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

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.

Automated summary

The study developed covalent and low molecular weight docetaxel delivery systems conjugated with N-acetyl-D-galactosamine, showing excellent affinity to ASGPR and high cytotoxicity against hepatocellular carcinoma cells. The glycoconjugates also exhibited significantly increased water solubility and prodrug lability, as well as selective toxicity against hepatoma cells compared to control cell lines. Additionally, specific ASGPR-mediated cellular uptake of the conjugates and enhanced generation of reactive oxygen species in HepG2 cells were observed, highlighting the potential of ASGPR-directed taxane drugs for selective therapy of hepatocellular carcinoma.