Nature-inspired nanoformulations for contrast-enhanced in vivo MR imaging of macrophages

Contrast Media Mol Imaging. 2014 Sep-Oct;9(5):372-82. doi: 10.1002/cmmi.1587. Epub 2014 Apr 14.

Abstract

Magnetic resonance imaging (MRI) of macrophages in atherosclerosis requires the use of contrast-enhancing agents. Reconstituted lipoprotein particles that mimic native high-density lipoproteins (HDL) are a versatile delivery platform for Gd-based contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, a naturally occurring methionine oxidation in the major HDL protein, apolipoprotein (apo) A-I, was exploited as a novel way to target HDL to macrophages. We also tested if fully functional GBCA-HDL can be generated using synthetic apo A-I peptides. The fluorescence and MRI studies reveal that specific oxidation of apo A-I or its peptides increases the in vitro macrophage uptake of GBCA-HDL by 2-3 times. The in vivo imaging studies using an apo E-deficient mouse model of atherosclerosis and a 3.0 T MRI system demonstrate that this modification significantly improves atherosclerotic plaque detection using GBCA-HDL. At 24 h post-injection of 0.05 mmol Gd kg(-1) GBCA-HDL containing oxidized apo A-I or its peptides, the atherosclerotic wall/muscle normalized enhancement ratios were 90 and 120%, respectively, while those of GBCA-HDL containing their unmodified counterparts were 35 and 45%, respectively. Confocal fluorescence microscopy confirms the accumulation of GBCA-HDL containing oxidized apo A-I or its peptides in intraplaque macrophages. Together, the results of this study confirm the hypothesis that specific oxidation of apo A-I targets GBCA-HDL to macrophages in vitro and in vivo. Furthermore, our observation that synthetic peptides can functionally replace the native apo A-I protein in HDL further encourages the development of these contrast agents for macrophage imaging.

Keywords: apolipoprotein A-I; atherosclerosis; biomimetic peptide; gadolinium; lipoprotein nanoparticle; macrophage; magnetic resonance imaging; oxidation; vulnerable plaque.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Tracking / methods
  • Contrast Media / chemistry*
  • Gadolinium / chemistry
  • Macrophages / diagnostic imaging*
  • Macrophages / metabolism
  • Magnetic Resonance Imaging*
  • Mice
  • Microscopy, Confocal
  • Nanoparticles / chemistry*
  • Radiography

Substances

  • Contrast Media
  • Gadolinium