A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

• Published in: Nature communications Vol. 5; no. 1; p. 3065
• Main Authors: Duivenvoorden, Raphaël, Tang, Jun, Cormode, David P., Mieszawska, Aneta J., Izquierdo-Garcia, David, Ozcan, Canturk, Otten, Maarten J., Zaidi, Neeha, Lobatto, Mark E., van Rijs, Sarian M., Priem, Bram, Kuan, Emma L., Martel, Catherine, Hewing, Bernd, Sager, Hendrik, Nahrendorf, Matthias, Randolph, Gwendalyn J., Stroes, Erik S. G., Fuster, Valentin, Fisher, Edward A., Fayad, Zahi A., Mulder, Willem J. M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2014; Nature Publishing Group
• Subjects: 59/5; 59/57; 639/925/352/152; 692/308; 692/699/249/2510/2100; 692/700/565/1436; Administration, Intravenous; Animals; Apolipoproteins; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Bioavailability; Biology; Cardiology; Cholesterol; Disease Models, Animal; Disease prevention; Dose-Response Relationship, Drug; Drug dosages; Heart attacks; High density lipoprotein; Histology; Humanities and Social Sciences; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immunology; Lipoproteins; Lipoproteins, HDL - administration & dosage; Lipoproteins, HDL - therapeutic use; Male; Medicine; Mice; Mice, Knockout; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - therapeutic use; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - prevention & control; Science; Science (multidisciplinary); Statins; Treatment Outcome; New York; United States > US; Massachusetts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4065

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation. Inflammatory processes in atherosclerotic lesions promote disease progression and plaque rupture. Here the authors load the drug statin into nanoparticles made of recombinant high-density lipoprotein and show that these accumulate in atherosclerotic plaques and reduce plaque inflammation in mice.