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

Raphaël Duivenvoorden, Jun Tang, David P. Cormode, Aneta J. Mieszawska, David Izquierdo-Garcia, Canturk Ozcan, Maarten J. Otten, Neeha Zaidi, Mark E. Lobatto, Sarian M. van Rijs, Bram Priem, Emma L. Kuan, Catherine Martel, Bernd Hewing, Hendrik Sager, Matthias Nahrendorf, Gwendalyn J. Randolph, Erik S. G. Stroes, Valentin Fuster, Edward A. Fisher, Zahi A. Fayad and Willem J. M. Mulder ()
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Raphaël Duivenvoorden: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Jun Tang: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
David P. Cormode: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Aneta J. Mieszawska: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
David Izquierdo-Garcia: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Canturk Ozcan: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Maarten J. Otten: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Neeha Zaidi: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Mark E. Lobatto: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Sarian M. van Rijs: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Bram Priem: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Emma L. Kuan: Institute for Immunology, Icahn School of Medicine at Mount Sinai
Catherine Martel: Washington University in St Louis
Bernd Hewing: Marc and Ruti Bell Program in Vascular Biology, NYU School of Medicine
Hendrik Sager: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street
Matthias Nahrendorf: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street
Gwendalyn J. Randolph: Washington University in St Louis
Erik S. G. Stroes: Academic Medical Center
Valentin Fuster: Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai
Edward A. Fisher: Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité–Universitaetsmedizin Berlin
Zahi A. Fayad: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
Willem J. M. Mulder: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4065

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