Study of the Multifunctional Magnetic Nanoparticle for Atherosclerosis Targeting, Distribution Imaging and Anti-Atherosclerosis Drug Delivery

Atherosclerosis can be seen in cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus and kidney disease and is the most common cause of death in Taiwan and in the world, higher than cancer. It is the main disease to cause myocardial infarction, ischemic stroke, and limb necrosis. The key factor of causing atherosclerosis is oxidized low-density lipoprotein (LDL) accumulated in the intima media of blood vessels. The oxidized LDL resulted in vascular endothelial cell dysfunction and a series of inflammatory reactions contributing to atherosclerosis. Presently, there is limited method to early diagnose the accumulated location and distribution of atherosclerosis plaque. Although oral statin can effectively reduce the cholesterol levels and cause regression of atherosclerosis, it has some side effects such as impaired liver function and muscle pain. Iron oxidative nanoparticles have magnetism, and can be lead to the lesion site by external magnetic field. Therefore, it can be used as drug carrier and MRI contrast agent to treat and diagnose disease. The structure of the temperature-sensitive drug/nanoparticle micelles material can be changed at its low critical solution temperature, so we can control the drug release by modifying the external temperature. The purposes of this project are (1) to establish an in vivo photochemical-induced carotid artery thrombosis animal model; (2) to investigate the feasibility of targeting atherosclerosis by magnetic nanoparticles and detecting the distribution of atherosclerosis by MR imaging; (3) to evaluate the feasibility of drug/nanoparticle compounds encapsulated in micelles which can be lead to the lesion site by an external magnetic field as a drug delivery system. First, we will establish a thrombosis animal model by implanting LED on rat common carotid artery and inducing the light source to stimulate the photosensitizer for generation of singlet oxygen to damage the endothelial cell. Second, we will synthesize vascular endothelial cell adhesion molecule conjugated magnetic nanoparticles for targeting atherosclerosis actively and also acting as a contract agent for MRI. When the particles injected into the body, it will target directly to atherosclerotic lesion and provide a method for early diagnosis of atherosclerotic lesion by MRI. Third, we will produce antibody conjugated thermo-responsive polymeric drug carrier. The magnetic nanoparticles and hesperetin or statin will be entrapped into the carrier to form magnetic thermo-responsive drug loaded nanocomplexes. When the nanocomplexes are injected into the body, it will be guided to the atherosclerotic lesion by external magnetic field. By using a high radio frequency induced heating machine to heat the temperature to about 42°C, the drug will be released at the atherosclerotic lesion for treatment. To evaluate the feasibility of this study, we will use immunohistochemical analysis and serial MRI imaging for localization of thrombus formation and for detecting the effectiveness of drug treatment. In addition, we will study the effectiveness and safety of nanoparticle compound by evaluating the amount of drug encapsulation, the amount of drug release, and the biocompatibility and cell compatibility of the nanocomplexes.

Project ID:PC10101-1441
External Project ID:NSC99-2628-B182-027-MY3