Development and evaluation of a solid lipid nanoparticle-based drug delivery system co-loaded with ivermectin and gefitinib, for targeting hsp27-mediated resistance in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a subtype of Breast Cancer which is negative for the presence of ER/PR and HER2 receptors. This type of Breast Cancer is a more aggressive, highly mesenchymal model with limiting targeted therapeutic options. TNBC is deemed triple negative for the three major biomarkers of Breast Cancer, but it is EGFR positive i.e., overexpression of the Epidermal Growth Factor Receptor (EGFR) is seen in TNBC, yet EGFR-targeted therapies like Gefitinib (EGFR-TKI) have shown limited efficacy due to intrinsic resistance mechanisms. Heat Shock Protein 27 (HSP27), a molecular chaperone protein, is often upregulated in many cancer models, including the aggressive, stem-cell oriented TNBC. It is known to contribute to bypass signaling mechanisms even in the presence of EGFR TKIs which leads to TNBC progression and drug resistance. Ivermectin, an FDA-approved antiparasitic agent, has been identified as an HSP27 inhibitor with anticancer potential. This study aims to develop and evaluate a Solid Lipid Nanoparticle (SLN)-based drug delivery system co-loaded with Gefitinib and Ivermectin to enhance therapeutic effects against TNBC. SLNs were synthesized using the solvent evaporation and emulsification method to improve drug solubility, stability, and targeted delivery. Cytotoxicity was assessed using the MTT assay and the anti-migratory effect was evaluated via the scratch assay. Furthermore, molecular analysis through RT- PCR was conducted to examine the expression of EGFR, HSP27, SHP-1, and EMT markers. The results demonstrated that SLN-encapsulated Gefitinib and Ivermectin exhibited enhanced cytotoxicity, significantly reduced cell migration, and modulated key molecular markers associated with TNBC progression. These findings suggest that SLN-based co-delivery of Gefitinib and Ivermectin holds potential as a novel therapeutic approach for overcoming drug resistance in TNBC.