There is a unmet clinical need for effectively treating diseases like ischemic stroke. During ischemic stroke, the blood-brain barrier (BBB) is disrupted, followed by the extravasation of blood components into the brain exacerbating ischemic injury. It is known that decreasing endothelial cell death and BBB permeability can prevent the influx of deleterious inflammatory molecules from the blood to the brain side and vice versa. Engineered nanoparticles (NPs), 1-100 nanometers in particle diameter, are widely used as drug delivery systems due to their versatility and modifiable physicochemical properties. Modification of the NPs with polymers like poly(ethylene glycol), for instance, ensures the stability of therapeutic agents in vivo against enzymatic degradation, renal clearance, and non-specific uptake by the immune system, resulting in increased circulation half-lives and prolonged tissue retention. Endothelial, but not neuronal expression of heat shock protein 27 kDa (HSP27), ameliorated BBB disruption and enhanced the overall sensorimotor recovery for nearly a month post-ischemia in a mouse model of stroke. We will develop polymer/HSP27 nanoparticles to decrease BBB permeability in ischemic stroke. Specifically, we are interested in comparing two polymers: poly(ethylene glycol)-b-poly(aspartate diethyltriamine) (PEG-DET) and poly(methacryloyloxyethyl phosphorylcholine) conjugated with dimethylaminoethyl methacrylate and butyl methacrylate (PMPC-DB) for HSP27 protein delivery due to their controlled and sustained-release properties, low toxicity, and biocompatibility with tissues and cells. We will characterize the physicochemical aspects of the formed NPs using dynamic light scattering (DLS) and native/denaturing polyacrylamide gel electrophoresis. We hypothesize that the delivery of HSP27 will decrease BBB permeability in ischemic brain endothelial cells, thus allowing them to retain their structure and function leading to improved outcomes in stroke therapies. We hope to overcome previously encountered barriers in stroke therapies, including poor bioavailability and drug-drug interactions that can dramatically affect patients’ quality of life.
