HDL as a contrast agent for medical imaging

Abstract

Contrast-enhanced MRI of atherosclerosis can provide valuable additional information on a patient's disease state. As a result of the interactions of HDL with atherosclerotic plaque and the flexibility of its reconstitution, it is a versatile candidate for the delivery of contrast-generating materials to this pathogenic lesion. We herein discuss the reports of HDL modified with gadolinium to act as an MRI contrast agent for atherosclerosis. Furthermore, HDL has been modified with fluorophores and nanocrystals, allowing it to act as a contrast agent for fluorescent imaging techniques and for computed tomography. Such modified HDL has been found to be macrophage specific, and, therefore, can provide macrophage density information via noninvasive MRI. As such, modified HDL is currently a valuable contrast agent for probing preclinical atherosclerosis. Future developments may allow the application of this particle to further diseases and pathological or physiological processes in both preclinical models as well as in patients.

Figure 1. In vivo T1-weighted MRI at different time points (pre- and post-injection of contrast agent at 0.5, 24 and 48 h) and dosages of gadolinium

White arrows point to the abdominal aorta; the insets denote a magnification of the aorta region. Parts of this figure are reproduced with permission from [9].

Figure 2. Imaging of atherosclerosis with synthetic, Gd-labled HDL

(A) Edmundson wheel representation of the ApoA-I mimicking peptide 18A. The peptide used in this study was 37pA, whose sequence is 18A-P-18A. (B) Schematic representation of 37pA, a synthetic, HDL-based contrast agent. (C) 37pA-Gd produced a similar degree of macrophage cholesterol efflux as native HDL. (D) T₁-weighted MRI of the aorta (arrows) of an ApoE^−/− mouse pre- and 24 h post-injection with 37pA-Gd. (E) Confocal microscopy of an excised aorta of an ApoE^−/− mouse injected 24 h previously with 37pA-Gd. Blue: nuclei, red: 37pA-Gd and green: macrophages. The extensive yellow coloration is due to colocalization of 37pA and macrophages. Parts of this figure are reproduced with permission from [22].

Figure 3. Nanocrystal core HDL allows imaging of atherosclerosis using MRI, computed tomography and fluorescence imaging techniques

(A) Nanocrystal core HDL. (B) Transmission electron microscopy (TEM) image of pellets (in paraformaldehyde) of macrophage cells that had been incubated with either Au-HDL or Au-PEG. (C) TEM image of Au-HDL uptake in a macrophage cell. (D) T₂-weighted MRI of pellets of macrophage cells that had been incubated with IO-HDL, IO-PEG or with media only. Confocal images of cells incubated with (E) QD-HDL or (F) QD-PEG. T₂*-weighted MR’s of the aorta of an ApoE^−/− mouse (G) preinjection and (H) 24 h postinjection of IO-HDL. (I) Micro-computed tomography image of an excised aorta of an ApoE^−/− mouse injected 24 h previously with Au-HDL. The bright spots indicate uptake of Au-HDL in atherosclerotic tissue. (J) Fluorescence image of an aorta excised from an ApoE^−/− mouse that had been injected 24 h previously with QD-HDL. AU: Silver; IO: Iron oxide; QD: Quantum dot. Adapted with permission from [22].