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.

Grant Number: 5R41NS130812-02
NIH Institute/Center: NIH
Principal Investigator: Jacob Brenner