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

Federico Capuana; Alkystis Phinikaridou; Rachele Stefania; Sergio Padovan; Begoña Lavin; Sara Lacerda; Eyad Almouazen; Yves Chevalier; Laurence Heinrich-Balard; René M. Botnar; Silvio Aime; Giuseppe Digilio

doi:10.1021/acs.jmedchem.1c01286

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

Federico Capuana, Alkystis Phinikaridou, Rachele Stefania, Sergio Padovan, Begoña Lavin, Sara Lacerda, Eyad Almouazen, Yves Chevalier, Laurence Heinrich-Balard, René M. Botnar, Silvio Aime, Giuseppe Digilio^*

^*Corresponding author for this work

Biomedical Engineering Department

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

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 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 (KD = 41 ± 12 μM), 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.

Original language	English
Pages (from-to)	15250-15261
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	20
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01286
Publication status	Published - 1 Oct 2021

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Capuana, F., Phinikaridou, A., Stefania, R., Padovan, S., Lavin, B., Lacerda, S., Almouazen, E., Chevalier, Y., Heinrich-Balard, L., Botnar, R. M., Aime, S., & Digilio, G. (2021). Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin. Journal of Medicinal Chemistry, 64(20), 15250-15261. https://doi.org/10.1021/acs.jmedchem.1c01286

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title = "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 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 (KD = 41 ± 12 μM), 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.",

author = "Federico Capuana and Alkystis Phinikaridou and Rachele Stefania and Sergio Padovan and Bego{\~n}a Lavin and Sara Lacerda and Eyad Almouazen and Yves Chevalier and Laurence Heinrich-Balard and Botnar, {Ren{\'e} M.} and Silvio Aime and Giuseppe Digilio",

note = "Funding Information: This project has received funding from the EU{\textquoteright}s H2020 research and innovation program under the grant agreement No. 668142 (SPCCT). This study was funded by the British Heart Foundation (RG/20/1/34802), the BHF Centre of Excellence (RE/08/03), and the Chilean Agency of Technology and Science (CONICYT-PIA-Anillo ACT1416). This work was also supported by the Wellcome EPSRC Centre for Medical Engineering at King{\textquoteright}s College London (WT 203148/Z/16/Z) and the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy{\textquoteright}s & St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London and King{\textquoteright}s College Hospital NHS Foundation Trust. Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

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doi = "10.1021/acs.jmedchem.1c01286",

language = "English",

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Capuana, F, Phinikaridou, A, Stefania, R, Padovan, S, Lavin, B, Lacerda, S, Almouazen, E, Chevalier, Y, Heinrich-Balard, L, Botnar, RM, Aime, S & Digilio, G 2021, 'Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin', Journal of Medicinal Chemistry, vol. 64, no. 20, pp. 15250-15261. https://doi.org/10.1021/acs.jmedchem.1c01286

TY - JOUR

T1 - Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin

AU - Capuana, Federico

AU - Phinikaridou, Alkystis

AU - Stefania, Rachele

AU - Padovan, Sergio

AU - Lavin, Begoña

AU - Lacerda, Sara

AU - Almouazen, Eyad

AU - Chevalier, Yves

AU - Heinrich-Balard, Laurence

AU - Botnar, René M.

AU - Aime, Silvio

AU - Digilio, Giuseppe

N1 - Funding Information: This project has received funding from the EU’s H2020 research and innovation program under the grant agreement No. 668142 (SPCCT). This study was funded by the British Heart Foundation (RG/20/1/34802), the BHF Centre of Excellence (RE/08/03), and the Chilean Agency of Technology and Science (CONICYT-PIA-Anillo ACT1416). This work was also supported by the Wellcome EPSRC Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z) and the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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 (KD = 41 ± 12 μM), 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.

AB - 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 (KD = 41 ± 12 μM), 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.

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U2 - 10.1021/acs.jmedchem.1c01286

DO - 10.1021/acs.jmedchem.1c01286

M3 - Article

AN - SCOPUS:85118597307

SN - 0022-2623

VL - 64

SP - 15250

EP - 15261

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

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

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