New small-molecule glycoconjugates of docetaxel and GalNAc for targeted delivery to hepatocellular carcinomaстатьяКраткое сообщение
Статья опубликована в высокорейтинговом журнале
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Дата последнего поиска статьи во внешних источниках: 24 февраля 2021 г.
Аннотация: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 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 docet-axel and a prodrug lability to intracellular conditions with half-life values from 25.5 to 42 hours. We also found that trivalent con-jugate 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 analogs. In addition, we showed enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.