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.

胶质母细胞瘤（GBM）是高死亡率的恶性肿瘤之一，并且血脑屏障（BBB）的存在严重限制了治疗剂在GBM病变中的渗透和组织蓄积。主动靶向纳米技术可以在大脑中实现有效的药物输送，同时成功率仍然很低。在这里，我们揭示了以前未曾探索过的现象，即具有主动靶向纳米技术的化学疗法通过抑制VEGF-PI3K-AKT信号传导途径引起病理性BBB功能恢复，并伴有Claudin-5和Occludin的表达上调。严重的是，病理性BBB功能恢复导致在GBM多次给药期间脑内主动靶向纳米技术转运的显着减少，从而导致GBM治疗药物的化疗失败。体内，这可能为其他中枢神经系统疾病的治疗提供新的视野。