Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene

Int J Nanomedicine. 2019 May 17:14:3645-3667. doi: 10.2147/IJN.S207837. eCollection 2019.

Abstract

Background: Neo-adjuvant chemotherapy is an effective strategy for improving treatment of breast cancers. However, the efficacy of this treatment strategy is limited for treatment of triple negative breast cancer (TNBC). Gene therapy may be a more effective strategy for improving the prognosis of TNBC. Methods: A novel 25 nucleotide sense strand of miRNA was designed to treat TNBC by silencing the Slug gene, and encapsulated into DSPE-PEG2000-tLyp-1 peptide-modified functional liposomes. The efficacy of miRNA liposomes was evaluated on invasive TNBC cells and TNBC cancer-bearing nude mice. Furthermore, functional vinorelbine liposomes were constructed to investigate the anticancer effects of combined treatment. Results: The functional miRNA liposomes had a round shape and were nanosized (120 nm). Functional miRNA liposomes were effectively captured by TNBC cells in vitro and were target to mitochondria. Treatment with functional liposomes silenced the expression of Slug and Slug protein, inhibited the TGF-β1/Smad pathway, and inhibited invasiveness and growth of TNBC cells. In TNBC cancer-bearing mice, functional miRNA liposomes exerted a stronger anticancer effect than functional vinorelbine liposomes, and combination therapy with these two formulations resulted in nearly complete inhibition of tumor growth. Preliminary safety evaluations indicated that the functional miRNA liposomes did not affect body weight or cause damage to any major organs. Furthermore, the functional liposomes significantly increased the half-life of the drug in the blood of cancer-bearing nude mice, and increased drug accumulation in breast cancer tissues. Conclusion: In this study, we constructed novel functional miRNA liposomes. These liposomes silenced Slug expression and inhibited the TGF-β1/Smad pathway in TNBC cells, and enhanced anticancer efficacy in mice using combined chemotherapy. Hence, the present study demonstrated a promising strategy for gene therapy of invasive breast cancer.

Keywords: Slug; TGF-β1/Smad; TNBC; functional miRNA liposomes; gene therapy.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Endocytosis / drug effects
  • Female
  • Gene Silencing*
  • Humans
  • Liposomes
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nanoparticles / chemistry*
  • Neoplasm Invasiveness
  • Particle Size*
  • Phosphatidylethanolamines / chemistry
  • Polyethylene Glycols / chemistry
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Snail Family Transcription Factors / genetics*
  • Transforming Growth Factor beta1 / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy*

Substances

  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
  • Antineoplastic Agents
  • Liposomes
  • MicroRNAs
  • Phosphatidylethanolamines
  • Smad Proteins
  • Snail Family Transcription Factors
  • Transforming Growth Factor beta1
  • Polyethylene Glycols