以血脑屏障上低密度脂蛋白受体相关蛋白-1作为新型药物跨血脑释药载体的转运机制研究及探索

The central nervous system is protected by blood brain barriers (BBB) which control the entry of compounds into the brain such as toxic agents, unnecessary hormones and bacterial, thereby regulating brain homeostasis. However, this very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the BBB. LRP-1 is one of the most expressed receptors on the BBB, and it exhibited a safe strategy in transporting across BBB. In addition, due to its fast transport and recycling time the LRP-1 receptor is difficult to saturate, which ensures the receptor cannot be permanently bound and may continue its natural function..We have screened several peptides targeting LRP-1 and those can be transported across BBB. However, the detailed mechanism of transportation induced by LRP-1 is still not clear at this moment, and also the screened peptides exhibited poor stabilities. The aim of this application is to investigate the detailed mechanism of LRP-1's transporting function, study the strategy for extending the peptide stability by self assembling characterization and build up a stable drug carrier across BBB in clinical.

血脑屏障（BBB）是脑与血液之间存在的一种生理屏障，用于保护脑组织受到不必要的化学物质、激素以及病菌导致的伤害。但是BBB也同样限制了药物进行脑组织，使很多药物不能在脑部达到有效治疗血药浓度。近年来，通过转运体达到脑组织定向释药的目的成为血脑屏障研究领域的热点之一。在血脑屏障上存在多个转运体，例如胰岛素、氨基酸等，但是其中的低密度脂蛋白相关蛋白（LRP-1）由于其丰富表达和较好的安全性，是最具有研究意义的转运体之一。课题组前期证实了LRP-1可作为血脑屏障转运体转运多肽分子，并初步筛选了具有LRP-1特异转运功能的多肽。但是，多肽通过LRP-1的转运机制还未被阐明；而且需要对多肽进行稳定性等优化。我们拟将通过本项目深入研究LRP-1转运特异多肽受体的机制，包括动力学和形态学，还将通过自组装技术对多肽进行修饰，使其能够成为具有载药空腔的跨血脑屏障释药载体。

血脑屏障（BBB）是脑与血液之间存在的一种生理屏障，用于保护脑组织受到不必要的化学物质、激素以及病菌导致的伤害。但是BBB也同样限制了药物进入脑组织，使很多药物不能在脑部达到有效治疗血药浓度。近年来，通过转运体达到脑组织定向释药的目的成为血脑屏障研究领域的热点之一。在血脑屏障上存在多个转运体，例如胰岛素、氨基酸等，但是其中的低密度脂蛋白相关蛋白（LRP-1）由于其丰富表达和较好的安全性，是最具有研究意义的转运体之一。课题组通过本课题证实了LRP-1可作为血脑屏障转运体转运多肽分子，并初步筛选了具有LRP-1特异转运功能的多肽。并尝试开展了LRP-1血脑屏障穿越肽与细胞毒药物的偶联工作，体内和体外实验均证实了细胞毒药物在LRP-1靶向多肽的转导下，大大提高了其在脑内的浓度和分布。本课题的研究结果对未来的新药开发和临床治疗均具有一定意义。