Shear force-ROS sequential responsive drug delivery system for improving cerebral thrombosis microcirculation and neurological function.

Abstract

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.