Next-generation nanomedicine for acute ischemic stroke - ABSTRACT / PROJECT SUMMARY Acute ischemic stroke is poised for a revolution. With the advent of mechanical thrombectomy in the last decade, the worst clots can be removed. While thrombectomy has improved outcomes, most treated patients still have severe deficits, in large part due to secondary injury caused by ischemia-reperfusion injury. To solve this problem, many neuroprotective drugs were trialed, but all failed, largely due to poor drug delivery to at-risk brain. Therefore, a new technology is needed to deliver neuroprotective drugs to re- and under-perfused brain. To meet this challenge, University of Pennsylvania spin-out NanoMuse will build on our two recent breakthroughs: First, we discovered that nano-scale drug carriers (nanocarriers) that bind to the endothelial marker VCAM can concentrate drugs in the brain >30x higher than if delivered without a nanocarrier, and >6x better than the best prior nanocarrier. In the gold-standard stroke model of transient middle cerebral artery occlusion (tMCAO) in mice, VCAM-nanocarriers loaded with the corticosteroid dexamethasone improved mortality and reduced infarct volume 32% (more than the 25% average of drugs that progressed to clinical studies). Second, we found that prior nanocarriers suffered from activation of the complement protein cascade, which limits nanocarrier uptake in the brain and produces an anaphylaxis-like reaction that drops the blood pressure (very dangerous in stroke). Therefore, we conjugated a human complement-inhibitor (Factor I) to the nanocarriers, and completely eliminated these problems. Now we will combine and extend these two innovations to develop our product, a nanocarrier that massively concentrates neuroprotective drugs in at-risk brain, initially in ischemic stroke patients after reperfusion. In Aim 1, we will optimize the nanocarriers (e.g., switching the VCAM-targeting moiety to an Fab antibody fragment) to minimize complement activation and phagocytosis of the particles, using mouse and human serum and leukocytes. In Aim 2, we will use the optimized nanocarriers to test 3 drugs for efficacy in the tMCAO mouse model: dexamethasone (already proven effective with our un-optimized nanocarrier), or mRNAs encoding two anti-inflammatory proteins (which we already showed were effective in other mouse models). We will measure infarct volume, behavioral outcomes, side effects, drug distribution, and mRNA-encoded protein production compared to untargeted or drug-free nanocarriers. The best mono-therapy and a combination therapy will be validated in tMCAO with advanced age. Our deliverable will be a nanocarrier to concentrates one or two anti-inflammatory drugs at the BBB in order to ameliorate infarct volume by > 25%. Our team is poised to do this, with clinicians who take care of stroke, nanotechnologists, business advisors with years of experience in neuro-critical care products, and a supportive university. Together, we will help usher in stroke’s next revolution.
