A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis

Biomaterials. 2022 Oct:289:121781. doi: 10.1016/j.biomaterials.2022.121781. Epub 2022 Sep 7.

Abstract

Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.

Keywords: Binary prodrug; Cancer stem cells; MDR1; Metastasis; Triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Caspase 3
  • Cell Line, Tumor
  • Humans
  • Irinotecan
  • Neoplasm Recurrence, Local / pathology
  • Neoplastic Stem Cells / pathology
  • Prodrugs* / pharmacology
  • Prodrugs* / therapeutic use
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / pathology

Substances

  • Prodrugs
  • Irinotecan
  • Aldehyde Dehydrogenase 1 Family
  • Caspase 3