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Contrast enhancement by lipid-based MRI contrast agents in mouse atherosclerotic plaques; a longitudinal study
Brigit den Adel1, Linda M van der Graaf, Ivo Que
1Department of Anatomy and Embryology, Leiden University Medical Center, the Netherlands.
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.
Insights
Gadolinium-based contrast agents, like micelles and liposomes, effectively visualize atherosclerotic plaques in mice for up to a week. Their size did not significantly impact plaque penetration, but timing is crucial for targeted agent development.
Area of Science:
- Biomedical Imaging
- Cardiovascular Research
- Nanotechnology
Background:
- Contrast-enhanced MRI is increasingly used for atherosclerotic plaque characterization.
- Limited data exists on optimal imaging time points for contrast agents in plaque imaging.
Purpose of the Study:
- To evaluate the plaque-enhancing capabilities of two gadolinium-based contrast agents (micelles and liposomes) in ApoE(-/-) mice using MRI.
- To determine the kinetic profile and longer-term enhancement of atherosclerotic plaques.
Main Methods:
- Intravenous injection of micelles and liposomes in ApoE(-/-) mice.
- T(1)-weighted MRI to assess signal enhancement in the aortic arch over 1 week.
- Confocal fluorescence microscopy and whole-body fluorescence imaging.
- Quantification of tissue and blood Gd-DTPA levels.
Main Results:
- Both micelles and liposomes significantly enhanced plaque contrast (260-280% CNR at 24h).
- A secondary peak in enhancement occurred around 60-72 hours, with slow decay over 1 week.
- Fluorescence imaging confirmed MRI findings of agent accumulation.
- Plaque permeation was size-independent in this model.
Conclusions:
- Intraplaque accumulation of both agents allows for prolonged plaque visualization.
- Distinguishing passive from targeted accumulation is challenging due to inherent accumulation.
- Extensive timing studies are necessary for developing targeted lipid-based contrast agents.
