AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma
AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma
复制标题
SC79 激活 AKT 可暂时重新打开病理性血脑屏障，从而改善胶质母细胞瘤的功能化纳米粒子治疗
DOI：
10.1016/j.biomaterials.2020.119793
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发表时间：
2020-04-01
期刊：
影响因子：
14
通讯作者：
Hu, Fuqiang
中科院分区：
文献类型：
--
作者：
Wen, Lijuan;Wang, Kai;Hu, Fuqiang
胶质母细胞瘤(GBM)是死亡率较高的恶性肿瘤之一，血脑屏障的存在严重限制了治疗药物在GBM病变部位的渗透和组织蓄积。主动靶向纳米技术可以实现高效的脑内药物输送，但成功率仍然很低。在这里，我们揭示了一个未知的现象，即主动靶向纳米技术化疗通过抑制VEGF-PI3K-AKT信号通路，并上调Claudin-5和occludin的表达，导致病理性BBB功能恢复。严重的是，在GBM多次给药过程中，病理性的BBB功能恢复导致脑内主动靶向纳米技术的转运显著减少，导致GBM治疗的化疗失败。为了解决这个问题，我们选择了AKT激动剂SC79来瞬时重新开放功能恢复的病理性血脑屏障，以持续脑内注射脑靶向纳米药物，最终在体内产生明显的抗GBM效应，这可能为其他中枢神经系统疾病的治疗提供新的视角。
Glioblastoma (GBM) is one of the malignant tumors with high mortality, and the presence of the blood brain barrier (BBB) severely limits the penetration and tissue accumulation of therapeutic agents in the lesion of GBM. Active targeting nanotechnologies can achieve efficient drug delivery in the brain, while still have a very low success rate. Here we revealed a previously unexplored phenomenon that chemotherapy with active targeting nanotechnologies causes pathological BBB functional recovery through VEGF-PI3K-AKT signaling pathway inhibition, accompanied with up-regulated expression of Claudin-5 and Occludin. Seriously, pathological BBB functional recovery induces a significant decrease of intracerebral active targeting nanotechnologies transport during GBM multiple administration, leading to chemotherapy failure in GBM therapeutics. To address this issue, we chose AKT agonist SC79 to transiently re-open functional recovering pathological BBB for continuously intracerebral delivery of brain targeted nanotherapeutics, finally producing an observable anti-GBM effect in vivo, which may offer new sight for other CNS disease treatment.