MiR-200c synergizes with trastuzumab-loaded gold nanoparticles to overcome resistance in ovarian cancer cells

Background: Trastuzumab (TZ) resistance remains a significant challenge in the treatment of human epidermal growth factor receptor 2 (HER2)-positive epithelial ovarian cancer (EOC), necessitating novel therapeutic strategies to improve treatment efficacy. Functionalized gold nanoparticles (AuNPs) constitute a promising platform for drug delivery and the ability to enhance tumor targeting via the enhanced permeability and retention (EPR) effect. miR-200c, a well-established tumor suppressor microRNA (miRNA), plays a crucial role in inhibiting epithelial-mesenchymal transition (EMT). However, its role in modulating HER2 signaling pathways and sensitizing ovarian cancer cells to TZ remains largely unexplored. Here, we investigate for the first time the combinatorial effect of miR-200c and thiol-functionalized AuNPs (< 10 nm) loaded with TZ (AuNPs-TZ) in overcoming TZ resistance and enhancing treatment efficacy in ovarian cancer cells. Results: Pristine AuNPs were not cytotoxic, confirming their biocompatibility as a nanocarrier for TZ delivery. AuNPs were loaded noncovalently with TZ and maintained colloidal stability to prevent aggregation while facilitating effective cellular uptake. Treatment of ovarian cancer cells overexpressing miR-200c with AuNPs-TZ significantly reduced cell viability and increased apoptosis. Immunoblot analysis showed a reduction of phosphorylated HER2 and downstream Kirsten Rat Sarcoma Virus (KRAS) signaling. Furthermore, transmission electron microscopy (TEM) demonstrated morphological changes in miR-200c-transfected ovarian cancer cells and confirmed the localization of AuNPs carrying TZs on the cell membrane and in the cytoplasm. Conclusions: These findings highlight the potential of AuNPs-TZ delivery combined with miR-200c as a promising therapeutic strategy to improve the response of HER2-positive EOC to TZ treatment. These results imply the need to further develop AuNP/miRNA-based combinatorial therapies as a viable nanomedicine approach for drug-resistant cancers.