Development Of Magnetic Resonance Contrast Agents

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Abstract

STAR BURST Dendrimers (D), and Ultra Small Iron Oxide Particles (USPIO) were developed as cellular tags in molecular imaging. A series of high generation (G) dendrimers (G =5, 7, 9, 10) were conjugated to DOTA and Gadolinium (III) ion was added to the 1/T1 and 1/T2 NMR dispersion profile for generations 5 through 10 dendrimer DOTA complexes. There is an increase in proton relaxation enhancement effect (PRE) from G 5 through G 7 and then leveling off at generations 9 and 10. Bio-distribution studies in rodents using radiolabled gadolinium 153 chelated to the DOTA- dendrimer complex reveals dose dependent effect for blood half life and tissue distribution. Cellular labeling was accomplished by incubating G9DOTA-Gd with cells in culture with Magnetic resonance imaging of the cells along with fluoresces studies indicating that G9DOTA-Gd was in the cytoplasm of cells. Long term stability and cell viability studies are being planned in order to determine which generation of DOTA-Gd should be used as the basis for specific labeling to target receptors or for drug delivery. Magnetodendrimers (MD) are iron oxide particles coated with Dendrimers. MD are a T2 star shortening susceptibility contrast agent and the are more efficient at shortening the T2 relaxation times of solution compared to other iron oxide based agents. The MD also are able to be used as molecular label since the dendrimers are used as transfection agents and therefore the MD can easily be incorporated into the cytoplasm of various cell cultures including malignancy and stem cells by simple incubation. MD has been used to magnetically label adult neural stem cells (NSC) and mesenchymal stem cells (MSC). Both NSC and MSC incorporated the MD and were clearly visible on MR imaging at 1.5 Tesla at a level of 10e6 cells. MD labeled NSC and MSC differentiated normally along appropriate cells lines. In addition, MD labeled stem cells was still viable and dividing after 10 days after labeling. MRI demonstrated that mouse embryonic stem cells labeled with MD were visualized when in transplanted into a spinal cord crush injury model.