Primary goals of this program are to synthesize and develop new gadolinium (Gd)-based macromolecular contrast media (MMCM) for magnetic resonance imaging (MRI), with a novel combination and arrangement of constituents chosen to achieve size monodispersity, blood pool retention, high dose efficiency, low immunogenic potential, high tolerance, complete and timely elimination from the body mostly through a renal route. The long-term objective is to identify one or more novel MMCM with characteristics strongly favoring translation to clinical practice for purposes of early cancer lesion detection, staging, and timely treatment evaluation in cancer patients. Central to the project will be the chemical synthesis of rationally-designed MMCM (12 in number chosen from 60 possibilities) initiated from a homogeneously-sized polyethyleneglycol (PEG) core having dendritic polylysine """"""""amplifiers"""""""" at both termini, to which amplifiers will be bound multiple highly-stable gadolinium (Gd)-based contrast enhancing molecules. Through comparison studies, effects of MMCM structural variables (PEG size, generation of dendritic polylysine, type of signal enhancing group/Gd chelate substituent) on their chemical, physical, biological and imaging properties will be defined. These properties will include: Gd content, chemical conjugation efficiency, solubility, osmolality, viscosity, stability, longitudinal relaxivity in water and plasma, hydrodynamic size, blood half-life, volume of distribution, whole body clearance, organ-specific biodistribution, imaging-assayed biological endpoints (fractional blood volume and microvessel leakiness) in a human breast cancer xenograft model compared to normal tissues (liver and muscle). The best MMCM will be evaluated in an MRI study for its potential to characterize and differentiate tumors of varying malignancy. Compared to previously described MMCM, the novel diagnostic MRI enhancing drugs to be developed in this project should find wide clinical utility in MRI because of their ability to better define the individual characteristics of tumors, to better differentiate benign from malignant lesions, and to better monitor cancer responses to treatment.
