# Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $53,994

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a devastating, progressive, neurodegenerative disease that affects millions of
Americans, yet there is no cure, and there are very limited treatment options. Failure of otherwise promising
drugs for AD may be due, in part, to poor penetration into the brain and/or large systemic dose requirements to
achieve therapeutic brain concentrations, resulting in off-target effects. To address blood brain barrier (BBB)
impenetrability, ultrasound-targeted microbubble cavitation (UTMC) is being explored as a new treatment
strategy for AD. In this approach, low intensity ultrasound is applied to intravenously injected ultrasound contrast
agents (microbubbles) as they traverse the microcirculation of the brain. UTMC causes transient endothelial
barrier hyperpermeability, allowing for site-specific delivery of therapeutics across the BBB. While UTMC shows
promise as a technique to increase BBB permeability, its underlying mechanisms are incompletely understood,
ultimately constraining clinical translation. My overarching goal is that UTMC directed to the brain offers an
approach to enhance drug delivery across the BBB for treatment of AD. To facilitate clinical translation of this
platform, my proposal will determine mechanisms mediating UTMC-induced BBB hyperpermeability and utilize
UTMC for delivering therapeutics directed at Ab plaques in vivo in the following Aims: (1) To identify
mechanisms by which UTMC causes transient BBB hyperpermeability. UTMC applied to umbilical vein
endothelial cells in vitro has been shown to change cytoskeletal dynamics, leading to inter-endothelial cell gaps,
which can increase paracellular permeability, and was associated with Ca2+ influx into cells in contact with, and
remote from, cavitating microbubbles. Extending these findings to the BBB, I hypothesize that UTMC-mediated
Ca2+ influx disrupts tight and adherens junctions between brain microvascular endothelial cells, and may also
lead to Ca2+-mediated changes in adjacent astrocytes. A contact co-culture in vitro transwell model of the BBB
will be used to study changes in function and structure (confocal microscopy) of endothelial cells and astrocytes
after UTMC. (2) To determine whether UTMC-mediated BBB opening, in combination with drug therapy,
will lower Ab plaque burden and improve the therapeutic window. I hypothesize that UTMC-mediated BBB
opening will decrease the dose required for a specific drug designed to lower Ab plaque deposition, thereby
minimizing off-target effects. The drug will be administered, and UTMC will be applied to the brain in a mouse
model of AD. Brain Ab plaques will be quantified by serial brain PET imaging. I have assembled an exceptional
multidisciplinary team of mentors and collaborators, along with specific coursework and seminars, to acquire the
necessary content expertise in AD biology, ultrasound theranostics, imaging, and murine AD models. Through
meetings with my mentors and conducti...

## Key facts

- **NIH application ID:** 10862637
- **Project number:** 5F30AG077800-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Grace Conway
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,994
- **Award type:** 5
- **Project period:** 2022-07-27 → 2027-07-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862637

## Citation

> US National Institutes of Health, RePORTER application 10862637, Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain (5F30AG077800-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10862637. Licensed CC0.

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