LIPOSOMAL CONTRAST AGENTS FOR MR IMAGING

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.