The Complex Fate in Plasma of Gadolinium Incorporated into High-Density Lipoproteins Used for Magnetic Imaging of Atherosclerotic Plaques

Abstract

We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL, and VLDL particles containing Gd chelated to phosphatidyl ethanolamine (DTPA-DMPE) and a lipidic fluorophore were used to demonstrate the transfer of Gd-phospholipids among plasma lipoproteins in vitro and in vivo. To determine the basis of this transfer, the roles of phospholipid transfer protein (PLTP) and lipoprotein lipase (LpL) in mediating the migration of Gd-DTPA-DMPE among lipoproteins were investigated. The results indicated that neither was an important factor, suggesting that spontaneous transfer of Gd-DTPA-DMPE was the most probable mechanism. Finally, two independent mouse models were used to quantify the relative contributions of HDL and LDL reconstituted with Gd-DTPA-DMPE to plaque imaging enhancement by MR. Both sets of results suggested that Gd-DTPA-DMPE originally associated with LDL was about twice as effective as that injected in the form of Gd-HDL, and that some of Gd-HDL’s effectiveness in vivo is indirect through transfer of the imaging agent to LDL. In conclusion, the fate of Gd-DTPA-DMPE associated with a particular type of lipoprotein is complex, and includes its transfer to other lipoprotein species that are then cleared from the plasma into tissues.

Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles

“…To determine that the paramagnetic and fluorescent dHDL and sHDL particles are specifically uptaken by J774A.1 macrophages and not a result of lipid exchange [ 35 ], we labeled the oxidized synthetic apo A-I H4 peptide using Dylight 488. We hypothesized that if uptake is specific, the Dylight 488-labeled oxidized Apo-AI H4 peptide along with the Rhodamine B-labeled lipid would be observed inside the cell.…”

High density lipoprotein mimicking nanoparticles for atherosclerosis

“…These types of GBCA-HDL mimicking NPs also showed in vivo efficacy in ApoE −/− mouse models [24]. Additionally, later in 2013, the same group conducted a study for clarifying the mechanism of using the Gd-HDL mimicking NPs for delivering Gd to the plaque and their fate in plasma [60]. In vitro and in vivo studies indicated that the possible delivery mechanism was that the Gd-DTPA-DMPE could be spontaneously transferred to the endogenous phospholipids and then cleared from the plasma [60].…”

High-Density Lipoprotein Nanobiologics for Precision Medicine

“…We have shown that HDL nanobiologics can be modified for their visualization using different imaging techniques, namely, optical imaging ,, (Figure A), MRI − ,,, (Figure B), CT , (Figure C), and PET , (Figure D). Each modality has its own strengths .…”