LIPOSOMES FOR TARGETING THERAPEUTICS TO THE LIVER

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This proposal describes our plans to develop an effective delivery system to target therapeutic agents to the injured liver. To accomplish this long-term objective, liposome technology will be developed and refined, and used in designing therapeutic strategies for different types of liver disease. Specific Aims: 1) to delineate the biodistribution of vitamin E-containing liposomes and to determine the mechanisms by which they inhibit acute liver injury, including studies, of NF-kappab activity; 2) to design variations in the phospholipid bilayer and in the contents of liposomes in order to improve the treatment of hepatic injury, including the ischemia/reperfusion injury of liver transplantation; and 3) to employ liposomes that contains inhibitors of cytokines plus antioxidants in the therapy of chronic liver disease. Methods: Indium labeling prior to liver perfusion and hepatic cell isolation will be employed to determine the biodistribution of the liposomes. The mechanisms by which the vitamin E-containing liposomes inhibit acute injury will be elucidated by Northern blot analysis of cytokines, by electron spin resonance analysis of oxygen radical formation, and by gel retardation assays, antisense oligoncleotide analysis, and transdominant mutation studies of NF-kappaB action. Variations in size, lipid composition, and therapeutic contents will be made in liposomes in an attempt to enhance their therapeutic potential. An antibody to transforming growth factor-Beta1 or an interleukin-1 receptor antagonist will be added to liposomes in an attempt to inhibit hepatic fibrosis in vivo. Health Relatedness: The successful design and use of liposomes lends itself to a wide range of possible therapeutic effect,s including: treatment of acute and chronic liver disease, preservation of donor livers in the peritransplant period, and the prophylactic rescue of the liver from the effects of toxic therapeutic drugs.