Multifunctional Liposomes Co-encapsulating Epigallocatechin-3-gallate (EGCG) and miRNA for Atherosclerosis Lesion Elimination

Atherosclerosis is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation as well as lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect by a single therapeutic method is limited. Combination of the two strategies could for one thing prevent lipid accumulation cause by inflammation and oxidative stress, for another thing promote lipid efflux from atherosclerotic plaque, to normalize arteries maximumly. Hence, a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate(EGCG) as well as a lipid-efflux promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide an effective protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28±2.28 nm characterized by DLS), making it easier to target to AS lesions which had a smaller vascular endothelial spaces. After internalized into cellular efficiently, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1β and MCP-1), which is due to the effect of EGCG. Besides, the lipid-efflux promoting protein ABCA1 was up-regulated when treated with lip@EGCG/miR-223. By the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which is a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in heart and aorta to that in kidney was significantly increased when compared with free drugs (the ratio was 6.27% for free miR-223 treated group, and was increased to 66.10% for lip@EGCG/miR-223 treated group.). By decreasing inflammation level and lipid accumulation, the arterial vessels in AS were normalized with less macrophages and micro-angiogenesis when treated with lip@EGCG/miR-223. Overall, this study demonstrates lip@EGCG/miR-223 can be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory and lipid-efflux promoting effects, which provides a novel strategy for safe and efficient management of atherosclerosis.