Gadolinium-containing phosphatidylserine liposomes for molecular imaging of atherosclerosis

Andrei Maiseyeu,Georgeta Mihai,Thomas Kampfrath,Orlando P Simonetti,Chandan K Sen,Sashwati Roy,Sanjay Rajagopalan,Sampath Parthasarathy

doi:10.1194/jlr.m800405-jlr200

Andrei Maiseyeu, Georgeta Mihai + Show 6 more

Open Access

https://doi.org/10.1194/jlr.m800405-jlr200

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Abstract

Exteriorized phosphatidylserine (PS) residues in apoptotic cells trigger rapid phagocytosis by macrophage scavenger receptor pathways. Mimicking apoptosis with liposomes containing PS may represent an attractive approach for molecular imaging of atherosclerosis. We investigated the utility of paramagnetic gadolinium liposomes enriched with PS (Gd-PS) in imaging atherosclerotic plaque. Gd-PS-containing Gd-conjugated lipids, fluorescent rhodamine, and PS were prepared and characterized. Cellular uptake in RAW macrophages (fluorescent uptake of rhodamine) was studied on a fluorescence plate reader, while Gd-PS-induced alteration in T1 relaxivity was evaluated using a 1.5 T MRI scanner. RAW cells demonstrate PS-dependent uptake of across a range of concentrations (2, 6, 12, and 20%) in comparison to control liposomes with no PS (0%). In vivo performance of Gd-PS was evaluated in the ApoE(-/-) mouse model by collection of serial T1 weighted gradient echo MR images using an 11.7 T MRI system and revealed rapid and significant enhancement of the aortic wall that was seen for at least 4 h after injection. Gd-PS-enriched liposomes enhance atherosclerotic plaque and colocalize with macrophages in experimental atherosclerosis.

Highlights

Exteriorized phosphatidylserine (PS) residues in apoptotic cells trigger rapid phagocytosis by macrophage scavenger receptor pathways
It is well known that exteriorized phosphatidylserine (PS) residues present in apoptotic cells promote macrophage recognition by macrophage scavenger receptor/CD36 followed by rapid phagocytosis [11, 12]
Liposomes containing PC, PG, and PS were incorporated with Gd-DTPA-SA along with the fluorescent dye Rhodamine B to allow for in vivo tracking

Summary

Introduction

Exteriorized phosphatidylserine (PS) residues in apoptotic cells trigger rapid phagocytosis by macrophage scavenger receptor pathways. The carrier moieties by virtue of preferential uptake by, or delivery to, specific pathways or receptors of relevance to the macrophage allow for “highpayload” delivery of the contrast agent and facilitate imaging with adequate signal to background noise ratios. Examples of such approaches include HDL [4] and LDL [5] lipoproteins incorporating Gd, polyethyleneglycol (PEG) grafted immunomicels [6, 7], and liposome vesicles [8] conjugated to antibodies targeting the macrophage scavenger receptor.

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