Nanoparticle delivery of siRNA against TWIST to reduce drug resistance and tumor growth in ovarian cancer models

Nanomedicine. 2017 Apr;13(3):965-976. doi: 10.1016/j.nano.2016.11.010. Epub 2016 Nov 25.

Abstract

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.

Keywords: Mesoporous silica nanoparticles; Ovarian cancer; Polyamidoamine dendrimers; Twist; siRNA.

MeSH terms

  • Animals
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Dendrimers / chemistry
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / pathology
  • Neoplasms, Glandular and Epithelial / therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Ovary / metabolism
  • Ovary / pathology
  • Porosity
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / therapeutic use*
  • RNAi Therapeutics / methods*
  • Silicon Dioxide / chemistry*
  • Twist-Related Protein 1 / genetics*

Substances

  • Dendrimers
  • PAMAM Starburst
  • RNA, Small Interfering
  • Twist-Related Protein 1
  • Silicon Dioxide