Nanoparticles-Facilitated Intracellular Transport of siRNAs against Individual Integrin Subunits Inhibits Growth of Breast Cancer Cells

Abstract

For cells and tissues, cell–cell and cell–extracellular matrix adhesion is important for proliferation, differentiation, and response to mechanical stimuli. This adhesion is provided by various cell adhesion molecules (CAMs). However, in breast cancer, depending upon the type and stage, this adherence is dysregulated where the expression of these cell adhesion molecules is either overregulated or unregulated, triggering essential oncogenic pathways. Thus, to control the invasiveness of tumor cells, and reduce metastasis, regulating the homophilic and heterophilic interaction of these molecules and controlling the essential cell pathways is important. In this study, we targeted critical CAMs- integrins to regulate their aberrated behavior via siRNAs delivery. However, as due to charge repulsion and propensity to be degraded by nucleases prior to reaching the target site, naked siRNAs are unable to cross plasma membrane, use of a suitable carrier vehicle is essential. Thus, we employed carbonate apatite (CA), to deliver the selected siRNAs targeting integrin αv, α6, β1, β3, β4, β5, and β6 subunits to various breast cancer cell lines and 4T1-breast cancer induced murine model. Delivery of individual integrin siRNAs complexed with CA nanoparticles (NPs) reduced cell viability and caused decrease in tumor burden. To check the gene knockdown effects on phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal–regulated kinases/mitogen-activated protein kinase (ERK/MAPK) pathways, Western blot analysis was performed, revealing downregulation of the signaling molecules. Thus, CA-facilitated gene therapy targeting various integrins could poise potential therapeutic modality against breast cancer.