Characterization and In Vitro and In Vivo Testing of CB2-Receptor- and NGAL-Targeted Paramagnetic Micelles for Molecular MRI of Vulnerable Atherosclerotic Plaque

• Published in: Molecular imaging and biology 2010-12, Vol.12 (6), p.635-651
• Main Authors: te Boekhorst, Bernard C. M., Bovens, Sandra M., Rodrigues-Feo, Juan, Sanders, Honorius M. H. F., van de Kolk, C. W. A., de Kroon, Antonius I. P. M., Cramer, Maarten-Jan M., Doevendans, Pieter A. F. M., ten Hove, Michiel, Pasterkamp, Gerard, van Echteld, Cees J. A.
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - antagonists & inhibitors; Acute-Phase Proteins - metabolism; Animals; CHO Cells; Cricetinae; Cricetulus; Feasibility Studies; Imaging; Lipocalin-2; Lipocalins - antagonists & inhibitors; Lipocalins - metabolism; Magnetic Resonance Imaging - methods; Magnetics - methods; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Micelles; Molecular Imaging - methods; Molecular Targeted Therapy; Oncogene Proteins - antagonists & inhibitors; Oncogene Proteins - metabolism; Phosphatidylethanolamines - chemistry; Plaque, Atherosclerotic - diagnostic imaging; Plaque, Atherosclerotic - metabolism; Polyethylene Glycols - chemistry; Radiography; Radiology; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Research Article
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-010-0323-z

Purpose Atherosclerotic plaque macrophages express the peripheral cannabinoid receptor (CB2-R) and promote fibrous cap degradation by secretion of neutrophil gelatinase-associated lipocalin 2 (NGAL). In this study, we report the preparation, characterization, and in vitro and in vivo testing of double-labeled (MR and fluorescent) CB2-R- and NGAL-targeted micelles. Procedures/Results Specific CB2-R agonists or antibodies directed to 24p3 (mouse homolog of NGAL) were incorporated into di-oleoyl-polyethylene glycol-phosphatidylethanolamine 1000 (DOPE-PEG1000) micelles or di-stearoyl-polyethylene glycol-phosphatidylethanolamine 2000 (DSPE-PEG2000) micelles. The hydrodynamic diameter, determined by dynamic light scattering, was 16.5 and 19.0 nm for CB2-R-targeted DOPE-PEG1000 and DSPE-PEG2000 micelles, respectively, and 23.0 nm for Ab-conjugated DSPE-PEG2000 micelles. In vitro and in vivo MRI and fluorescence microscopy showed specific binding of CB2-R-targeted and 24p3-targeted micelles to in vitro systems and to aortic plaque in apoE −/− /eNOS −/− mice, respectively. Conclusions CB2-R- and NGAL-targeted micelles show promise as tools for in vivo characterization of vulnerable plaque.