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

Abstract

One antitumor β-elemene derivative W-105 and three novel hepatocyte-targeting prodrugs (W-1-5, W-2-9, and W-3-8) were designed and synthesized. W-105 (IC 50 6.107 μM) could cause cell apoptosis through upregulating the activity of caspase-3. The hepatocytetargeting capacities of the aimed compounds followed the W-105 (parent compound) < W-1-5 (monodentate-galactose) < W-2-9 (bidentategalactose) < W-3-8 (tridentate-galactose) order, which is attributed to the excellent affinity of the galactose ligand to ASGPR and the galactosecluster recognition effect. Furthermore, prodrugs W-3-8 exhibited good antitumor activity and low toxic side effects. The liquid chromatographymass spectrometry (LC-MS) assays revealed that prodrugs (W-1-5, W-2-9, and W-3-8) could release the antitumor pharmacophore in the presence of GSH (mimic the condition of the tumor cell) and maintain the low-toxic structures in the absence of GSH (mimic the condition of the normal cell). The release mechanisms of prodrugs were also proposed. Overall, these prodrugs developed in this study had potential in the treatment of liver cancer.

Glutathione‐triggered prodrugs: Design strategies, potential applications, and perspectives

“…138 Wang et al designed a series of prodrugs (20, 21, and 22) that utilize asialoglycoprotein-mediated targeting to hepatocytes, incorporating the anticancer agent W-105, a galactose moiety as a hepatocyte-targeting ligand, and a disulfide linker sensitive to GSH (Figure 13). 139 Upon decomposition of the prodrug's disulfide bond by GSH, the resulting thiol group does not undergo ring closure, as demonstrated in the study. Both in vitro and in vivo experiments indicated a preferential hepatocyte-targeting capacity of the prodrugs in the following order: 20 (monodentate-galactose) < 21 (bidentate-galactose) < 22 (tridentate-galactose) lactose.…”

Design, Synthesis, and Biomedical Applications of Glycotripods for Targeting Trimeric Lectins

“…The synthesized gly-coconjugates of docetaxel have better water solubility (21-75 fold increase) than the parental docetaxel and have binding affinity in the nanomolar range for ASGPR. The docetaxel-based glycoconjugates facilitate the enhanced generation of ROS in In 2021, Wang and coworkers [34] synthesized hepatocyte targeting β-elemene based prodrug using tridentate conjugated galactoside (Figure 6A). The synthesized prodrug tri-Galelemene shows good anticancer activity and low cytotoxic effect.…”

“…In 2021, Wang and coworkers [34] synthesized hepatocyte targeting β ‐elemene based prodrug using tridentate conjugated galactoside (Figure 6A). The synthesized prodrug tri‐Gal‐elemene shows good anticancer activity and low cytotoxic effect.…”

Expression and functions of transient receptor potential channels in liver diseases

“…Reassuringly, a safe hepatic-targeted prodrug system has been recently established and validated in NAFLD and HCC in vitro as well as in vivo models. The system relies on the excellent affinity of the galactose to asialoglycoprotein receptors specifically expressed in hepatocytes 109 , 110 , 111 . This efficient drug delivery system supplies therapeutic potential to optimize liver disease treatment using TRP channel drugs by minimizing adverse effects resulted from other organs or tissues.…”