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 cancerrelated 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 b3 integrin siRNA via lipid ECO-based nanoparticles (ECO/sibβ). Treatment of TNBC cells with ECO/sibβ was sufficient to effectively silence b3 integrin expression, attenuate TGFβ-mediated EMT and invasion, restore TGFb-mediated cytostasis, and inhibit three-dimensional organoid growth. Modification of ECO/sibβ nanoparticles with an RGD peptide via a PEG spacer enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted ECO/sibβ 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/sibβ nanoparticles were free of metastases and relapse, in comparison with untreated mice. Collectively, these results highlight ECO/sibβ nanoparticles as a promising therapeutic regimen to combat TNBC.