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

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

Author information

1
SignaBlok Inc., Shrewsbury, MA, 01545, USA.

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

PMID:
24729189
PMCID:
PMC4197124
DOI:
10.1002/cmmi.1587
[Indexed for MEDLINE]
Free PMC Article

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