Imaging monocytes with iron oxide nanoparticles targeted towards the monocyte integrin MAC-1 (CD11b/CD18) does not result in improved atherosclerotic plaque detection by in vivo MRI.
Imaging of macrophages with superparamagnetic iron oxide particles (SPIO) has been performed to improve detection of atherosclerotic plaque inflammation in human and mouse studies by molecular magnetic resonance imaging (MRI). Since affinity of the monocyte/macrophage integrin MAC-1 (CD11b/CD18) is upregulated in inflammation, we generated a contrast agent targeting CD11b (CD11b-SPIOs) for improved macrophage detection in plaques. CD11b-SPIOs and non-targeted SPIOs (control-SPIOs) were incubated in vitro with human monocytes/macrophages. As quantified by SPIO-induced MRI signal extinction, intracellular iron-content was significantly higher in monoytes/macrophages incubated with CD11b-SPIO than with control-SPIO in vitro (p < 0.05), suggesting an improved uptake of CD11b-SPIOs into monocytes. Therefore, the aortic arch (AA) and vessel branches of ApoE(-/-)-knockout mice on a Western-type diet were imaged before and 48 h after contrast agent injection of either CD11b-SPIOs or control-SPIOs, using a 9.4 T animal MRI system. The SPIO-induced change in the MRI signal was quantified, as well as the macrophage-content by anti-CD68 immunhistochemistry and the iron-content by Prussian-blue staining. However, SPIO-induced signal extinction in in vivo-MRI was similar in CD11b-SPIO and control-SPIO-injected animals, with a non-significant trend towards an improved uptake of CD11b-SPIOs in the subclavian artery and subsections of the AA. These data correlated well with the results obtained by histology. Although in vitro MRI-data indicated an increased uptake of targeted CD11b-SPIOs in monocytes/macrophages, in vivo mouse data do not allow improved atherosclerotic plaque detection compared WITH non-targeted SPIOs. Therefore, CD11b-targeted MRI contrast labelling of monocytes/macrophages does not seem to be a successful strategy in stable atherosclerotic plaques such as found in the ApoE(-/-)-knockout-model. However, the impressive correlation between MRI and histology data encourages further development of inflammation- and plaque-specific contrast agents for vulnerable plaque imaging.
Department of Cardiology and Angiology, University of Freiburg, Freiburg, Germany. constantin.vonzurmuehlen@uniklinik-freiburg.de
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von zur Muhlen
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Fink-Petri
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Salaklang
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D
Paul
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Neudorfer
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Berti
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Merkle
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Peter
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Bode
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von Elverfeldt
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D039481:CD11b Antigen / Q000737:chemistry*; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D058226:Plaque, Atherosclerotic / Q000175:diagnosis* / Q000378:metabolism
D001057:Apolipoproteins E; D039481:CD11b Antigen; D003287:Contrast Media; D005290:Ferric Compounds; C000499:ferric oxide