(555d) Lipid Nanoparticle Mediated Drug Delivery for Targeting Inflammation Site in Atherosclerosis

Atherosclerosis is an arterial disease that involves build-up of plaques composed of cholesterol and macrophages inside the walls. This process is associated with attachment of the low density lipoprotein (LDL) particles to the proteoglycan of endothelium at the site of infection. These LDL particles are highly susceptible to oxidation and further induce inflammation by increasing the leukocyte adhesiveness and permeability to the endothelium. This condition may lead to complications like myocardial infarction or cerebrovascular accident which are leading causes of death in the world. Targeted drug delivery using nanoparticles has several advantages over the traditional drug delivery method such as reduced dosage of drug, lesser side effects, decrease in cost of therapy and increased accumulation of drug within the target tissue. Liposomes are very biocompatible and highly tunable for specific applications. Thus they can be loaded with suitable drugs and can be efficiently used for targeting the inflammation site in atherosclerosis. In this project, we are developing a highly customizable lipid based nanoparticle drug delivery vehicle for targeting inflammation sites of atherosclerosis plaques. We have engineered lipid nanoparticles (LNPs) of various sizes, surface charges, and coating density of hydrophilic polymer using non-cationic lipid and cholesterol components. LNPs were characterized by both photon correlation spectroscopy to determine particle size distribution, hydrodynamic diameter, and polydispersity, and by zeta potential measurements to determine nanoparticle surface charge characteristics and to quantify colloidal stability. Our preliminary cell uptake studies using FITC tagged LNPs indicate the nanocarriers were internalized into the cytosol and provided confidence that we target endothelial and smooth muscle cells in the atherosclerotic environment. A comparative study is underway to determine the targeting efficiency of antibody tagged LNPs to endothelial and smooth muscle cells. We are investigating cellular response with optical microscopy, and probing biochemical changes using a novel 3D co-culture platform of endothelial cells and smooth muscle cells we have developed. Further, we will be testing Atorvastatin drug encapsulated particles in combating oxidative stress in endothelial and smooth muscle cells. The inhibitory effects on production of the proinflammatory cytokines were studied following the nanoparticle targeting experiments. A significant decrease in production of proinflammatory cytokines was observed when the cells were treated with drug loaded lipid nanoparticles. The future work of this research involves optimization of the process along with ex-vivo studies using the inflamed artery extracted from pig.