立即达到高水平并迅速重新分布。对于脑，迅速达到约0.107%给药剂量/克脑的稳定状态，皮下给药6小时后，71%的脑放射性代表完整的i -131-壬卡硼烷。肺和肝的稳态值分别为每克注射剂量的1.53和0.89%。I-131-雷纳卡硼烷注入脑侧脑室后，通过不饱和系统迅速从脑中排出。综上所述，这些结果表明，甲萘卡硼烷具有酶抗性，能够通过跨膜扩散穿过血脑屏障并在脑内大量积累。这支持了它们作为靶向中枢神经系统的治疗剂的使用。
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 rhenacarboranesthat, 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-kappa(2)-(2,2'-N 2C10H6(Me){(CH2)(7)I-131}-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 I-131-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 I-131-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratiosfor brain, lung, and liver showed classic patterns for a lipidsoluble 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 I-131-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. I-131- 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.