Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)

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PROJECT SUMMARY/ABSTRACT There is a long-standing unmet need for innovative brain drug delivery strategies to solve clinical challenges in the treatment of brain tumors and other central nervous system diseases, which are major public health problems in the United States. Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) can address this unmet need by achieving noninvasive, spatially targeted, and efficient drug delivery to diseased brain sites without jeopardizing healthy brain regions and other organs. FUSIN utilizes the intranasal route for direct nose-to-brain drug administration, bypassing the BBB and minimizing systemic exposure. It also uses transcranial focused ultrasound (FUS) induced microbubble cavitation (i.e., volumetric expansion and contraction of the microbubble) to enhance the delivery of IN-administered agents to the FUS- targeted brain location. We have been supported by NIH/NIBIB (R01EB027223, 4/1/2019–1/31/2023) to develop FUSIN in mice. The objective of this renewal application is to establish the biophysical mechanism of FUSIN and obtain compelling large-animal data to support the clinical translation of FUSIN. Our objective will be achieved by completing the following three specific aims: Aim 1 will establish the biophysical mechanisms of FUSIN using mouse models; Aim 2 will optimize FUSIN for efficient and safe brain drug delivery in a large animal model (pigs); Aim 3 will demonstrate the clinical translation potential of FUSIN in a large animal disease model (pig glioblastoma model). This project is significant because FUSIN has the potential to radically advance the treatment of a broad spectrum of brain diseases by enhancing therapeutic agent delivery to diseased brain sites, substantially reducing systemic toxicity, and eliminating the need for invasive surgery. A multidisciplinary team with expertise in ultrasound engineering, cancer biology, radiochemistry, radiology, and neuro-oncology will advance FUSIN through the research phase and into future clinical trials. This study has three main innovations: (1) it proposes a novel mechanism for FUSIN, which is through microbubble cavitation-enhanced glymphatic transport of intranasal-administered agents; (2) it is the first to scale-up FUSIN from small to large animals; (3) the pig glioblastoma model provides a unique model that is crucial for obtaining unequivocal evidence in support of the clinical translation of FUSIN. The proposed research is expected to have a powerful impact on the research field of brain drug delivery. The outcomes of this project are expected to advance our knowledge of the biophysical mechanisms underlying microbubble-mediated drug transport in the brain, produce a unique platform technology for drug delivery in the brain of large animals, and gather large animal data needed to translate FUSIN into the clinic.