Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer

Worapol Ngamcherdtrakul, Jingga Morry, Shenda Gu, David J. Castro, Shaun M. Goodyear, Thanapon Sangvanich, Moataz M. Reda, Richard Lee, Samuel A. Mihelic, Brandon L. Beckman, Zhi Hu, Joe W. Gray, Wassana Yantasee

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47-nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine-polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2 nanoparticles produce apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2-) cells. One dose of the siHER2-nanoparticles reduces HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.

Original languageEnglish (US)
Pages (from-to)2646-2659
Number of pages14
JournalAdvanced Functional Materials
Volume25
Issue number18
DOIs
StatePublished - May 13 2015

Keywords

  • breast cancer
  • cancer nanomedicine
  • mesoporous silica nanoparticles

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics

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    Ngamcherdtrakul, W., Morry, J., Gu, S., Castro, D. J., Goodyear, S. M., Sangvanich, T., Reda, M. M., Lee, R., Mihelic, S. A., Beckman, B. L., Hu, Z., Gray, J. W., & Yantasee, W. (2015). Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer. Advanced Functional Materials, 25(18), 2646-2659. https://doi.org/10.1002/adfm.201404629