Advancing non-invasive imaging techniques for tracking cellular therapeutics in vivo

Olivia C. Sehl, University of Western Ontario

Abstract

Cell therapies, including mesenchymal stem cells (MSC) and regulatory T cells (Tregs) have shown potent and long-lasting therapeutic benefit in several disease applications. Unfortunately, the effectiveness of these therapies is variable and following administration, it is largely unknown where therapeutic cells traffic and how many persist over time. This thesis aims to advance and compare iron- and fluorine-19 (¹⁹F)-based magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) for therapeutic cell tracking.

First, we developed a trimodal imaging approach to study MSC fate in vivo. In a mouse model, iron-labeled MSC were detected by MRI and MPI, and each modality provided unique information on MSC quantity (MPI) and anatomical localization (MPI) in vivo. In these same mice, ¹⁹F MRI was used to assess inflammatory influx to the injection site after intravenous administration of ¹⁹F-perfluorocarbon agent. Next, the sensitivity and cellular detection limits of ¹⁹F MRI were compared to MPI. MPI showed superior sensitivity, as fewer iron-labeled cells could be detected with MPI (4000 MSCs) compared to ¹⁹F-labeled cells with ¹⁹F MRI (256,000 MSCs) using the same imaging time. For cell tracking, estimation of cell number is critical, so we sought to develop and test four methods to select and quantify MPI signal from an image. In this project, it is demonstrated that while MPI signal scales directly linear with the amount of iron present, 3 users showed more accurate and precise quantification when they considered a larger area for each signal in the image. In the final chapter, we demonstrate a clinically-applicable ¹⁹F MRI imaging approach for tracking in vivo biodistribution of Tregs. This approach involved a dual tuned MRI surface coil with sensitive bSSFP imaging sequence on a 3 Tesla human MRI. The ability to non-invasively quantify and image injected cells in vivo with high sensitivity will improve the efficacy and safety of cell therapy.