A branched small molecule-drug conjugate nanomedicine strategy for the targeted HCC chemotherapy.

Abstract

Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.

• Authors: Sha-Sha Li, Cheng-Mei Zhang, Jing-De Wu, Chao Liu, Zhao-Peng Liu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 228 Pg. 114037 (Jan 15 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 34883290 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Small Molecule Libraries
• Galactosamine
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Galactosamine (chemistry, pharmacology)
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Molecular Structure
• Nanomedicine
• Paclitaxel (chemistry, pharmacology)
• Small Molecule Libraries (chemistry, pharmacology)
• Structure-Activity Relationship