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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.

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro systems, (e) evaluated the impact radiation therapy has on blood-brain barrier integrity in normal and pathological brain, and (f) provided a discussion on the mathematical models used to evaluate blood-brain barrier pharmacokinetics in both normal and pathophysiological conditions.