Zhang Huijuan, Wang Jingjing, Tian Yingmei, Wang Chaoqun, Hou Lin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou, China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
J Control Release. 2025 Feb 10;378:195-208. doi: 10.1016/j.jconrel.2024.12.005. Epub 2024 Dec 13.
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.
缺血性中风发病率和致残率高，严重威胁人类健康。脑栓塞和脑功能受损是该疾病的两个主要临床特征。因此，快速恢复脑供血并同步改善受损神经功能是治疗中风的关键。在此，基于脑血栓的微环境和受损神经元的病理特征，我们构建了一种剪切力和活性氧（ROS）双响应系统（UK@Fuc/CDPC-PTPCS），用于依次靶向递送溶栓剂尿激酶（UK）和神经保护药物胞质胆碱（CDPC）。结果证明，静脉给药后，UK@Fuc/CDPC-PTPCS可通过岩藻糖胶（Fuc）对活化血小板上过度表达的P-选择素的主动识别能力快速定位到脑血栓部位。随后，急剧增加的血液剪切力通过破坏β-环糊精（β-CD）的主客体相互作用分离核壳结构，因此壳层中负载的UK首先释放以快速溶栓，然后恢复脑供血。之后，中风归巢肽（SHp）修饰的CDPC-PTPCS核心主动识别缺血受损神经元细胞。然后高细胞内ROS触发CDPC在特定部位释放以发挥神经保护作用。本研究为缺血性中风提供了一种新的治疗策略。
