Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin

Abstract

Dysfunctional elastin turnover plays a major role in the progression of atherosclerotic plaques. Failure of tropoelastin cross-linking into mature elastin leads to the accumulation of tropoelastin within the growing plaque, increasing its instability. Here we present Gd 4 -TESMA, an MRI contrast agent specifically designed for molecular imaging of tropoelastin within plaques. Gd 4 -TESMA is a tetrameric probe composed of a tropoelastin-binding peptide (the VVGS-peptide) conjugated with four Gd(III)-DOTA-monoamide chelates. It shows a relaxivity per molecule of 34.0 ± 0.8 mM –1 s –1 (20 MHz, 298 K, pH 7.2), a good binding affinity to tropoelastin ( K D = 41 ± 12 μM), and a serum half-life longer than 2 h. Gd 4 -TESMA accumulates specifically in atherosclerotic plaques in the ApoE –/– murine model of plaque progression, with 2 h persistence of contrast enhancement. As compared to the monomeric counterpart (Gd-TESMA), the tetrameric Gd 4 -TESMA probe shows a clear advantage regarding both sensitivity and imaging time window, allowing for a better characterization of atherosclerotic plaques.

Nanomedicine for Diagnosis and Treatment of Atherosclerosis

“…[138] Due to the specific accumulation of tropoelastin within the plaque, Gd 4 -TESMA made up of four Gd (III)-DOTA-monoamide chelate conjugated with a tropoelastin-binding peptide (the VVGS-peptide) was introduced to illustrate the location and size of plaque through MR imaging tropoelastin. [139] In another research, Gd-DTPA was incorporated in the CNP, a complex nanoparticle selfassembled by protamine peptide TPP1880 and low molecular weight fucoidan LMWF8875, to target P-selectin overexpressed on the inflammatory endothelial cells surface. [140] On the other hand, iron oxide nanoparticles-based MR contrast agents exhibit low signal on T2 weighting, which shortens T2 value by altering the local magnetic field strength and accelerating dephasing mediated by spin-spin effects.…”

Extracellular Matrix Targeted MRI Probes

“…The targeting vector approach has been used for imaging of total tissue elastin (Gd-ESMA), [22][23][24][25][26][27][28][29][30][31] and the precursor molecule tropoelastin (Gd-TESMA). [32][33][34] These agents consist either of a peptidomimetic or peptide targeting moiety linked to a Gd(III)complex. Gd-ESMA was initially developed using the DTPA chelator, but to facilitate clinical translation the DTPA was later replaced by a DOTA derivative.…”

“…The targeting vector approach has been used for imaging of total tissue elastin (Gd‐ESMA), [22–31] and the precursor molecule tropoelastin (Gd‐TESMA) [32–34] . These agents consist either of a peptidomimetic or peptide targeting moiety linked to a Gd(III)‐complex.…”

“…Despite the promising results using Gd‐TESMA, signal enhancement peaked at 30 minutes post‐injection limiting imaging to ∼1 h. To overcome this challenge, the tetrameric Gd 4 ‐TESMA agent was developed by replacing the single Gd‐DO3AAm unit with a small [Gd‐DO3AAm] 4 unit. This modification increased the relaxivity per molecule by ∼4‐fold [34] . The tetrameric Gd 4 ‐TESMA increased the contrast‐to‐noise ratio between the plaque and blood (by 6‐fold) and doubled the imaging time‐window (to 2 h) to study atherosclerosis in mice [34] .…”

“…This modification increased the relaxivity per molecule by ∼4‐fold [34] . The tetrameric Gd 4 ‐TESMA increased the contrast‐to‐noise ratio between the plaque and blood (by 6‐fold) and doubled the imaging time‐window (to 2 h) to study atherosclerosis in mice [34] . This approach may facilitate imaging of tissues requiring longer scans and/or higher signal (e.g., for imaging the coronary arteries).…”