title: Contrast enhancement by lipid-based MRI contrast agents in mouse atherosclerotic plaques; a longitudinal study.
abstract: The use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of two differently sized gadolinium-based contrast agents to enhance atherosclerotic plaques in ApoE(-/-) mice was evaluated with MRI. We obtained a kinetic profile for contrast enhancement, as the literature data on optimal imaging time points is scarce, and assessed the longer-term kinetics. Signal enhancement in the wall of the aortic arch, following intravenous injection of paramagnetic micelles and liposomes, was followed for 1 week. In vivo T(1)-weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy of NIR(664) incorporated in the contrast agents and quantification of tissue and blood Gd-DTPA. Both micelles and liposomes enhanced contrast in T(1)-weighted MR images of plaques in the aortic arch. The average contrast-to-noise ratio increased after liposome or micelle injection to 260 or 280% respectively, at 24 h after injection, compared with a pre-scan. A second wave of maximum contrast enhancement was observed around 60-72 h after injection, which only slowly decreased towards the 1 week end-point. Confocal fluorescence microscopy and whole body fluorescence imaging confirmed MRI-findings of accumulation of micelles and liposomes. Plaque permeation of contrast agents was not strongly dependent on the contrast agent size in this mouse model. Our results show that intraplaque accumulation over time of both contrast agents leads to good plaque visualization for a long period. This inherent intraplaque accumulation might make it difficult to discriminate passive from targeted accumulation. This implies that, in the development of targeted contrast agents on a lipid-based backbone, extensive timing studies are required.
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, the Netherlands.
authors.forename: Brigit
authors.initials: B
authors.lastname: den Adel
authors.forename: Linda M
authors.initials: LM
authors.lastname: van der Graaf
authors.forename: Ivo
authors.initials: I
authors.lastname: Que
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Strijkers
authors.forename: Clemens W
authors.initials: CW
authors.lastname: Löwik
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weerd
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000000981:diagnostic imaging* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D003287:Contrast Media / Q000493:pharmacokinetics / Q000494:pharmacology*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008055:Lipids / Q000493:pharmacokinetics / Q000494:pharmacology*; D008081:Liposomes / Q000493:pharmacokinetics / Q000494:pharmacology; D018810:Magnetic Resonance Angiography / Q000379:methods*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008823:Micelles; D058226:Plaque, Atherosclerotic; D011859:Radiography; D013997:Time Factors; D041622:Tomography, Optical / Q000379:methods
chemical_list: D001057:Apolipoproteins E; D003287:Contrast Media; D008055:Lipids; D008081:Liposomes; D008823:Micelles; D019786:Gadolinium DTPA