Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe...

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 Gd₄-TESMA, an MRI contrast agent specifically designed for molecular imaging of tropoelastin within plaques. Gd₄-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 microM), and a serum half-life longer than 2 h. Gd₄-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 Gd₄-TESMA probe shows a clear advantage regarding both sensitivity and imaging time window, allowing for a better characterization of atherosclerotic plaques.