Atherosclerotic plaque composition: analysis with multicolor CT and targeted gold nanoparticles

Abstract

Purpose: To investigate the potential of spectral computed tomography (CT) (popularly referred to as multicolor CT), used in combination with a gold high-density lipoprotein nanoparticle contrast agent (Au-HDL), for characterization of macrophage burden, calcification, and stenosis of atherosclerotic plaques.

Materials and methods: The local animal care committee approved all animal experiments. A preclinical spectral CT system in which incident x-rays are divided into six different energy bins was used for multicolor imaging. Au-HDL, an iodine-based contrast agent, and calcium phosphate were imaged in a variety of phantoms. Apolipoprotein E knockout (apo E-KO) mice were used as the model for atherosclerosis. Gold nanoparticles targeted to atherosclerosis (Au-HDL) were intravenously injected at a dose of 500 mg per kilogram of body weight. Iodine-based contrast material was injected 24 hours later, after which the mice were imaged. Wild-type mice were used as controls. Macrophage targeting by Au-HDL was further evaluated by using transmission electron microscopy and confocal microscopy of aorta sections.

Results: Multicolor CT enabled differentiation of Au-HDL, iodine-based contrast material, and calcium phosphate in the phantoms. Accumulations of Au-HDL were detected in the aortas of the apo E-KO mice, while the iodine-based contrast agent and the calcium-rich tissue could also be detected and thus facilitated visualization of the vasculature and bones (skeleton), respectively, during a single scanning examination. Microscopy revealed Au-HDL to be primarily localized in the macrophages on the aorta sections; hence, the multicolor CT images provided information about the macrophage burden.

Conclusion: Spectral CT used with carefully chosen contrast agents may yield valuable information about atherosclerotic plaque composition.

Figure 1a:

(a) Graph shows energy dependence of x-ray attenuation of water due to Compton scatter and photoelectric effect, as compared with attenuation of k-edge material (ie, gold). (b) Schematic illustration of macrophage-targeted gold core nanoparticle Au-HDL. HDL = high-density lipoprotein. (c) Characterization of Au-HDL on negative-stain transmission electron microscopy (TEM) image.

Figure 1b:

(a) Graph shows energy dependence of x-ray attenuation of water due to Compton scatter and photoelectric effect, as compared with attenuation of k-edge material (ie, gold). (b) Schematic illustration of macrophage-targeted gold core nanoparticle Au-HDL. HDL = high-density lipoprotein. (c) Characterization of Au-HDL on negative-stain transmission electron microscopy (TEM) image.

Figure 1c:

(a) Graph shows energy dependence of x-ray attenuation of water due to Compton scatter and photoelectric effect, as compared with attenuation of k-edge material (ie, gold). (b) Schematic illustration of macrophage-targeted gold core nanoparticle Au-HDL. HDL = high-density lipoprotein. (c) Characterization of Au-HDL on negative-stain transmission electron microscopy (TEM) image.

Figure 2a:

CT images of phantom containing various concentrations of Au-HDL, an iodinated contrast agent, and calcium phosphate powder, Ca₃(PO₄)₂, to simulate calcium-rich tissue. (a) Labeled conventional CT image; (b) spectral CT energy bin images; and (c) gold, iodine, photoelectric, and Compton images derived from energy bins are shown.

Figure 2b:

CT images of phantom containing various concentrations of Au-HDL, an iodinated contrast agent, and calcium phosphate powder, Ca₃(PO₄)₂, to simulate calcium-rich tissue. (a) Labeled conventional CT image; (b) spectral CT energy bin images; and (c) gold, iodine, photoelectric, and Compton images derived from energy bins are shown.

Figure 2c:

CT images of phantom containing various concentrations of Au-HDL, an iodinated contrast agent, and calcium phosphate powder, Ca₃(PO₄)₂, to simulate calcium-rich tissue. (a) Labeled conventional CT image; (b) spectral CT energy bin images; and (c) gold, iodine, photoelectric, and Compton images derived from energy bins are shown.

Figure 3a:

Images of artery phantom. (a) Labeled CT image; (b) spectral CT images; and (c) overlay of gold, iodine, photoelectric, and Compton images are shown. Ca₃(PO₄)₂ = calcium phosphate.

Figure 3b:

Images of artery phantom. (a) Labeled CT image; (b) spectral CT images; and (c) overlay of gold, iodine, photoelectric, and Compton images are shown. Ca₃(PO₄)₂ = calcium phosphate.

Figure 3c:

Images of artery phantom. (a) Labeled CT image; (b) spectral CT images; and (c) overlay of gold, iodine, photoelectric, and Compton images are shown. Ca₃(PO₄)₂ = calcium phosphate.

Figure 4:

A–C, Spectral CT images of thorax and abdomen in apo E–KO mouse injected 24 hours earlier with Au-HDL. D, E, Spectral CT images near bifurcation of aorta in apo E–KO mouse injected with Au-HDL and an iodinated emulsion contrast agent (Fenestra VC) for vascular imaging.