β3 Integrin siRNA-Loaded Multifunctional Nanoparticle Therapy for Metastatic Breast Cancer

M. Gujrati, J.G. Parvani, W.P. Schiemann, Z.R. Lu
Case Western Reserve University, US

Keywords: siRNA, nanoparticle, metastatic breast cancer

Summary:

Successful siRNA-mediated cancer therapy requires the use of multifunctional nanoparticle systems to overcome the barriers associated with delivery. We have recently developed a cationic lipid-based carrier, ECO, which efficiently delivers siRNA intracellularly to induce potent gene silencing. ECO forms stable nanoparticles (NPs) with siRNA that protect the payload against degradation, promote endosomal escape following cellular internalization, and facilitate cytosolic siRNA release via a glutathione-dependent mechanism. In breast cancer, β3 integrin is linked to the acquisition of metastasis via TGF-β-induced epithelial-to-mesenchymal transition (EMT). As such, silencing of β3 integrin with ECO NPs (ECO/siβ3 NPs) may be an attractive therapeutic means of combating metastatic breast cancer. In NME cells stimulated with TGF-β, ECO/siβ3 NPs successfully induced silencing of β3 integrin, restored expression levels of EMT markers (N-cadherin and E-cadherin), and suppressed the formation of actin stress fibers, a hallmark event that occurs during EMT. Importantly, in a 3D organotypic model, treatment of metastatic NME cells with ECO/siβ3 NPs both inhibited growth and led to a decrease in mammosphere size. Taken together, the multifunctional ECO NPs loaded with β3 integrin siRNA are a promising therapeutic modality for the treatment of metastatic breast cancer.