Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque

Abstract

Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE(-/-) mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T(1) -weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T(1) -weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6 min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets.

Targeting of ICAM-1 on vascular endothelium under static and shear stress conditions using a liposomal Gd-based MRI contrast agent

“…Previous studies have demonstrated that targeted iron-oxide-based MR-contrast agents are able to create hypo-intense signals on T 2 * -weighted images in regions of VCAM-1 or P-selectin expression in mouse models of atherosclerosis and brain inflammation [17-19]. Alternatively, the use of targeted Gd-based probes, which create signal hyperenhancement on T 1 -weighted images, has been explored as well [20-22]. Choi et al used anti-ICAM-1 antibodies decorated with Gd-DTPA moieties to highlight muscular inflammation on in vivo MRI, whereas Sipkins et al performed ex vivo MRI to visualize brain inflammation using paramagnetic liposomes [20,21].…”

“…In this study, we introduce a novel liposomal contrast agent functionalized with anti-ICAM-1 (aICAM-1) antibodies for sensitive multimodal magnetic resonance imaging (MRI) and fluorescence imaging of endothelial ICAM-1 expression. MRI enables in vivo high-resolution imaging of ICAM-1 expression in an anatomical context, whereas ex vivo fluorescence microscopy can be used to study the spatial distribution of the liposomes at the tissue and cellular level [9]. Because of the relatively large diameter of the liposomes (100–150 nm), passive extravasation from the blood is expected to be minimal and liposomes will be largely confined to the blood pool, which facilitates the detection of intravascular targets such as ICAM-1.…”

Internalization of paramagnetic phosphatidylserine-containing liposomes by macrophages

“…Furthermore, the larger size of nanocarriers promotes a higher level of uptake in diseased tissues by the enhanced permeability and retention (EPR) effect [6,7]. Importantly, to address the inflammatory response in cardiovascular disease, the drug-containing nanocarriers should be delivered with high specificity to inflammatory cells in the diseased tissue.…”

Noninvasive Detection of Macrophages in Atheroma Using a Radiocontrast-Loaded Phosphatidylserine-Containing Liposomal Contrast Agent for Computed Tomography

“…Size-dependent contrast uptake by plaque-associated macrophages remains a contentious topic. A comprehensive study evaluated three forms of gadolinium: unencapsulated form (Gd-HP-DO3A), in association with micelles (~15 nm) and encapsulated in liposomes (~125 nm) in atherosclerotic mice [17]. The unencapsulated form rapidly entered the aortic wall but washed out within an hour and the micelles were retained within the aortic wall for up to 24 hours.…”