Supramolecular copolymer modified statin-loaded discoidal rHDLs for atherosclerotic anti-inflammatory therapy by cholesterol efflux and M2 macrophage polarization

化学 胆固醇 流出 毒品携带者 生物物理学 药物输送 药理学 细胞生物学 生物化学 生物 有机化学
作者
Qiqi Zhang,Jianhua He,Fengfei Xu,Xinya Huang,Yanyan Wang,Wenli Zhang,Jianping Liu
出处
期刊:Biomaterials Science [The Royal Society of Chemistry]
卷期号:9 (18): 6153-6168 被引量:9
标识
DOI:10.1039/d1bm00610j
摘要

Foam cells with the pro-inflammatory macrophage phenotype (M1) play an essential role in atherosclerosis progression. Either cellular cholesterol removal or drug intervention was reported to polarize M1 into the anti-inflammatory phenotype (M2) for atherosclerosis regression. These might be realized simultaneously by drug-loaded discoidal reconstituted high-density lipoproteins (d-rHDLs) with the functions of cellular cholesterol efflux and targeted drug delivery on macrophages. However, cholesterol reception can drive the remodelling of d-rHDLs, which serves to release drugs specifically in the atherosclerotic plaque but might incur premature drug leakage in blood circulation. Given that, the proposed strategy is to inhibit the remodelling behaviour of the carrier in blood circulation and responsively accelerate it under the atherosclerotic microenvironmental stimulus. Herein, atorvastatin calcium-loaded d-rHDL was modified by a PEGylated ferrocene/β-cyclodextrin supramolecular copolymer (PF/TC) to construct ROS-responsive PF/TC-AT-d-rHDL, which is expected to possess plasma stability and biosafety as well as triggered drug release by cholesterol efflux promotion. As a result, PF/TC-AT-d-rHDL could responsively dissemble into β-cyclodextrin modified AT-d-rHDL under the ROS-triggered dissociation of PF/TC, therefore exhibiting increased cholesterol efflux from the cholesterol donor and drug release through the remodelling behaviour of the carrier in vitro. Moreover, PF/TC-AT-d-rHDL enhanced cellular cholesterol removal in foam cells after response to ROS, inhibiting intracellular lipid deposition compared with other d-rHDL carriers. Interestingly, cellular drug uptake was significantly promoted upon cellular cholesterol removal by restoring the permeability and fluidity of foam cell membranes as indicated by flow cytometry and fluorescence polarization analysis, respectively. Importantly, compared with untreated foam cells, PF/TC-AT-d-rHDL obviously increased the ratio of M2/M1 by 6.3-fold, which was even higher than the effect of PF/TC-d-rHDL (3.4-fold) and free drugs (1.9-fold), revealing that PF/TC-AT-d-rHDL synergistically promoted the M2 polarization of macrophages. Accordingly, PF/TC-AT-d-rHDL boosted the secretion of anti-inflammatory cytokines and inhibited that of inflammatory cytokines. Collectively, PF/TC-AT-d-rHDL exerted synergistic M2 polarization effects on foam cells for atherosclerotic immunomodulatory therapy via responsively mediating cholesterol efflux and delivering drugs.
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