The primary goal of this research program is the development of contrast agents for vascular blood pool imaging with reduced leakage of the contrast agent through the vascular walls. The project intends to accomplish this objective by developing gadolinium (Gd) contrast agents with ligands derivatized with a polymeric chain to increase the hydrodynamic volume of the contrast agent. The project will focus on using polymers that have a documented history of blood contact use. In this project carbohydrate polymers will be fractionated into well-defined narrow molecular weight distribution samples. Each sample will be characterized for key physical properties; molecular weight and hydrodynamic dimensions by light scattering and intrinsic viscosity measurements. Diethylenetriaminepentaacetic acid (DTPA) will be the complexing agent for gadolinium (Gd), Chemistry will be developed to covalently attach DTPA to the carbohydrate polymer through a relatively labile linkage. DTPA conjugation efficiencies and the impact of DTPA conjugation on key polymer physical properties will be determined. Additionally, the effect of attaching pure DTPA versus Gd-DTPA complexes on polymer-conjugation efficiency will be assessed. The hydrolytic degradation of HA-DTPA-Gd complexes will be assessed in vitro. The R1 and R2 relaxation rates of the new contrast agents will be determined using inversion recovery and spin echo methods. R1 relaxation rates will be determined for a range of both B0 field strength and a range of polymer-complex molecular weights. The R2 relaxation rates for selected Gd-ligand-polymer complexes with optimal imaging performance will be measured to determine if they are adequately slow to avoid significant spin dephasing effects. Molecular modeling will estimate the impact of the DTPA ligand and DTPA-GD complex on the physical dimensions of the polymers in solution. The knowledge gained from this technology development program will allow progression to the necessary in vivo animal and clinical testing required for regulatory approval and commercialization.
