Reactive Oxygen Species-Responsive Nanoparticles for the Treatment of Ischemic Stroke

Abstract

Ischemic stroke is a leading cause of death and long-term disability worldwide, yet availability of current treatments is limited. The downstream events resulting from cerebral ischemia lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous antioxidant mechanisms. Thus, treatments that can reduce this imbalance can limit the extent of injury resulting from ischemic stroke. In this work, the potential of novel ROS-scavenging PEGylated polymeric nanoparticles (NPs) composed of poly(propylene sulfide) (PPS) (PPS-NPs) for ischemic stroke therapy is evaluated in vitro and in a mouse model of stroke. In vitro results show that PPS-NPs display remarkable anti-oxidant and anti-inflammatory properties, whilst exhibiting negligible cytotoxicity. NPs administered intravenously rapidly accumulate in ischemic brain regions as visualized through fluorescence imaging, reduced infarct volume, blood-brain barrier damage, neuronal loss, and neuroinflammation as determined by immunohistochemistry, and improved recovery of neurological function as determined through behavioral analyses. Crucially, the data show that the therapeutic time window for administration of PPS-NPs extends up to 3 h, a clinically relevant time window for stroke. The findings provide new strong evidence that these NPs may be an effective antioxidant therapy for ischemic stroke.