Abstract 13: Development of Functionalized Nanoparticle Platform for Reducing Atherosclerosis
No therapy is currently available to enhance the removal of cholesteryl esters (CE) from existing atherosclerotic plaques to facilitate plaque regression. Such a strategy is crucial to reduce the burden of existing disease in addition to preventing the progression targeted by the current therapeutics. Earlier studies from our laboratory have established the anti-atherogenic role of CE hydrolase (CEH)-mediated CE mobilization from macrophage foam cells and final elimination of cholesterol by the liver. While transgenic expression of CEH was used in pre-clinical animal studies, increase in human CEH by activation of Liver-X-receptor (LXR) was also established. Increased lipogenesis induced by LXR ligands precludes their use. The current studies focused on the development of mannose-functionalized dendrimer nanoparticles (DNPs) for the delivery of LXR ligand (TO901317) or CEH expression vector to plaque associated macrophage foam cells. As shown in the Figure, mannose functionalization restricts the uptake of DNPs to macrophages and minimal uptake was seen with primary hepatocytes (A). Western diet fed LDLR-/- mice were injected (iv) with DNPs and tissues harvested 48 later to monitor gene expression by QPCR. DNP-mediated delivery of LXR ligand (DNP-LXR) increased the target gene expression (ABCA1, ABCG1) in plaque associated macrophage foam cells in the aortic arch with no effects on target gene expression in the liver (B) demonstrating the specific delivery of LXR ligand. Comparable increase in CEH activity was seen following exposure of macrophages to free LXR ligand and DNP-delivered LXR ligand (C) and DNP-mediated delivery of CEH expression vectors driven either by CMV or SR-A promoter induced dramatic increase in CEH expression (D). These data establish functionalized DNP as a suitable platform for specific and functional delivery of drugs or DNA to plaque associated macrophages to enhance processes involved in cholesterol removal and plaque regression.
Author Disclosures: S. Ghosh: None. J. Wang: None. J. Bie: None. Q. Yuan: None. O. Zolotarskaya: None. H. Yang: None.
- © 2015 by American Heart Association, Inc.