Project Summary Stroke is the leading cause of disability in the United States. Despite the effectiveness of thrombolysis and thrombectomy, outcomes after stroke remain poor and effective cerebroprotectant therapies are needed. This project will leverage the complementary expertise of a Stroke Neurologist/Immunologist and a Bioengineer/Imaging scientist to jointly develop and test drug delivery of cerebroprotectants by lipid nanoparticles that specifically target the ischemic brain. Ischemic stroke after vascular occlusion dramatically alters tissue metabolism. A hypoxic environment ensues due to reduced oxygen supply to shift metabolism towards anaerobic glycolysis for energy supply, and which in turn produces excessive acidic byproducts which are extruded into the extracellular environment. Thus, the hypoxic and acidic microenvironment of an ischemic lesion may be exploited to direct infarct-specific therapy. We will use hypoxia- and pH-sensitive lipid nanoparticles that cross the blood-brain barrier to deliver high payloads of cerebroprotective and anti-inflammatory agents specifically into the ischemic brain. Our hypothesis is that hypoxia and pH targeted nanoparticles will enhance drug delivery into the ischemic brain, maximizing cerebroprotection and improving stroke outcomes. Preliminary work in our experimental model of ischemic stroke using these lipid nanoparticles show the nanoparticle accumulate in the ischemic brain within minutes and persist for at least two days. These can be tracked longitudinally by MRI due to the co-incorporation of gadolinium along with cerebroprotectant medications in the nanoparticles. We propose two Aims to study the concentration and duration of drug delivery to the ischemic brain and test the effects on infarct volume, inflammation, and functional outcomes in mice after transient middle cerebral artery occlusion. If successful, the strategy can be applied to other candidate drugs for stroke as well as other diseases characterized by tissue hypoxia and acidosis. Given the biocompatibility of all materials used to synthesize lipid nanoparticles, we expect high translational potential of this method into larger species and eventually into clinical tests.

Project Narrative Outcomes after stroke remain poor. The overall goal of the proposal is to develop and test new nanoparticles that specifically target the brain after stroke and slowly deliver high doses of medications to protect the stroked brain region over several days and improve outcomes.