Development and Evaluation of Magnetic Resonance Contrast Agents

Clinical Center

Investigators

Linked publications & trials

Abstract

STAR BURST dendrimers (D) and ultra-small iron oxide particles (USPIOs) were developed as cellular tags in molecular imaging. A series of high generation (G) dendrimers (G=5, 7, 9, 10) was conjugated to 1,4,7,10-tetraazacyclododecane-N,N?,N",N"?-tetraacetate (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 (PRE) effect from G 5 through G 7, which levels off at generations 9 and 10. Biodistribution studies in rodents using radiolabeled 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 fluorescence studies indicating that G9DOTA-Gd was in the cytoplasm of cells. Adding transfection agents in solution with G9DOTA-Gd provided evidence for a molecular switch by altering the PRE properties by shielding other inner-sphere interaction of water with the last coordination site of gadolinium in the DOTA chelate. This served to "turn off" the PRE effects of MR contrast agent, and the switch could be turned on with a change in pH. Further work is planned to determine if the macromolecular contrast agent with a switch can be incorporated into cells and turned on by changing metabolic processes in the cell. A new class of iron-oxide-based contrast agents, in which the traditional dextran coating was replaced with dendrimers, are known as magnetodendrimers (MD). MD are a T2 star shortening susceptibility contrast agent that are more efficient at shortening the T2 relaxation times of solution compared with other iron-oxide-based agents. The MD also can be used as molecular label, as 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. Alteration in the PRE properties can be demonstrated, along with identification of iron oxide in cells, using Prussian blue staining on histology. Further work is planned to determine the duration that the MD labels will remain visible using in vivo MR imaging techniques.