Macromolecular agents composed of either serum albumins or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size. This is attributed to the flexibility and segmental motions within the polymer chain. To obviate this deficiency, a new class of MRI contrast agents has been developed based upon the polyamidoamine form of Starburst dendrimers wherein the terminal amines are modified with chelating agents and then gadolinium complexes are formed. Such constructs have been shown to possess a molar relaxivity up to 6 times that of the simple Gd-DTPA currently employed in the clinic, and better than twice that of other macromolecular agents. As we have been able to demonstrate excellent conventional MR imaging and 3D time of flight MR angiograms, studies have been expanded to thoroughly explore the utility of these agents and to determine the effects of dendrimer size (clearance and localization), the number of gadolinium complexes included within the construct (relaxivity and effects of charge), and toxicity of this class of agent. A preliminary work has been performed in rodent models, the above studies are planned to proceed in canine model systems. Additionally, a CRADA has been secured for this investigation to assure a supply of the dendrimers as well as to maintain their consistency and purity. Preliminary experiments have demonstrated the chelated Bi(III) bound to dendrimers possessed greater contrast on a molar basis when employed as CT contrast agents when compared to the iodine based agents currently used in the clinic. To further investigate this use of dendrimers, studies have been initiated to compare the use of iodine-albumin based CT agents versus iodine-dendrimer CT contrast agents versus Chelated Bi(III)-dendrimer based contrast agents.
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