Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota, USA.
Drug Metab Dispos. 2013 Jan;41(1):33-9. doi: 10.1124/dmd.112.048322. Epub 2012 Sep 26.
Despite aggressive treatment with radiation and chemotherapy, recurrence of glioblastoma multiforme (GBM) is inevitable. The objective of this study was to show that the blood-brain barrier (BBB), through a combination of tight junctions and active efflux transporters in the brain microvasculature, can significantly restrict delivery of molecularly targeted agents to invasive glioma cells. Transgenic mice lacking P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) were used to study efflux of erlotinib at the BBB. A U87 rat xenograft model of GBM was used to investigate the regional distribution of erlotinib to the tumor, and brain regions surrounding the tumor. The effect of concurrent administration of elacridar on regional tumor distribution of erlotinib was evaluated. We show that erlotinib transport across an intact BBB is significantly restricted due to P-gp- and Bcrp-mediated efflux transport. We then show that the BBB is sufficiently intact in areas of brain adjacent to the tumor core to significantly restrict erlotinib delivery. Inhibition of P-gp and Bcrp by the dual inhibitor elacridar dramatically increased erlotinib delivery to the tumor core, rim, and normal brain. These results provide conclusive evidence of the impact that active efflux at the BBB has on the delivery of molecularly targeted therapy to different tumor regions in glioma. These data also support the possibility that the repeated failure of clinical trials of new drugs for gliomas may be in part due to a failure to achieve effective concentrations in invasive tumor cells that reside behind an intact BBB.
尽管采用了积极的放疗和化疗，胶质母细胞瘤（GBM）仍不可避免地会复发。本研究的目的是证明血脑屏障（BBB）通过脑微血管中的紧密连接和主动外排转运体的组合，可以显著限制分子靶向药物递送到侵袭性神经胶质瘤细胞。使用缺乏 P 糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp）的转基因小鼠来研究 BBB 处的厄洛替尼外排。使用 U87 大鼠 GBM 异种移植模型研究厄洛替尼在肿瘤和肿瘤周围脑区的区域分布。评估同时给予 elacridar 对厄洛替尼区域性肿瘤分布的影响。我们表明，由于 P-gp 和 Bcrp 介导的外排转运，厄洛替尼穿过完整的 BBB 的转运受到显著限制。然后，我们表明，与肿瘤核心相邻的脑区的 BBB 足够完整，可以显著限制厄洛替尼的递送。双抑制剂 elacridar 抑制 P-gp 和 Bcrp 可显著增加厄洛替尼向肿瘤核心、边缘和正常脑的递送。这些结果提供了确凿的证据，证明了 BBB 处的主动外排对胶质母细胞瘤不同肿瘤区域的分子靶向治疗药物递送的影响。这些数据还支持这样一种可能性，即胶质母细胞瘤新药临床试验的反复失败可能部分是由于未能在完整的 BBB 后面的侵袭性肿瘤细胞中达到有效浓度。
