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

Nat Commun. 2014;5:3065. doi: 10.1038/ncomms4065.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Intravenous
  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Lipoproteins, HDL / administration & dosage
  • Lipoproteins, HDL / therapeutic use*
  • Male
  • Mice
  • Mice, Knockout
  • Nanoparticles / administration & dosage
  • Nanoparticles / therapeutic use*
  • Plaque, Atherosclerotic / genetics
  • Plaque, Atherosclerotic / prevention & control*
  • Treatment Outcome

Substances

  • Apolipoproteins E
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipoproteins, HDL