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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.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Petrov RA,Mefedova SR,Yamansarov EY,Maklakova SY,Grishin DA,Lopatukhina EV,Burenina OY,Lopukhov AV,Kovalev SV,Timchenko YV,Ondar EE,Ivanenkov YA,Evteev SA,Vaneev AN,Timoshenko RV,Klyachko NL,Erofeev AS,Gorelkin PV,Bel

doi

10.1021/acs.molpharmaceut.0c00980

subject

Has Abstract

pub_date

2021-01-04 00:00:00

pages

461-468

issue

1

eissn

1543-8384

issn

1543-8392

journal_volume

18

pub_type

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