The long term goal of this project is to develop magnetic resonance imaging (MRI) contrast agents that will improve breast cancer diagnosis and reduce the long term morbidity of breast cancer patients. A number of known cellular changes associated with cancer can effect the parameters that control the blood-to-tissue transport of a drug or contrast agent. Dynamic MR mammography (MRM) takes advantage of only one of these cellular changes associated with cancer: tumor secreted angiogenic factors. We propose to take advantage of other changes, tumor secreted vascular permeability factors, to improve detection, diagnosis, and/or treatment via the enhanced permeability and retention effect. The project has four specific aims. First we will determine the physiochemical properties that influence the efficacy of macromolecular MRI contrast agents prepared from Starburst Dendrimers, and second prepare macromolecular contrast agents with the optimal relativity, pharmacokinetics, and biological properties for both the passive and active targeting to breast tumors. The third is to develop extracellular fluid space agents with higher relaxivities and slightly prolonged half-lives for improving dynamic contrast enhanced MRM. The final specific aim is to determine the in vivo pharmacokinetics and biodistributions in healthy rats and those with chemically induced breast tumors. As part of this aim we will determine if breast tumors express an enhanced permeability and retention of dendrimer-based agents, compared with normal tissue, and the physicochemical properties that influence this uptake. We will attach 2-(4-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid, and 2-(4'-isothiocyanatobenzyl)- 1,4,7,10-tetraazacyclodoecane-N, N', N"""""""", N'""""""""-tetraacetic acid to dendrimers differing in size, interior density, and the density of the surface groups. Measurements of the nuclear magnetic relaxation dispersion profiles of the Gd(III)-complexes, the electron paramagnetic resonance studies of the VO(II)-complexes, the electron paramagnetic relaxation dispersion profiles of Gd(III)-complexes, and O nuclear magnetic resonance studies of Gd(III)- complexes in 5% H217O will provide the data on how tr tau tau and tv influence the relaxtivity of these agents. Induction of the breast tumors will proceed with the injection of high doses, 180 mg/kg, of N-ethyl-N- nitrosourea into 30 d old female Sprague Dawley rats. In vivo results on the pharmacokinetics and biodistribution will be obtained by the injection of tracer amounts of 155 Gd(III) bound to these dendrimer-polychelates. Contrast enhancement kinetics will be obtained on the tumors at 1.5 and 4.7T. This information will enable the rational design of effective passive or antigen directed MR contrast agents for the diagnosis of breast cancer and other pathologies.
