Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis

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.

Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis

“…Using HA–coated nanocomplexes decorated with lectin-like oxidized low-density lipoprotein receptor (LOX-1) siRNA cell-penetrating peptides, Zhao et al demonstrated reductions in plaque area by 28% and neutral lipid content by 37%, as well as less infiltration of macrophages and chemokines in ApoE −/− mice [ 113 ]. Mu et al loaded simvastatin into biodegradable HA-coated polymeric micelles and found that treatment with these particles resulted in significantly reduced plaque size in ApoE −/− mice on HFD [ 114 ]. In these studies, HA may have also played an anti-oxidative role further improving the observed therapeutic effects.…”

Extracellular matrix: paving the way to the newest trends in atherosclerosis

“…The rationale to develop peptidomimetics to mimic the protective role or block detrimental actions of ECM molecules for the plaque was described by Lv et al [ 16 ▪▪ ] for COMP. In addition, several studies have employed CD44-hyaluronan interactions for targeting atherosclerosis, designing hyaluronan-coated polymeric micelles targeting CD44 overexpressing macrophages [ 22 , 23 ]. Further research is needed to characterise proteoglycan remodelling by degrading enzymes for example proteoglycanases, heparinase, at different stages of the atherosclerosis, introducing novel targets or biomarkers.…”

Recent Advances in ROS-Sensitive Nano-Formulations for Atherosclerosis Applications

“…Some polymers have also been exploited as antioxidants, and their ROS-quenching effect is mainly attributed to their special structures and inherent catalytic properties. An amphiphilic block copolymer, poly(ethylene glycol)–poly(tyrosine-ethyl oxalyl), was synthesized and self-assembled into micelles loaded with simvastatin, a kind of statin drug with antioxidant and anti-inflammatory effects [ 82 , 83 , 84 ]. This kind of micelle can consume ROS in pathologic sites and exert a synergistic antioxidant effect with simvastatin.…”

“…This kind of micelle can consume ROS in pathologic sites and exert a synergistic antioxidant effect with simvastatin. Intravenous administration of micelles in ApoE −/− mice can efficiently reduce the lesion area of plaque, showing great therapeutic effects on atherosclerosis [ 84 ]. Another case is represented by PBAPs that can be oxidized by H 2 O 2 to generate phenolic compounds.…”