New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

Abstract

In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21–75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20–35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.

Development of Asialoglycoprotein-Mediated Hepatocyte-Targeting Antitumor Prodrugs Triggered by Glutathione

“…This may be because ASGPR on the cell membrane was almost saturated by galactose, being consistent with our previous experiments. It was reported that monovalent N -acetyl- d -galactosamine (GalNAc) or trivalent (GalNAc) 3 can competitively inhibit the uptake of GalNAc-conjugated docetaxel in HepG2 cells, also supporting our results. Clearly, the hepatocyte-targeting capacity of prodrugs ( W-1-5, W-2-9 , and W-3-8) is driven by the specific recognition of the galactose group toward ASGPR.…”

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

“…Typical targeting ligands mainly include antibodies, folic acid, galactose/lactose and some oligopeptides. [14][15][16] The galactosyl receptor, asialoglycoprotein receptor (ASGPR), is abundant on the surface of liver tumor cells. Therefore, the carrier modified with galactose could introduce active targeting capability and convenient internalization through endocytosis of liver tumor cells.…”

Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability

“…Two N -acetylgalactosamine derivatives A and B were used as structural blocks to produce atorvastatin conjugates (Scheme 1). Azides A and B were previously successfully applied by our group for the synthesis of several antitumor drug conjugates (doxorubicin, 14 paclitaxel, 15 and docetaxel 16 ). Therefore, in this work the ligands were obtained using the earlier elaborated techniques.…”