The ischemic strokes seriously threaten human health with high incidence and disability rates. Cerebral embolism and impaired brain function are the two major clinical features of this disease. Therefore, rapid restoration of cerebral blood supply and synchronous improvement of impaired neurological function is the key to treating strokes. Herein, based on the microenvironment of cerebral thrombosis and pathological characteristics of damaged neurons, we constructed a shear force and reactive oxygen species (ROS) dual-responsive system (UK@Fuc/CDPC-PTPCS) for sequential targeted delivery of thrombolytic agent urokinase (UK) and neuroprotective drug cytosolic choline (CDPC). Results proved that after intravenous administration, UK@Fuc/CDPC-PTPCS can quickly locate to cerebral thrombosis site via the active recognition capability of fucoidan (Fuc) to P-selectin overexpressed on activated platelets. Subsequently, the sharply increased blood shear force separated the core-shell structure by breaking the host-guest interaction of β-cyclodextrin (β-CD), so the UK loaded in the shell was first released to rapid thrombolysis and then restored cerebral blood supply. Afterward, the stroke homing peptide (SHp) modified CDPC-PTPCS core actively recognized ischemic damaged neuronal cells. Then high intracellular ROS triggered CDPC release at specific sites to exert neuroprotective effects. This study offered a new therapeutic strategy for ischemic stroke.

中文翻译：

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用于改善脑血栓形成、微循环和神经功能的 Shear force-ROS 序贯响应给药系统


缺血性中风严重威胁人类健康，发病率和残疾率高。脑栓塞和脑功能受损是本病的两大临床特征。因此，脑供血的快速恢复和受损神经功能的同步改善是治疗中风的关键。在此，基于脑血栓形成的微环境和受损神经元的病理特征，我们构建了剪切力和活性氧 （ROS） 双响应系统 （UK@Fuc/CDPC-PTPCS），用于溶栓剂尿激酶 （UK） 和神经保护药物胞质胆碱 （CDPC） 的序贯靶向递送。结果证明，静脉给药后，UK@Fuc/CDPC-PTPCS 可通过岩藻多糖 （Fuc） 对活化血小板上过表达的 P-选择素的主动识别能力快速定位到脑血栓形成部位。随后，急剧增加的血液剪切力通过打破 β-环糊精 （β-CD） 的主客体相互作用分离了核壳结构，因此加载在壳中的 UK 首先被释放到快速溶栓，然后恢复脑血供。之后，卒中归巢肽 （SHp） 修饰的 CDPC-PTPCS 核心积极识别缺血性受损神经元细胞。然后，高细胞内 ROS 触发特定位点的 CDPC 释放以发挥神经保护作用。本研究为缺血性卒中提供了一种新的治疗策略。