title: ASGPR-Mediated Uptake of Multivalent Glycoconjugates for Drug Delivery in Hepatocytes.
abstract: Liver cells are an essential target for drug delivery in many diseases. The hepatocytes express the asialoglycoprotein receptor (ASGPR), which promotes specific uptake by means of N-acetylgalactosamine (GalNAc) recognition. In this work, we designed two different chemical architectures to treat Wilson's disease by intracellular copper chelation. Two glycoconjugates functionalized with three or four GalNAc units each were shown to enter hepatic cells and chelate copper. Here, we studied two series of compounds derived from these glycoconjugates to find key parameters for the targeting of human hepatocytes. Efficient cellular uptake was demonstrated by flow cytometry using HepG2 human heptic cells that express the human oligomeric ASGPR. Dissociation constants in the nanomolar range showed efficient multivalent interactions with the receptor. Both architectures were therefore concluded to be able to compete with endogeneous asialoglycoproteins and serve as good vehicles for drug delivery in hepatocytes.
authors.affiliation: Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, 17 rue des martyrs, 38054, Grenoble cedex 09, France.|Université Grenoble Alpes, DCM, CNRS, DCM, 570 rue de la chimie, 38041, Grenoble cedex 09, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Monestier
authors.affiliation: Université Grenoble Alpes, iRTSV-LCBM, CEA, iRTSV-LCBM, CNRS, iRTSV-LCBM, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Charbonnier
authors.affiliation: Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Gateau
authors.affiliation: Université Grenoble Alpes, iRTSV-LCBM, CEA, iRTSV-LCBM, CNRS, iRTSV-LCBM, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Cuillel
authors.affiliation: Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Faustine
authors.initials: F
authors.lastname: Robert
authors.affiliation: Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Lebrun
authors.affiliation: Université Grenoble Alpes, iRTSV-LCBM, CEA, iRTSV-LCBM, CNRS, iRTSV-LCBM, 17 rue des martyrs, 38054, Grenoble cedex 09, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mintz
authors.affiliation: Université Grenoble Alpes, DCM, CNRS, DCM, 570 rue de la chimie, 38041, Grenoble cedex 09, France.|Institut Universitaire de France, 103 boulevard Saint-Michel, 75005, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Renaudet
authors.affiliation: Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, 17 rue des martyrs, 38054, Grenoble cedex 09, France. pascale.delangle@cea.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: Delangle
mesh_terms: D037263:Asialoglycoprotein Receptor / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003300:Copper / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D005434:Flow Cytometry; D006001:Glycoconjugates / Q000737:chemistry* / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D018980:Williams Syndrome / Q000188:drug therapy
chemical_list: D037263:Asialoglycoprotein Receptor; D006001:Glycoconjugates; D003300:Copper
keywords: ASGPR; drug targeting; glycopeptide; receptors; synthetic drugs