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

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.

Grant Number: 5R01EB027223-08
NIH Institute/Center: NIH
Principal Investigator: Hong Chen