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Silencing β3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple-Negative Breast Cancer.

Abstract
Metastatic breast cancer is the second leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Because previous studies coupled β3 integrin (ITGB3) to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/siβ3). Treatment of TNBC cells with ECO/siβ3 was sufficient to effectively silence β3 integrin expression, attenuate TGFβ-mediated EMT and invasion, restore TGFβ-mediated cytostasis, and inhibit three-dimensional organoid growth. Modification of ECO/siβ3 nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/siβ3 nanoparticles in vivo alleviated primary tumor burden and, more importantly, significantly inhibited metastasis. In the span of 16 weeks of the experiments and observations, including primary tumor resection at week 9 and release from the treatment for 4 weeks, the mice bearing orthotopic, TGFβ-prestimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/siβ3 nanoparticles were free of metastases and relapse, in comparison with untreated mice. Collectively, these results highlight ECO/siβ3 nanoparticles as a promising therapeutic regimen to combat TNBC.
AuthorsJenny G Parvani, Maneesh D Gujrati, Margaret A Mack, William P Schiemann, Zheng-Rong Lu
JournalCancer research (Cancer Res) Vol. 75 Issue 11 Pg. 2316-25 (Jun 1 2015) ISSN: 1538-7445 [Electronic] United States
PMID25858145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright©2015 American Association for Cancer Research.
Chemical References
  • ITGB3 protein, human
  • Integrin beta3
  • RNA, Small Interfering
Topics
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Epithelial-Mesenchymal Transition (drug effects, genetics)
  • Female
  • Humans
  • Integrin beta3 (genetics)
  • Mice
  • Nanoparticles (administration & dosage, chemistry)
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • RNA, Small Interfering (administration & dosage, chemistry)
  • Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)
  • Xenograft Model Antitumor Assays

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