New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma
| Autor: | Olga Y. Burenina, Dmitrii A Grishin, Yan A. Ivanenkov, Sergey V. Kovalev, Yury V. Timchenko, Alexander Vaneev, Svetlana Yu. Maklakova, Alexander G. Majouga, Natalia L. Klyachko, Rostislav A Petrov, Alexander Erofeev, Elena K. Beloglazkina, Emil Yu. Yamansarov, Roman Timoshenko, Petr V. Gorelkin, Elena V Lopatukhina, Evgenia E Ondar, Sergei A Evteev, Anton V Lopukhov, Sofiia R Mefedova |
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| Rok vydání: | 2020 |
| Předmět: |
Carcinoma
Hepatocellular Glycoconjugate Pharmaceutical Science Asialoglycoprotein Receptor Docetaxel Small Molecule Libraries Cell Line Tumor Drug Discovery medicine Humans Cytotoxicity chemistry.chemical_classification Drug Carriers Taxane Chemistry Liver Neoplasms Hep G2 Cells Prodrug Ligand (biochemistry) Small molecule HEK293 Cells Biochemistry Liver A549 Cells PC-3 Cells Hepatocytes Molecular Medicine Asialoglycoprotein receptor Glycoconjugates medicine.drug |
| Zdroj: | Molecular pharmaceutics. 18(1) |
| ISSN: | 1543-8392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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