# Improved glyburide therapy via acid- triggered release functional nanoparticles and therapeutic imaging

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $367,550

## Abstract

Stroke is the leading cause of disability and death in the U.S. Intravenous administration of tPA within 3 hours
of symptom onset remains the only FDA-approved pharmacotherapy. Novel approaches to improving the
treatment of stroke are in high demand. We recently discovered that the SUR1-TRPM4 channel is upregulated
de novo in all cell types of the neurovascular unit following ischemia and channel blockade using glyburide
achieved robust, clinically-relevant beneficial effects in multiple preclinical models. This finding has led to a
phase II GAMES-RP trial. Clinical results revealed a trend toward improved survival and a significant reduction
in edema but failed to meet the primary endpoint. The degree of swelling reduction was insufficient to prevent
decompressive craniectomy or significantly increase clinical outcome. Further analysis showed that the unmet
efficacy is due to the limitations associated with the current formulation. First, glyburide in the current
formulation has limited penetration into the ischemic brain and thus does not allow fully capitalizing its anti-
edema and neuron protective actives. Second, the current formulation does not accommodate the requirement
for prompt drug administration. To overcome these limitations, we propose to develop a novel nanoformulation,
acid responsive, stroke- targeting, antioxidant nanoparticles (ARSTA NPs), to enhance the delivery and
efficacy of glyburide. As preliminary work, we developed an innovative approach for isolating natural
nanomaterials from medicinal natural products (MNPs), and identified betulinic acid (BA) that forms NPs. We
showed that BA NPs penetrated the ischemic brain, effectively reduced brain infarction through regulation of
the antioxidant and pro-inflammatory pathways, and mediated efficient delivery of glyburide to the brain. We
demonstrated that the ischemic microenvironment is acidic. We developed chemistry to convert BA to betulinic
amine (BAM) and showed that BAM NPs released glyburide in a rate significantly greater than BA NPs in
acidic pH. We screened a collection of MNPs and identified three new nanomaterials that have anti-stroke
activity and drug delivery capacity comparable to BA. We demonstrated that targeted delivery of NPs to the
ischemic brain can be achieved through surface conjugation of AMD3100. We developed a PET imaging
approach for non-invasive monitoring stroke recovery by measuring synapse density. Building on these
progress, we propose to synthesize and characterization of ARSTA NPs for targeted delivery of glyburide to
the ischemic brain in Aim 1, and to evaluate glyburide-loaded ARSTA NPs for treating ischemic stroke and the
PET imaging approach for non-invasively monitoring post-stroke functional recovery in Aim 2. The success of
this project will result in a new paradigm for treating ischemic stroke and for non-invasively monitoring post-
stroke functional recovery, which can be translated into clinical applications to improve clinical mana...

## Key facts

- **NIH application ID:** 10409778
- **Project number:** 5R01NS110721-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kevin Navin Sheth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,550
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409778

## Citation

> US National Institutes of Health, RePORTER application 10409778, Improved glyburide therapy via acid- triggered release functional nanoparticles and therapeutic imaging (5R01NS110721-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409778. Licensed CC0.

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