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in vivo MRI

Vcam Immunofluorescence

Figure 5.9. MRI of atherosclerotic lesions using novel iron oxide nanoparticles. A Cholesterol-fed apoE-/- mice were imaged via MRI using gadolinium-protected graph copolymer to delineate vascular lumen and structural aortic abnormalities such as narrowing (arrows). Axial images (at the level of the green line) were then obtained before (B) and 24 hours after (C) administration of the magnetic VCAM-1-Targeted Nanoparticle (VNP). Note the decrease in signal intensity of the eccentrically thickened aortic wall between the two arrows. D Ex vivo MRI confirms extensive low signal changes in the aortic wall induced by VNP accumulation (arrows), further corroborated by macroscopic epifluorescence imaging of Cy 5.5 in VNP (E). F-H Histological validation of MR findings. F Hematoxylin/eosin section of the aorta image in B and C confirms eccentric wall thickening (x2). Comparative immunofluorescence of VCAM-1 expression (G, green) and VNP accumulation (H, red). Nuclei in G and H are counterstained with DAPI (blue). Note that there is extensive colocalization of VCAM-1 expression and VNP. Images provided by courtesy of Weissleder. Reprinted from Kelly et al. (2005), with permission of Lippincott Williams & Wilkins.

Figure 5.9. MRI of atherosclerotic lesions using novel iron oxide nanoparticles. A Cholesterol-fed apoE-/- mice were imaged via MRI using gadolinium-protected graph copolymer to delineate vascular lumen and structural aortic abnormalities such as narrowing (arrows). Axial images (at the level of the green line) were then obtained before (B) and 24 hours after (C) administration of the magnetic VCAM-1-Targeted Nanoparticle (VNP). Note the decrease in signal intensity of the eccentrically thickened aortic wall between the two arrows. D Ex vivo MRI confirms extensive low signal changes in the aortic wall induced by VNP accumulation (arrows), further corroborated by macroscopic epifluorescence imaging of Cy 5.5 in VNP (E). F-H Histological validation of MR findings. F Hematoxylin/eosin section of the aorta image in B and C confirms eccentric wall thickening (x2). Comparative immunofluorescence of VCAM-1 expression (G, green) and VNP accumulation (H, red). Nuclei in G and H are counterstained with DAPI (blue). Note that there is extensive colocalization of VCAM-1 expression and VNP. Images provided by courtesy of Weissleder. Reprinted from Kelly et al. (2005), with permission of Lippincott Williams & Wilkins.

nanoparticles (MIONs), were labeled with different synthetic small molecules. The screening identified nanoparticles that could discriminate among different cell types as well as among different physiological states of the same cell type, e.g. macrophage activation status.

The feasibility of using such a novel nanoparticle for imaging of atherosclerosis has been explored by Kelly et al. (2005). An MR contrast agent consisting of « 6 peptides with high affinity for VCAM-1 as identified with iterative phage display, coupled to a Cross-Linked Iron Oxide (CLIO) nanoparticle similar to MION, was internalized by VCAM-1 expressing cells while the control particle without the specific peptides failed to accumulate in those cells (Kelly et al., 2005). The cellular specificity of the VCAM-targeted nanoparticle (VNP) was clearly modified, since accumulation in macrophages was 11 times lower than in endothelial cells. Initial imaging findings with a limited number of animals (n = 3) showed extensive MR signal loss in atherosclerotic plaques of cholesterol-fed apoE-/- mice while the control nanoparticle showed no uptake at the same dose (5 mg Fe/kg body weight) (Figure 5.9). Fluorescence microscopy confirmed uptake in VCAM-expressing cells of the plaque. Moreover, no significant uptake of the VCAM-1-targeted nanoparticles was found in wild-type mice. Alternatively, an anti-VCAM-1 antibody has been coupled to a cross-linked iron oxide particle for in vivo imaging of activated endothelium in a murine inflammatory model (Tsourkas et al., 2005).

Another novel nanoparticle was created by conjugating an anti-human E-selectin antibody fragment to a cross-linked iron oxide particle. E-selectin expression in an Matrigel model with functional blood vessels was detectable with in vivo MRI (Kang et al., 2006). This contrast agent could possibly detect early changes in endothelial phenotype in atherosclerosis.

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