UNC-CH Physics and Astronomy Master’s Presentation

Christian McHugh

“Gas microbubbles as a 129Xe carrier and as a contrast agent for MRI”

Hyperpolarized (HP) 129Xe is an inert noble gas that has been widely used in biomedical applications of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) because of its extraordinary sensitivity to different molecular environments. Chemical exchange saturation transfer (CEST) is an MR technique that can increase sensitivity by two to three orders of magnitude. CEST can be combined with HP 129Xe (hyperCEST), and it can be used to reveal signals from low-concentration sources that could not be observed directly with HP 129Xe NMR spectroscopy. When 129Xe is in chemical exchange, magnetization can be transferred between environments. By applying radiofrequency pulses, the dilute solute signal can be saturated, and consequently, the dominant solvent signal would become attenuated, thus leading to the indirect detection of the solute. HyperCEST has been demonstrated in vitro with nanoemulsions, gas vesicles, cryptophane-A, as well as cucurbit[6]uril, which has been the only carrier to have been tested in vivo. Here, we explore the use of gaseous microbubbles as a possible carrier for HP 129Xe in vivo, and as a dual contrast agent for MR and ultrasound experiments. Microbubbles have long been used as an ultrasound vascular contrast agent, and they also have been used for targeted delivery of drugs and oxygen in vivo. In order to assess the feasibility of using gas microbubbles as an MR contrast agent, experiments using high resolution NMR spectroscopy and hyperCEST were performed in vitro in a suspension of microbubbles. Monte Carlo simulations were then used to simulate chemical exchange and the resulting NMR spectra. Our experimental results show that, while microbubbles at the dosage typically used for in vivo ultrasound experiments cannot be directly detected by HP 129Xe NMR, they can produce a strong hyperCEST effect. The Monte Carlo simulation under the same experimental conditions used in our in vitro experiment replicated experimental results. Microbubble dissolution simulations showed that, under the experimental conditions used in our in vitro experiments, the volume of the microbubbles increases before stabilizing, but the amount of growth depends on the degree of saturation of the dissolved gases. These data are encouraging and open the door for the use microbubbles as an in vivo dual contrast agent for MRI and ultrasound. The goal of this work will be to fully characterize microbubbles as an in vitro hyperCEST agent and demonstrate their utility for in vivo MRI.