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.

Engineering Tumour Cell-Binding Synthetic Polymers with Sensing Dense Transporters Associated with Aberrant Glutamine Metabolism

“…Because BzlSer is a competitive inhibitor for ASCT2 with an inhibition constant ( K i ) of 0.9 mM 29 , apparent K d values of these polymers can be estimated by assuming a simple inhibition model 30 . PLys(Gln)-100 showed apparent K d value of 62 nM, which is comparable to the K d value of potent ligands 13 .…”

“…The cells were analysed using flow cytometer, and half maximal inhibitory concentrations (IC 50 ) of BzlSer were calculated. Apparent dissociation constant ( K d ) of the polymers were estimated using the obtained IC 50 values, following Cheng-Prusoff equation (1) 30, 39 :where K i is the apparent inhibition constant of BzlSer for ASCT2 (0.9 mM), and [L] is the polymer concentration in this assay. For the inhibition of PLys(Gln)-50 and PLys(α-Glu)-100, concentration of both polymers was changed to 3 μM.…”

An oxime-based glycocluster microarray

“…With these aldehyde surfaces in hand, four aminooxyglycosylated structures have been synthesized to be immobilized. On the basis of recent binding studies performed with lectin and cyclopeptide-based glycoclusters in solution [30][31][32][33][34][35][36][37] and on solid-support, [38][39][40][41] we have selected similar structures ( Fig. 2) for this study that are: (i) tetravalent cyclopeptides displaying β-lactose 1a or α-N-acetylgalactosamine 1b and (ii) monomeric glycans 2a-b 40 which are selective for lectins PNA from Arachis hypogaea ( peanut) and HPA (Helix pomatia agglutinin) respectively.…”

Supramolecular glyco-poly-cyclodextrin functionalized thin-layer manganese dioxide for targeted stimulus-responsive bioimaging

“…This suggests the sharp difference in preferred multivalent glycostructures of ASGPr and MR probably because of the different membrane-bound architectures of the receptors. [26][27][28] To corroborate the receptor-targeting ability of the probes, a competition assay was carried out. The result indicated that the presence of increasing free D-mannose and D-galactose gradually suppressed the fluorescence of poly-CD 100 and poly-CD 6 probe produced in MDA-MB-231 and Hep-G2 cells, respectively (Fig.…”