Abstract 3964: Nanoparticle-Mediated Monocyte-Selective Transfection of Dominant-Negative Monocyte Chemoattractant Protein-1 (MCP-1) Gene Inhibits Plaque Rupture in ApoE-Deficient Mice

Abstract

Preventing rupture of unstable plaque is the most effective strategy for acute coronary syndrome (ACS). Monocytes/macrophages play a key role in plaque destabilization and rupture. Monocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) play an essential role in regulating monocyte recruitment and activation. Blockade of the MCP-1/CCR2 pathway by nanoparticle (NP)-mediated monocyte-selective transfection of dominant-negative MCP-1 (7ND) gene inhibits plaque rupture. We prepared bioabsorbable PLGA NP (mean diameter = 200 nm). Intravenous administration of NP incorporated with 7ND gene (5 mcg plasmid/1 mg PLGA) resulted in incorporation of NP via phagocytosis and gene transfer into CD11b + circulating monocytes, and suppressed monocyte function. We then examined the effect of 7ND-NP on plaque rupture of brachiocephalic arteries in apoE-deficient mice fed with high-fat diet and infused with angiotensin II (Figure A ). At 20 weeks, animals were divided into no treatment group and those treated weekly with intravenously 7ND-NP or FITC-NP (Figure B ). FITC-NP was detected in macrophages of destabilized brachiocephalic arterial plaques, but not in those of stable aortic plaques. 7ND-NP did not affect the size of atheroma, but did reduce the occurrence of plaque rupture (Figure C ), macrophage infiltration, and tissue factor expression. Blockade of MCP-1/CCR2 pathway by NP-mediated monocyte-targeting gene transfer stabilized atheroma and prevented plaque rupture. This nanotechnology platform may be a less invasive therapeutic strategy for stabilizing rupture-prone plaques and thus preventing ACS.