Development of targeted delivery systems for early detection and genetically therapeutic intervention of cardiovascular disease.

摘要

Atherosclerosis is a primary cause of heart disease and stroke. It is known that early detection of atherosclerotic lesions would significantly reduce the risk. One of the objectives in this thesis is to evaluate a noninvasive radioimaging method for detecting early atherosclerotic plaques. A novel polyiodinated cholesterol analog, cholesterol 1,3-diiopanoate glyceryl ether (C2I), radiolabeled with 125I, was incorporated into acetylated low density lipoprotein (AcLDL) which is considered as an atherosclerotic plaque seeking carrier. 125I-C2I was also prepared as a chylomicron-like emulsion. 125I-C2I/AcLDL or 125I-C2I emulsion was intravenously injected into apoE/LDL receptor (LDLR) double knockout mice that serve as an atherosclerosis animal model. The ex vivo images of radioactivity accumulated in the aortas 24 hours postinjection were compared to the atherosclerotic lesions revealed by histological studies. It was found that both C2I/AcLDL and 125I-C2I emulsion resulted in accumulation of radioactivity at the site of early atherosclerotic lesions, and therefore may be useful for early detection of atherosclerosis.; The second part of this thesis focused on the development of a liver-targeting liposome vector for systemic gene therapy, with the objective of delivering mouse LDLR gene to the liver of the LDLR-knockout mouse, an animal model closely resembling human FH conditions. (Abstract shortened by UMI.)