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WIREs Nanomed Nanobiotechnol
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Artificial high‐density lipoprotein‐mimicking nanotherapeutics for the treatment of cardiovascular diseases

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Abstract Despite the ability of current efficacious low‐density lipoprotein‐cholesterol–lowering therapies to reduce total cardiovascular disease (CVD) risks, CVD still poses major risks for morbidity and mortality to the general population. Because of the pleiotropic endothelial protective effects of high‐density lipoproteins (HDL), the direct infusion of reconstituted HDL (rHDL) products, including MDCO‐216, CER001, and CSL112, have been tested in clinical trials to determine whether direct infusion of rHDL can reduce coronary events in CVD patients. In addition to these rHDL products, in the past two decades, there has been an increased focused on designing artificial HDL‐mimicking nanotherapeutics to produce complementary therapeutic strategies for CVD patients beyond lowering of atherogenic lipoproteins. Although recent reviews have comprehensively discussed the developments of artificial HDL‐mimicking nanoparticles as therapeutics for CVD, there has been little assessment of “plain” or “drug‐free” HDL‐mimicking nanoparticles as therapeutics alone. In this review, we will summarize the clinical outcomes of rHDL products, examine recent advances in other types of artificial HDL‐mimicking nanotherapeutics, including polymeric nanoparticles, cyclodextrins, micelles, metal nanoparticles, and so on; and potential new approaches for future CVD interventions. Moreover, success stories, lessons, and interpretations of the utility and functionality of these HDL‐mimicking nanotherapeutics will be an integral part of this article. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Current concepts in HDL maturation and its potential relationship to atherosclerosis
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(a) “Construction of modular multifunctional CREKA micelles, made up of a DSPE tail, a poly(ethylene glycol) (PEG2000) spacer, and a variable polar head group (X) of CREKA. CREKA micelles can specifically target the aortic tree of atherosclerotic mice. Micelles were injected intravenously and allowed to circulate for 3 h. The aortic tree was excised after perfusion and imaged ex vivo.” Figures combined and reproduced with permission from Peters et al. (2009). Copyright 2009. National Academy of Sciences. (b) “Schematic of HA PAM synthesis and targeting calcification found in atherosclerotic plaque.” Figures combined and reproduced with permission from Chin et al. (2019). Copyright 2019. Royal Society of Chemistry
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(a) “Synthesis of biomimetic HDL using an Au NP core for use as a therapeutic. Au NPs of 5 nm in diameter were surface‐functionalized with ApoA‐I and then with two phospholipids, 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[3‐(2‐pyridyldithio) propionate] (yellow) and 1‐2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine (green).” Reprinted with permission from Thaxton et al. (2009). Copyright 2009. American Chemical Society. (b) “Self‐assembly of a mixture of DPPC/MPDP PE/2‐MPT (175:175:175) on three apoA‐I loaded AuNPs.” Reprinted with permission from Lai et al. (2017). Copyright 2017. American Chemical Society. (c) “Representative synthesis of the three nanocrystal HDLs for imaging atherosclerotic plaque and their imaging of atherosclerosis. Confocal microscopy images of aortic sections of mice injected with nanocrystal HDL. Red is nanocrystal HDL, macrophages are green, and nuclei are blue. Yellow indicates colocalization of nanocrystal HDL with macrophages and is indicated by arrowheads.” Reprinted with permission from Cormode et al. (2008). Copyright 2008. American Chemical Society
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(a) “Schematic presentation of cyclodextrin polymer for effective and safe treatment of atherosclerosis. (b) Preferential accumulation of CDP in atherosclerotic plaques. Representative ex vivo bright‐field and fluorescence images of the dissected aorta. Quantification of fluorescence in the dissected aorta and major organs as measured by NIR fluorescence imaging system. (c) βCDP showed an improved anti‐atherosclerotic efficacy of compared with HPβCD in mice.” Reprinted with permission from Kim et al. (2020). Copyright 2020. Elsevier
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“Dose response of cholesterol mobilization following 5A‐POPC and 5A‐SM infusions at 30 mg/kg (dashed line) and 100 mg/kg (solid line) in normal rats. Unesterified cholesterol or FC mobilization by 5A‐POPC (a) and 5A‐SM (b). Infusion of 5A‐POPC (dotted line) and 5A‐SM (dashed line) leads to rapid cholesterol mobilization in the HDL subfraction 30 min post dose relative to baseline (solid line). Lipoproteins were separated by gel filtration chromatography and cholesterol levels were analyzed post fraction collection. Peaks at 12, 14, and 18 min represent VLDL, LDL, and HDL, respectively (c). Effect of 5A‐POPC and 5A‐SM rHDL on atherosclerosis regression in ApoE−/− mice. Aortas were dissected and plaque areas were visualized by Oil Red O staining. Representative lesion images and corresponding quantitative analyses of the aortas (d) and the aortic root cross‐sections (e). N = 7–8 animals per group. (*) Denotes statistically significant differences with p values of at least <0.05; (**) indicates p values of <0.01.” Reprinted with permission from Schwendeman et al. (2015). Copyright 2015. Elsevier
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(a) “Schematic depiction of the synthesis of PLGA–HDL by microfluidic technology. PLGA–HDL nanoparticles target atherosclerotic plaques. (b) The preferential interaction of PLGA–HDL with macrophages was confirmed with flow cytometry analysis. Mean fluorescence of macrophages, pancreatic endothelial cells, smooth muscle cells, and hepatocytes incubated with PEG–PLGA NP (white) and PLGA–HDL (black). (c) Cholesterol efflux assay of native‐HDL, PLGA–HDL, and microfluidic‐synthesized HDL on human macrophage‐like THP‐1 cells at 50 μg/ml. (d) Fluorescence imaging of excised aortas of ApoE‐/‐ mice injected with placebo or PLGA–HDL nanoparticles. (e) Fluorescent activated cell sorting of digested aortas injected with PLGA–HDL; the label DiR is mainly associated with monocytes and macrophages in the aorta.” Figures combined and reprinted with permission from Sanchez‐Gaytan et al. (2015). Copyright 2015. American Chemical Society
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“PEGylation of sHDL led to beneficial changes (increase in mobilized cholesterol) in sHDL particle pharmacokinetic and pharmacodynamic behaviors (a). Pharmacodynamic assessment after IV administration of sHDL particles modified with different amount of PEGylated lipids. The level of total cholesterol (b) and free cholesterol (c) in rat serum were determined by commercially available kits. Data are shown as statistically significant differences of TC and FC changes for each group compared with sHDL group with p < 0.0001.” Reprinted with permission from Li et al. (2018). Copyright 2018. American Chemical Society
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