Conway, Grace Elizabeth
(2024)
Ultrasound-targeted microbubble cavitation facilitates drug delivery across the blood-brain barrier.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of Americans. To date, there is no cure for AD, and the treatment options are limited. One of the challenges in developing new treatments for AD and other neurological disorders is the restrictive blood-brain barrier (BBB). The BBB protects the central nervous system but as a consequence also limits the permeability of most drugs. Therefore, new methods are needed to open the BBB safely and transiently to allow therapeutics to enter the brain. One technique that is being explored to reversibly open the BBB is ultrasound-targeted microbubble cavitation (UTMC). In this approach, external ultrasound is applied to intravenously injected contrast agents (microbubbles [MBs]) as they transit through the microcirculation of target tissue. MBs are gas-filled lipid microspheres which cavitate under ultrasound exposure, causing shear stress to the microvascular endothelium, which temporarily increases endothelial barrier permeability. When UTMC is applied to the brain, it induces transient BBB hyperpermeability. This dissertation studies UTMC for BBB opening in an in vitro model of the BBB and the 5XFAD mouse model, an in vivo system that recapitulates aspects of AD pathology. We develop a contact co-culture transwell model of the BBB to study the mechanisms of UTMC-induced BBB hyperpermeability. We show that UTMC increases transcellular and paracellular permeability. Moreover, UTMC-induced BBB hyperpermeability is calcium-dependent and occurs, at least in part, due to a Ras homolog gene family, member A (RhoA)-dependent mechanism. In our in vivo studies, we develop a protocol for opening the BBB in the right hemisphere of 5XFAD mice. UTMC concentrates LY2886721 (LY, a beta-site amyloid precursor protein cleaving enzyme 1 [BACE1] inhibitor) in the brain and decreases beta-amyloid levels compared to non-insonified brain. Taken together, these research projects provide mechanistic insight into UTMC-mediated BBB opening and use this drug delivery strategy to increase the efficacy of a small molecule developed for the treatment of AD. Ultimately, these findings should help facilitate the translation of UTMC-mediated BBB opening to the clinic.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
29 May 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
25 June 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
215 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ultrasound, microbubble, blood-brain barrier |
| Date Deposited: |
14 Oct 2024 14:29 |
| Last Modified: |
14 Oct 2024 14:29 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46627 |
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