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2015 ; 75
(11
): 2316-2325
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Silencing ?3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and
Metastasis of Triple-Negative Breast Cancer
#MMPMID25858145
Parvani JG
; Gujrati MD
; Mack MA
; Schiemann WP
; Lu ZR
Cancer Res
2015[Jun]; 75
(11
): 2316-2325
PMID25858145
show ga
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 ?3 integrin (ITGB3) to epithelial-mesenchymal
transition (EMT) and metastasis, we exploited ?3 integrin as a therapeutic target
to treat TNBC by delivering ?3 integrin siRNA via lipid ECO-based nanoparticles
(ECO/si?3). Treatment of TNBC cells with ECO/si?3 was sufficient to effectively
silence ?3 integrin expression, attenuate TGF?-mediated EMT and invasion, restore
TGF?-mediated cytostasis, and inhibit three-dimensional organoid growth.
Modification of ECO/si?3 nanoparticles with an RGD peptide via a PEG spacer
enhanced siRNA uptake by post-EMT cells. Intravenous injections of RGD-targeted
ECO/si?3 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,
TGF?-prestimulated MDA-MB-231 tumors that were treated with RGD-targeted ECO/si?3
nanoparticles were free of metastases and relapse, in comparison with untreated
mice. Collectively, these results highlight ECO/si?3 nanoparticles as a promising
therapeutic regimen to combat TNBC.
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