LIPOSOMAL CONTRAST AGENTS FOR MR IMAGING

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This application addresses the development of liposomal contrast agents for Magnetic Resonance Imaging (MRI) to improve the detection of liver and spleen metastases and to serve as a marker of tumor perfusion. Current diagnostic imaging techniques such as scintigraphy and computed tomography (CT) do not optimally detect hepatic or splenic lesions, particularly lymphoma. Water-soluble iodinated contrast agents have been used to improve the detection of malignancy by CT, but there are attendant problems due to rapid equilibration with the extravascular space and rapid excretion. To overcome this problem, liposomal iodinated contrast media, which target to the reticuloendothelial system have also been used for CT and have resulted in improved detection of malignancy, However, a limitation to their use had been the high toxic doses of lipid needed to deliver sufficient iodine to provide contrast enhancement by CT. MRI contrast agents, most noticeably Gd-DTPA, provide contrast enhancement at concentrations at least ten-fold lower than CT contrast media, the attendant toxicity due to high doses of lipid should be reduced. Additionally, because liposomes may only exist from the circulation via fenestrated epithelia, it may be expected that the liposomal contrast agent will serve as a better indicator of tumor vascularity and hence perfusion than free Gd-DTPA, which may have consequences for directing therapy. Large unilamellar vesicles of 50 to 400 nm diameter will be prepared by a freeze-thaw extrusion procedure with various enapsulated contrast media including Gd-DTPA, Gd-DOTA and magnetite using a variety of lipid compositions. The vesicles will be characterized with respect to size, trapping efficiency, in vitro stability in saline, serum and on storage, in vitro relaxivity and clearance from circulation of rats. Imaging of normal and tumor-bearing rats will be done pre- and post-contrast and for rats with intrahepatic tumors, MRI images correlated with histological analysis. Biodistribution and toxicity testing will follow on appropriate liposomal systems.