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 Gray, Wassana Yantasee

Research output: Contribution to journalArticle

87 Citations (Scopus)

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

Fingerprint

breast
Silicon Dioxide
Small Interfering RNA
delivery
Polymers
cancer
Silica
Nanoparticles
silicon dioxide
nanoparticles
polymers
Tumors
Blood
tumors
blood
oncogenes
Polyethyleneimine
production engineering
dosage
blood cells

Keywords

  • breast cancer
  • cancer nanomedicine
  • mesoporous silica nanoparticles

ASJC Scopus subject areas

  • Biomaterials
  • Electrochemistry
  • Condensed Matter Physics
  • Electronic, Optical and Magnetic Materials

Cite this

Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer. / Ngamcherdtrakul, Worapol; Morry, Jingga; Gu, Shenda; Castro, David J.; Goodyear, Shaun M.; Sangvanich, Thanapon; Reda, Moataz M.; Lee, Richard; Mihelic, Samuel A.; Beckman, Brandon L.; Hu, Zhi; Gray, Joe; Yantasee, Wassana.

In: Advanced Functional Materials, Vol. 25, No. 18, 13.05.2015, p. 2646-2659.

Research output: Contribution to journalArticle

Ngamcherdtrakul, W, Morry, J, Gu, S, Castro, DJ, Goodyear, SM, Sangvanich, T, Reda, MM, Lee, R, Mihelic, SA, Beckman, BL, Hu, Z, Gray, J & Yantasee, W 2015, 'Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer', Advanced Functional Materials, vol. 25, no. 18, pp. 2646-2659. https://doi.org/10.1002/adfm.201404629
Ngamcherdtrakul, Worapol ; Morry, Jingga ; Gu, Shenda ; Castro, David J. ; Goodyear, Shaun M. ; Sangvanich, Thanapon ; Reda, Moataz M. ; Lee, Richard ; Mihelic, Samuel A. ; Beckman, Brandon L. ; Hu, Zhi ; Gray, Joe ; Yantasee, Wassana. / Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer. In: Advanced Functional Materials. 2015 ; Vol. 25, No. 18. pp. 2646-2659.
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