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ASGPR‐Mediated Uptake of Multivalent Glycoconjugates for Drug Delivery in Hepatocytes |
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| Authors: | Dr Marie Monestier Peggy Charbonnier Dr Christelle Gateau Dr Martine Cuillel Faustine Robert Colette Lebrun Dr Elisabeth Mintz Prof Olivier Renaudet Dr Pascale Delangle |
| Affiliation: | 1. Université Grenoble Alpes, INAC-SCIB, CEA, INAC-SCIB, Grenoble cedex 09, France;2. Université Grenoble Alpes, DCM, CNRS, DCM, Grenoble cedex 09, France;3. Université Grenoble Alpes, iRTSV-LCBM, CEA, iRTSV-LCBM, CNRS, iRTSV-LCBM, Grenoble cedex 09, France;4. Institut Universitaire de France, Paris, France |
| 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. |
| Keywords: | ASGPR drug targeting glycopeptide receptors synthetic drugs |
