Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 18, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12951-020-00744-w
Keywords
Simvastatin; ROS-responsive; Hyaluronic acid; Macrophages; Antioxidative stress
Funding
- National Natural Science Foundation of China [82070366, 81720108022, 81601539]
- Fundamental Research Funds for the Central Universities, Nanjing University [2020-021414380462]
- key project of Jiangsu Commission of Health [K2019025]
- social development project of science and technology project in Jiangsu Province [BE2017707]
- Key medical talents of the Jiangsu province
- 13th Five-Year health promotion project of the Jiangsu province [ZDRCA2016064]
- Jiangsu Provincial Key Medical Discipline (Laboratory) [ZDXKA2016020]
- project of the sixth peak of talented people [WSN-138]
- Nanjing Medical Science and technique Development Foundation [ZKX19018, QRX17057]
- China Postdoctoral Science Foundation [2019M661804]
- Jiangsu Province postdoctoral Science Foundation [2019k060]
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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.
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