4.8 Article

Amelioration of atherosclerotic inflammation and plaques via endothelial adrenoceptor-targeted eNOS gene delivery using redox-sensitive polymer bearing L-arginine

期刊

JOURNAL OF CONTROLLED RELEASE
卷 262, 期 -, 页码 72-86

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.07.019

关键词

Redox-sensitive polymeric nanoparticles; L-arginine; Targeted delivery; Endothelial nitric oxide synthase; Inflammation; Atherosclerosis

资金

  1. National Research Foundation of Korea [2014049587, 2015003019]
  2. Brain Korea 21 plus program [22A20130011095]

向作者/读者索取更多资源

Endothelial dysfunction combined with inflammation leads to atherosclerosis. Endothelium-specific delivery of therapeutic agents at the cellular level-specifically in vivo-is still a difficult task for proper management of atherosclerosis. We designed a redox-sensitive poly(oligo-L-arginine) (rsPOLA) playing dual roles as an endothelium alpha-2 adrenoceptors(alpha-2ARs)-targeted gene carrier and as a substrate for endothelial nitric oxide synthase (eNOS). Overexpression of alpha-2ARs on atherosclerotic endothelial cells was confirmed and the eNOS/rsPOLA nanoplexes following systemic injection demonstrated to 1) enhance eNOS gene delivery into endothelial cells via alpha-2ARs/L-arginine specific binding, 2) increase intracellular level of nitric oxide, 3) suppress inflammatory response in endothelium and finally 4) reduce atherosclerotic plaque in a Ldlr(-/-) atherosclerotic mouse model. Among the tested nanoplexes [ eNOS/rsPOLA, eNOS/{poly(oligo-D-arginine), rsPODA} and eNOS/(racemic mixture, rsRM)], eNOS/rsPOLA reduced atherosclerotic inflammation most effectively as we hypothesized. Current treatment strategy provides strong potential for further development of a gene therapeutic system to ameliorate inflammation and progressive atherosclerotic plaques.

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