Doctor of Philosophy
Paula J. Foster
Introduction: This thesis aims to advance magnetic resonance imaging (MRI) for imaging cellular therapeutics. Traditional, proton-based, MRI provides detailed anatomical images, particularly of soft tissue. However, in order to obtain information at a cellular level specialized imaging agents are required to detect the cells of interest. Perfluorocarbons containing non-radioactive fluorine-19 (19F) are both biologically safe and MR sensitive. Methods: Pre-clinical 19F-MRI was implemented on a Varian 9.4T MRI scanner, using a dual 19F/1H-tuned birdcage volume coil. Mesenchymal stromal cells (MSC) were pre-labeled with a commercial, FDA approved 19F-perfluorocarbon emulsion, then implanted intramuscularly into the mouse hindlimb. To track the inflammation resulting from transplantation, a dual-agent cellular MRI technique was developed. This technique utilizes 19F to track MSC and superparamagnetic iron oxide nanoparticles (SPIO) to image macrophages, through the presence of signal quenching. A clinical imaging protocol was developed to translate 19F-MRI on a 3T GE MR750 scanner with a dual 19F/1H-tuned surface coil. Peripheral blood mononuclear cells (PBMC) were labeled with a FDA-approved 19F-agent and injected into a ham shank phantom for protocol optimization. Results: The balanced steady-state free precession pulse sequence was chosen for all studies due to the high signal-to-noise per unit time. Image acquisition was optimized for 19F detection sensitivity, accuracy of quantification, and compatibility with isoflurane. In vivo quantification of MSC on the day of implantation was in strong agreement with the expected number of cells. The change in 19F-signal was quantified over time and compared between two murine transplantation models. When iron oxide was administered i.v., the migration of immune cells could be tracked to the injection site. The presence of SPIO decreased both the 1H and 19F signal, indicating that transplant rejection was occurring. On a clinical system, as few as 4x106 PBMC could be imaged following both surface and subcutaneous injection. The minimum number of detectable cells was strongly influenced by intracellular 19F uptake. Conclusions: 19F-MRI is a promising tool for imaging cellular therapeutics. By pre-labeling cells of interest, they can be localized and the change in signal can be quantified over time. The technique shows promise for both pre-clinical and clinical applications.
Gaudet, Jeffrey M., "Development and Optimization of 19F-MRI for Tracking Cellular Therapeutics" (2016). Electronic Thesis and Dissertation Repository. 4250.
Available for download on Saturday, April 01, 2017