SUMMARY

Vascular and interstitial barriers constitute major obstacles to the systemic delivery of therapeutics into brain tumors. Microbubble-enhanced focused ultrasound (FUS) is a promising technology to overcome these rate-limiting factors to clinically effective drug delivery in intracranial malignancies. Despite progress, the effective translation of this technology to the clinics is hampered by the limited understanding on FUS-mediated mass transport in the brain tumor microenvironment. This research is focused on gaining fundamental understanding of ultrasound-mediated neurovascular transport dynamics with the overarching goal to establish the principles for effective ultrasound-mediated drug delivery in brain tumors. More specifically, this work integrates mathematical modeling with quantitative imaging to establish a quantitative framework to examine the role of microbubble dynamics in alleviating vascular and interstitial barriers to drug delivery. Particular emphasis was put on the physicochemical properties of therapeutic molecules and how microbubble enhanced FUS can improve their transport in the brain tumor microenvironment. Collectively, the proposed formwork and fundamental investigations provided new insights on the neurovascular transport dynamics and led to novel FUS-drug combinations for improved drug delivery in brain tumors.