title: Nature-inspired nanoformulations for contrast-enhanced in vivo MR imaging of macrophages.
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.
authors.affiliation: SignaBlok Inc., Shrewsbury, MA, 01545, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Sigalov
mesh_terms: D000818:Animals; D058948:Cell Tracking / Q000379:methods; D003287:Contrast Media / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D008264:Macrophages / Q000000981:diagnostic imaging* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*; D011859:Radiography
chemical_list: D003287:Contrast Media; D005682:Gadolinium
keywords: apolipoprotein A-I; atherosclerosis; biomimetic peptide; gadolinium; lipoprotein nanoparticle; macrophage; magnetic resonance imaging; oxidation; vulnerable plaque
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