Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity

Abstract Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker α V β 3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted i...

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Autores principales:	Jamila Hedhli, Andrzej Czerwinski, Matthew Schuelke, Agata Płoska, Paweł Sowinski, Lukas La Hood, Spencer B. Mamer, John A. Cole, Paulina Czaplewska, Maciej Banach, Iwona T. Dobrucki, Leszek Kalinowski, Princess Imoukhuede, Lawrence W. Dobrucki
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a13378b9daa048489352531ff02d2d26
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spelling	oai:doaj.org-article:a13378b9daa048489352531ff02d2d262021-12-02T12:31:45ZSynthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity10.1038/s41598-017-03224-82045-2322https://doaj.org/article/a13378b9daa048489352531ff02d2d262017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03224-8https://doaj.org/toc/2045-2322Abstract Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker α V β 3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted imaging of α V β 3 activity (a radiolabeled version, 64Cu-NOTA-PEG4-cRGD2, for PET imaging, and a fluorescent version, FITC-PEG4-cRGD2, for in vitro work). We investigated the performance of this probe at the receptor, cell, organ, and whole-body levels, including its use to detect diabetes associated impairment of ischemia-induced myocardial angiogenesis. Both versions of the probe were found to be stable, demonstrated fast receptor association constants, and showed high specificity for α V β 3 in HUVECs (K d ~ 35 nM). Dynamic PET-CT imaging indicated rapid blood clearance via kidney filtration, and accumulation within α V β 3-positive infarcted myocardium. 64Cu-NOTA-PEG4-cRGD2 demonstrated a favorable biodistribution, slow washout, and excellent performance with respect to the quality of the PET-CT images obtained. Importantly, the ratio of probe uptake in infarcted heart tissue compared to normal tissue was significantly higher in non-diabetic rats than in diabetic ones. Overall, our probes are promising agents for non-invasive quantitative imaging of α V β 3 expression, both in vitro and in vivo.Jamila HedhliAndrzej CzerwinskiMatthew SchuelkeAgata PłoskaPaweł SowinskiLukas La HoodSpencer B. MamerJohn A. ColePaulina CzaplewskaMaciej BanachIwona T. DobruckiLeszek KalinowskiPrincess ImoukhuedeLawrence W. DobruckiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jamila Hedhli Andrzej Czerwinski Matthew Schuelke Agata Płoska Paweł Sowinski Lukas La Hood Spencer B. Mamer John A. Cole Paulina Czaplewska Maciej Banach Iwona T. Dobrucki Leszek Kalinowski Princess Imoukhuede Lawrence W. Dobrucki Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
description	Abstract Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker α V β 3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted imaging of α V β 3 activity (a radiolabeled version, 64Cu-NOTA-PEG4-cRGD2, for PET imaging, and a fluorescent version, FITC-PEG4-cRGD2, for in vitro work). We investigated the performance of this probe at the receptor, cell, organ, and whole-body levels, including its use to detect diabetes associated impairment of ischemia-induced myocardial angiogenesis. Both versions of the probe were found to be stable, demonstrated fast receptor association constants, and showed high specificity for α V β 3 in HUVECs (K d ~ 35 nM). Dynamic PET-CT imaging indicated rapid blood clearance via kidney filtration, and accumulation within α V β 3-positive infarcted myocardium. 64Cu-NOTA-PEG4-cRGD2 demonstrated a favorable biodistribution, slow washout, and excellent performance with respect to the quality of the PET-CT images obtained. Importantly, the ratio of probe uptake in infarcted heart tissue compared to normal tissue was significantly higher in non-diabetic rats than in diabetic ones. Overall, our probes are promising agents for non-invasive quantitative imaging of α V β 3 expression, both in vitro and in vivo.
format	article
author	Jamila Hedhli Andrzej Czerwinski Matthew Schuelke Agata Płoska Paweł Sowinski Lukas La Hood Spencer B. Mamer John A. Cole Paulina Czaplewska Maciej Banach Iwona T. Dobrucki Leszek Kalinowski Princess Imoukhuede Lawrence W. Dobrucki
author_facet	Jamila Hedhli Andrzej Czerwinski Matthew Schuelke Agata Płoska Paweł Sowinski Lukas La Hood Spencer B. Mamer John A. Cole Paulina Czaplewska Maciej Banach Iwona T. Dobrucki Leszek Kalinowski Princess Imoukhuede Lawrence W. Dobrucki
author_sort	Jamila Hedhli
title	Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
title_short	Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
title_full	Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
title_fullStr	Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
title_full_unstemmed	Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity
title_sort	synthesis, chemical characterization and multiscale biological evaluation of a dimeric-crgd peptide for targeted imaging of α v β 3 integrin activity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a13378b9daa048489352531ff02d2d26
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Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity

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