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.
Highlights
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 [1,2,3]
Synthesis of polymers As shown in Scheme 2, Mal-PEG-Ptyr copolymers were obtained via the ring-opening polymerization of tyrosine N-carboxyanhydride (Tyr-NCA) using Mal-PEG-NH2 as the initiator (Scheme 1)
LO2 exhibited weak Cy5 fluorescence after treatment with Cy5-labeled HA-coated PEMs (HPEMs). These results indicated the CD44-mediated endocytosis of LPS-induced RAW264.7 against HAcoated micelles
Summary
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 [1,2,3]. Clinical data has shown that orally administered statins can reduce the risk of cardiovascular disease (CVD) and attenuate the development of atherosclerotic plaques [7]. It was reported that high-dose statins probably induced body weight loss and abnormal serum biomarkers [11]. All these imperfections hinder the further application of statins in the clinical practice
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