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.