Monitoring of Ultrasound-Mediated Gas Delivery by Hyperpolarized Xenon Gas MRI

About This Grant

ABSTRACT There is currently no imaging tool capable of visualizing gas diffusion from the bloodstream into tissue in distal organs. This critical gap limits not only our understanding of fundamental gas exchange physiology—such as vascular permeability, interstitial resistance, and gas tissue uptake—but also our ability to optimize a wide range of emerging ultrasound-based therapeutic strategies, including barrier modulation (e.g., blood–brain barrier opening), neuromodulation, and the targeted delivery of drugs, genes, and gases. The latter is a promising therapeutic strategy for conditions such as cancer, stroke, and traumatic brain injury, with gases like O2, and xenon shown to modulate cellular metabolism and enhance cancer and stroke treatment efficacy. Ultrasound, particularly focused ultrasound, plays a central role in these therapies by enabling localized gas release from microbubble carriers, thereby minimizing off-target effects. However, no imaging tool currently exists that can visualize or quantify the distribution and compartmentalization of the gas following its ultrasound-triggered release. The long-term goal of this project is to develop and validate a magnetic resonance (MR) imaging tool capable of real-time monitoring and quantification of gas release and diffusion from the vasculature into tissue parenchyma after microbubble disruption. To achieve this goal, we propose using microbubbles filled with hyperpolarized xenon-129 (HPXe), an MR-visible gas with a diffusivity in tissues similar to oxygen and with a unique chemical shift that enables compartment-specific tracking of the gas across blood, interstitial, and tissue spaces. In Aim 1, we will synthesize and characterize HPXe-filled microbubbles, optimizing their xenon retention, gas-carrying capacity, and MR relaxation properties. In Aim 2, we will employ real-time MR imaging and spectroscopy to monitor and quantify HPXe release and diffusion following focused ultrasound-mediated microbubble disruption, with particular emphasis on measuring gas delivery to and distribution within distinct tissue compartments. At the end of this project, we will have a novel MR imaging tool capable of directly measuring gas diffusion from the vasculature into tissues with both spatial and temporal resolution. Although designed to optimize ultrasound-mediated gas delivery protocols, by enabling real-time assessment of tissue permeability this tool has broader relevance across a broader range of ultrasound-based therapies. Furthermore, this tool might offer a more efficient strategy for delivering HPXe gas to distal organs and tissues, expanding the utility of emerging HPXe MRI techniques beyond pulmonary applications.