Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke
Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke
复制标题
微血栓——针对急性缺血性中风的神经血管重塑和增强微循环灌注的胶束
DOI：
10.1002/adma.201808361
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发表时间：
2019-05-01
影响因子：
29.4
通讯作者：
Jiang, Chen
中科院分区：
文献类型：
--
作者：
Lu, Yifei;Li, Chao;Jiang, Chen
再灌注损伤是缺血性脑卒中发病后神经功能完全恢复和临床溶栓治疗的主要障碍。复杂的细胞级联反应包括氧化应激、神经炎症和脑血管损伤，发生在神经血管单位内，导致微血栓形成和最终的神经元死亡。在这项工作中，开发了一种多靶胶束系统，以同时调节参与这些事件的各种细胞类型。简而言之，雷帕霉素被封装在由活性氧（ROS）响应性和纤维蛋白结合聚合物组成的自组装胶束中，以在缺血性病变内实现胶束保留和受控药物释放。在缺血条件下，胶束促进的ROS消除和抗应激信号通路干扰的组合加强了神经元的存活。体内结果表明，通过胶束极化M2小胶质细胞修复和血脑屏障保护，神经血管单位的整体重塑，导致增强的神经保护和血液灌注。这一策略提供了一个概念证明，即神经血管单位可以作为缺血性中风治疗与纳米药物的综合目标。
Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self‐assembled micelles that are consisted of reactive oxygen species (ROS)‐responsive and fibrin‐binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood–brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.