Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer
Date
2024-04-26
Journal Title
Journal ISSN
Volume Title
Publisher
Advanced Therapeutics
Abstract
The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, this work develops therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and β-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress β-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.
Description
This is the peer reviewed version of the following article: M. N. Dang, S. Suri, K. Li, C. Gomez Casas, G. Stigliano, R. S. Riley, M. A. Scully, E. C. Hoover, S. B. Aboeleneen, G. C. Kramarenko, E. S. Day, Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer. Adv. Therap. 2024, 2300426. https://doi.org/10.1002/adtp.202300426, which has been published in final form at https://doi.org/10.1002/adtp.202300426. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. © 2024 Wiley-VCH GmbH. This article will be embargoed until 04/26/2025.
Keywords
gold nanoparticles, gene regulation, signal cascade interference, RNA interference, targeted therapy, combination therapy, lung metastasis
Citation
M. N. Dang, S. Suri, K. Li, C. Gomez Casas, G. Stigliano, R. S. Riley, M. A. Scully, E. C. Hoover, S. B. Aboeleneen, G. C. Kramarenko, E. S. Day, Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer. Adv. Therap. 2024, 2300426. https://doi.org/10.1002/adtp.202300426