ENHANCED MRI FOR TUMOR VASCULAR INTEGRITY AND PERFUSION

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Contrast enhancing pharmaceuticals can improve the diagnostic benefit of proton magnetic resonance imaging (MRI) by increasing contrast differences between normal and abnormal tissues and by providing functional information as shown in laboratory experiments and human trials. The general objectives of this proposal are to evaluate in comparison tests both a FDA-approved MRI contrast agent (Gd-DTPA dimeglumine) and several novel compounds with potential for improved characterization of tumor composition and function. Specific tumor characteristics to be assessed include differences between viable and necrotic tumor components, feeding vascularity, blood volume, relative perfusion, capillary permeability, and changes induced by therapy. The design of the proposed research includes animal imaging studies to define the efficacy of a series of paramagnetic gadolinium-chelate derivatives ranging in molecular weights from 550 to 92,000 Daltons. The macromolecular compounds are designed to produce unusually high dose effectiveness and to serve as probes of abnormal capillary permeability. Candidate drugs will also be tested and compared for properties of dose effectiveness, stability, osmolality, metabolism and diagnostic effectiveness in hopes of defining one or more clinically useful drug. Enhancement characteristics in carcinoma, sarcoma, and lymphoma models will be compared to normal tissues and inflammatory lesions. The utility of contrast enhanced imaging for tumor treatment response will be assessed in tumor-bearing animals receiving either radiation or chemotherapy. The proposed investigations require the combined disciplines of diagnostic imagining, synthetic chemistry, NMR physics, pharmacology, nuclear imagining, and radiation oncology. Specific compounds to be compared include: a) Gd-DTPA dimeglumine, b) Gd-DTPA-N- methylpropandiol, a novel low-osmolar agent, c) albumin-(Gd-DTPA d) proteinoid-(Gd-DTPA, and 3) (Gd-DTPA)-labeled polysaccarhides. The long term goal is to develop new imaging strategies and new agents for the contrast enhanced MRI that will improve the diagnostic evaluation of tumors and tumor therapies.