Gas microbubbles have been widely used as ultrasound (US) vascular imaging agents and, more recently, for targeted delivery of drugs and gases in vivo. Their safety profile and their potential as molecular imaging probes make them ideal contrast agents also for MRI. Thus, considering the increase in US/MRI applications that could benefit from a dual-modality contrast agent, gas microbubbles present a promising alternative to gadolinium or iron-oxide based contrast agents. Previous detection of gas microbubbles by MRI has focused primarily on the reduction of the transverse relaxation time (T2 and T2*) of nearby water protons caused by magnetic susceptibility gradients generated at the gas–liquid interface. However, these susceptibility effects are relatively weak. As a result, the microbubble dosage required to obtain acceptable MR contrast is much higher than dosages typically used for clinical ultrasound imaging. We hypothesize that MR sensitivity to gas microbubbles can be enhanced significantly by using HyperCEST. HyperCEST combines Chemical Exchange Saturation Transfer (CEST) and hyperpolarized xenon-129 (HPXe) and can boost MR sensitivity by several orders of magnitude. This hypothesis is supported by recent studies showing hyperCEST detection of gas nanovescicles at picomolar concentrations. Compared to gas nanovescicles, microbubbles have increased xenon-host capacity, lower exchange rate, and a much narrower frequency distribution, thus are expected to saturate hyperCEST detection sensitivity. Additionally, we hypothesize that targeted delivery of gas microbubbles coupled with HPXe inhalation will enhance HPXe signal from distal organs, thereby enabling dissolved-phase xenon MR applications that capitalize on the relatively high solubility of this gas and its impressive sensitivity to its chemical environment. These two hypothesis will be tested through the following specific aims: 1. To characterize and optimize the physical and magnetic resonance properties of microbubbles as hyperCEST agents, in vitro and in vivo; 2. To quantify HPXe signal amplification obtained from US-guided targeted delivery of gas microbubbles. If successful, the proposed research will establish gas microbubbles as a safe and effective dual modality US/MR contrast agent that can easily be disseminated to the research community and transformed into a molecular imaging agent, ultimately resulting in clinical translation. Additionally, direct imaging of gas diffusion in tissues by HPXe after US-assisted targeted release of microbubbles, will enable direct monitoring of microbubbles delivery of biologically active gases and drugs.