Author ORCID Identifier

https://orcid.org/0000-0002-5799-0514

Semester

Fall

Date of Graduation

2022

Document Type

Thesis

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Paul Lockman

Committee Co-Chair

William Petros

Committee Member

Jeffrey Carpenter

Committee Member

Patrick Callery

Committee Member

Manish Ranjan

Abstract

Transcranial low-intensity focused ultrasound is a unique technology to modulate the integrity of tight endothelial junctions and transiently increase BBB/BTB permeability to enhance therapeutic delivery. Despite promising early studies, present literature lacks agreement on key experimental conditions, which restricts our knowledge and the technique's widespread translation. This dissertation first provides a critical review of the current gaps in knowledge regarding the universal use of LiFUS in preclinical and clinical use. We then identify key parameters for translational and predictable opening of the BBB using a 3T MRI coupled with a clinical device. Our investigation highlights that passive permeability of the BBB following LiFUS is correlated to microbubble and cavitation dose. We also observe a biphasic and size-dependent increase in BBB permeability. Next, we studied the application of the clinical LiFUS parameters to evaluate efficacy and survival of combinatorial chemotherapy in a preclinical model of breast cancer brain metastases. When LiFUS was combined with paclitaxel and Doxil, we saw an additive increase in therapeutic efficacy and slower tumor progression. Lastly we explored the time-dependent effect of LiFUS on brain physiology and identified inflammation-associated understudied areas for improving LiFUS assisted CNS therapy.

Embargo Reason

Publication Pending

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