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“Polymultivalent” polymer/peptide-cluster conjugates for an enhanced targeting of cells expressing ##-integrins v
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Damien Duret, Adrien Grassin, Maxime Henry, Thibault Jacquet, Fabien Thoreau, Sandrine Denis-Quanquin, Jean-Luc Coll, Didier Boturyn, Arnaud Favier, and Marie-Thérèse Charreyre Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/ acs.bioconjchem.7b00362 • Publication Date (Web): 02 Aug 2017 Downloaded from http://pubs.acs.org on August 4, 2017
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Bioconjugate Chemistry
“Polymultivalent” polymer/peptide-cluster conjugates for an enhanced targeting of cells expressing v3-integrins Damien Duret,a,b Adrien Grassin,c Maxime Henry,d Thibault Jacquet,d Fabien Thoreau,c,d Sandrine Denis-Quanquin,e Jean-Luc Coll,d* Didier Boturyn,c* Arnaud Favier,a,b* Marie-Thérèse Charreyrea,b a
Univ Lyon, Université Lyon 1, INSA de Lyon, CNRS, Laboratoire Ingénierie des Matériaux Polymères, UMR5223, F69621 Villeurbanne, France. b Univ Lyon, Ens de Lyon, CNRS, Laboratoire Joliot-Curie, USR3010, F-69364 Lyon, France. c Univ. Grenoble Alpes, CNRS, DCM UMR 5250, F-38000 Grenoble, France. d Centre de Recherche UGA-INSERM U1209 - UMR CNRS 5309, Institute for Advanced Biosciences, F-38700 Grenoble, France. e Univ Lyon, Ens de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie, UMR5182, F-69342 Lyon, France. Supporting Information Placeholder ABSTRACT: A new class of “polymultivalent” ligands combining several ligand-clusters and a water-soluble biocompatible polymer is introduced. These original conjugates bear two levels of multivalency. They are prepared by covalent coupling of a controlled number of tetrameric cRGD peptide-clusters along a well-defined copolymer synthesized by RAFT polymerization. The presence of multiple copies of peptide-clusters on the same polymer backbone resulted in a much higher relative potency than the free cluster reference. Thanks to the “polymultivalency”, up to ~2 orders of magnitude potency enhancement was reached in a competitive cell adhesion assay (nanomolar range IC50 values). In addition, confocal microscopy and flow cytometry demonstrated that fluorescent “polymultivalent” conjugates (emitting in the farred/near-infrared) were able to specifically and selectively label cells expressing v3-integrin, the natural receptor of cRGD.
Biospecific molecular recognition plays a pivotal role in many life processes and often relies on the multivalent interactions between ligands and their target receptors.1 For several years now, the concept of multivalency has been taken over by chemists to design a wide range of multivalent ligands consisting in several monovalent ligands grafted onto a multifunctional scaffold for diagnostic and/or therapeutic applications.2 As reported by Kiessling et al., multivalent ligands can interact with their target through various mechanisms, including chelating, subsite binding, statistical rebinding, steric stabilization and clustering effects.3 Considering ligand systems either soluble or dispersible in water, two categories can be distinguished depending on the size of the scaffold. On the one hand, a large number of clusters of ligands have been prepared from different low molecular weight scaffolds (ca
