Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating ather
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Journal of Nanobiotechnology Open Access
RESEARCH
Hyaluronic acid‑coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis Dan Mu1* , Jianhui Li2, Yu Qi3, Xuan Sun3, Yihai Liu2, Song Shen2, Yuyu Li4, Biao Xu3,5* and Bing Zhang1,6*
Abstract Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the cellular uptake experiment demonstrated that SIM-loaded HA-coated micelles can be effectively internalized by LPS-induced RAW264.7 cells and showed high cytotoxicity against the cells, but low cytotoxicity against LO2 cells. In mouse models of atherosclerosis, intravenously SIM-loaded HA-coated micelles can effectively reduce plaque content of cholesterol, resulting in remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system provides a promising and innovative option against atherosclerosis. Keywords: Simvastatin, ROS-responsive, Hyaluronic acid, Macrophages, Antioxidative stress Introduction Atherosclerosis is a chronic, systemic inflammatory disease of the large and medium-sized arteries, characterized by the development of plaques due to the retention of lipids in the artery wall and infiltration of leukocytes, which can lead to life-threating events such as myocardial infarction and stroke [1–3]. The inflammatory area *Correspondence: [email protected]; [email protected]; zhangbing_ [email protected] 1 Department of Radiology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan road, Nanjing 210008, Jiangsu, China 3 Department of Cardiology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China Full list of author information is available at the end of the article
recruits monocytes, differentiating into macrophages. Upon ingestion of low-density lipoprotein (LDL), macrophages would die or even lead to cellular rupture, recruiting additional immune cells to inflammatory area [4]. Due to the decisive role and abundance in the progression of plaque, macrophages could achieve targeting capacity of plaques. CD44 is one of the specific biomarkers of macrophages and
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