Salinomycin-Loaded Small-Molecule Nanoprodrugs Enhance Anticancer Activity in Hepatocellular Carcinoma

Int J Nanomedicine. 2020 Sep 15:15:6839-6854. doi: 10.2147/IJN.S236928. eCollection 2020.

Abstract

Background: There is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC.

Methods: We constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG2000. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice.

Results: Delivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient.

Conclusion: Our results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.

Keywords: cancer stem cells; hepatocellular carcinoma; salinomycin; self-assemble; small-molecule prodrugs.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Humans
  • Irinotecan / analogs & derivatives*
  • Irinotecan / chemistry
  • Irinotecan / pharmacology
  • Irinotecan / therapeutic use
  • Linoleic Acid / chemistry
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles / chemistry
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Phosphatidylethanolamines / chemistry
  • Polyethylene Glycols / chemistry
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Prodrugs / therapeutic use
  • Pyrans / administration & dosage
  • Pyrans / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
  • Antineoplastic Agents
  • LA-SN38
  • Phosphatidylethanolamines
  • Prodrugs
  • Pyrans
  • Polyethylene Glycols
  • salinomycin
  • Irinotecan
  • Linoleic Acid

Grants and funding

This work was supported by the National S&T Major Project (No. 2017ZX10203205), the National Natural Science Foundation of China (No. 81801824), the Key Research & Development Plan of Zhejiang Province (No. 2019C03050) and the Major Science and Technology Project of Zhejiang Province (No. 2018C04010).