Intracellular MRI Contrast Agents for High Magnetic Fields

MRI magnets are constantly evolving with technologies for higher fields, improving sensitivity and increasing resolution. Major achievements in MRI magnet technology in recent years include the successful construction of a 21.1-T, 900-MHz magnet system built at the National High Magnetic Field Laboratory and the soon to be completed series connected hybrid system capable of reaching 36 T. However, contrast agents used in MRI today are mostly based on iron oxides and gadolinium, which both have limited high field properties. A full assessment of the high field properties of existing contrast agents as well as alternate paramagnetic options, such as dysprosium, is required to better utilize these compounds for biomedical applications. This dissertation involves the evaluation of existing intracellular MRI contrast agents at high magnetic fields as well as the development of a novel bimodal contrast agent optimized for these high fields. The focus is on the performance of the agents with emphasis on cell labeling and tracking in biological systems. This dissertation will provide background on contrast agents and their relaxation properties as well as the cell lines and animal models used. An assessment of commercially available iron oxide particles as intracellular contrast agents was performed utilizing a rat microglia cell line. Internalized iron particles were imaged in tissue mimicking phantom at two high magnetic fields and evaluated based on contrast generated with increasing iron dose or cell concentration. Results show that iron oxide has limited benefit at higher magnetic fields mainly due to saturation below 1 T. The labeling of human mesenchymal stem cells (hMSC) with the same super-paramagnetic iron oxide nanoparticles was performed to evaluate uptake, viability, proliferation and differentiation for in vivo implantation. To improve upon commercial agents, a novel bimodal contrast agent based on dysprosium and quantum dots was fabricated and analyzed. These nanoparticles were developed using the quantum dot not only as a fluorescent agent, imparting bimodal imaging capabilities, but also as a platform for increasing the number of Dy3+ that can be conjugated and delivered on a single nanoparticle to increase relaxivity. These particles have at least comparable T2 contrast to existing iron oxide agents, and the potential for increased improvement with advent of fields above 21.1 T (Rosenberg et al. Magn. Reson. Med., 64 (3) 2010). Bimodal fluorescent particles based on iron oxide were applied to in vivo animal models of traumatic brain injury for cellular tracking of an endogenous cell population, the neural progenitor cells of the subventricular zone, as well as exogenous, pre-labeled hMSCs. Data suggests increase labeling or migration of endogenous cell populations while exogenous labeled cells track to site of neuronal injury following an intra-arterial injection into the carotids. The impacts of these findings are discussed with respect to high field cell tracking in neurodegenerative processes.