Characterization and in vitro and in vivo testing of CB2-receptor- and NGAL-targeted paramagnetic micelles for molecular MRI of vulnerable atherosclerotic plaque.
OBJECTIVE
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.
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.
te Boekhorst
Bernard C M
BC
Department of Cardiology, University Medical Center, Utrecht, The Netherlands. b.c.m.teboekhorst@umcutrecht.nl
Bovens
Sandra M
SM
Rodrigues-Feo
Juan
J
Sanders
Honorius M H F
HM
van de Kolk
C W A
CW
de Kroon
Antonius I P M
AI
Cramer
Maarten-Jan M
MJ
Doevendans
Pieter A F M
PA
ten Hove
Michiel
M
Pasterkamp
Gerard
G
van Echteld
Cees J A
CJ
D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005240:Feasibility Studies; D000071068:Lipocalin-2; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008823:Micelles; D057054:Molecular Imaging / Q000379:methods*; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011859:Radiography; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D008823:Micelles; D015513:Oncogene Proteins; D010714:Phosphatidylethanolamines; D043885:Receptor, Cannabinoid, CB2; C071332:Lcn2 protein, mouse; D011092:Polyethylene Glycols