LIPOSOMES FOR TARGETING THERAPEUTICS TO THE LIVER

本提案描述了我们制定有效交付的计划 系统将治疗剂靶向损伤的肝脏。 完成 这一长期目标，将开发脂质体技术， 完善，并用于设计不同类型的治疗策略， 肝脏疾病 具体目的：1）描述 含维生素E的脂质体，并确定 他们抑制急性肝损伤，包括研究，NF-κ B 活性; 2）设计磷脂双层和磷脂膜中的变化。 脂质体的含量，以改善肝硬化的治疗。 损伤，包括肝脏缺血/再灌注损伤 移植;以及3）使用含有以下抑制剂的脂质体： 细胞因子加抗氧化剂治疗慢性肝病 方法：采用肝灌注前铟标记法， 分离将被用来确定生物分布的 脂质体。 维生素E脂质体的作用机制 抑制急性损伤将通过北方印迹分析阐明， 细胞因子，氧自由基电子自旋共振分析 形成，并通过凝胶阻滞试验， 分析和NF-κ B作用的转显性突变研究。 大小、脂质组成和治疗内容物的变化将是可能的。 在脂质体中制备，以试图增强其治疗潜力。 转化生长因子-β 1或白细胞介素-1抗体 将受体拮抗剂加入到脂质体中 体内肝纤维化。 健康相关性：成功的设计和 脂质体的使用使其自身具有广泛的可能的治疗效果 效果包括：治疗急性和慢性肝病， 移植围手术期供体肝脏的保存， 预防性拯救肝脏免受毒性治疗药物的影响 毒品

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.