Next-generation breast cancer therapies: leveraging nanoparticles and immunoliposomes for targeted drug and mirna delivery

Abstract

This thesis investigates innovative nanoparticle-based approaches for targeted breast cancer therapy, addressing key challenges in drug resistance, gene modulation, and targeted delivery. The research comprises three interconnected studies, each exploring distinct nanoparticle platforms and their molecular mechanisms of action. The initial study focused on methotrexate-conjugated gold nanoparticles (MTX GNPs) designed to overcome chemoresistance in breast cancer cell lines. MTX GNPs demonstrated significant efficacy in inducing apoptosis via mitochondrial mediated pathways in both MCF-7 and MDA-MB-231 cell lines. Molecular analysis revealed modulation of key apoptotic markers, including upregulation of pro apoptotic genes (Bax, Caspase-3, Caspase-9, APAF-1, p53) and downregulation of anti-apoptotic gene Bcl-2. The nanoconjugates exhibited enhanced cellular uptake through folate receptor-mediated endocytosis, bypassing the resistance mechanisms associated with the reduced folate carrier (RFC). The second study explored miRNA delivery using PEGylated gold nanoparticles, focusing on miR-206, which is typically downregulated in Luminal-A breast cancer. This nano-complex effectively delivered miR-206 to MCF-7 cells, resulting in G0 G1 cell cycle arrest and altered mitochondrial membrane potential. Mechanistically, the delivered miR-206 downregulated the NOTCH 3 pathway, a critical signaling cascade in breast cancer progression. This study highlighted the potential of nanoparticle-mediated miRNA delivery in regulating key oncogenic pathways and restoring tumor-suppressive functions. The final study presented an immunoliposomal formulation co-encapsulating paclitaxel and miRNA inhibitors for targeted therapy in HER2-positive breast cancer. This approach demonstrated synergistic antineoplastic effects both in vitro and in vivo. The immunoliposomes, functionalized with anti-HER2 antibodies, exhibited preferential uptake in HER2-overexpressing cells. Paclitaxel induced mitotic arrest and apoptosis through microtubule stabilization, while the co delivered miRNA inhibitors modulated specific oncogenic pathways, enhancing the overall therapeutic efficacy. In vivo xenograft studies showed significant tumor regression with minimal systemic toxicity, as confirmed by histopathological assessments. Collectively, these studies elucidate the multifaceted potential of nanoparticle-based delivery systems in enhancing therapeutic efficacy through improved drug delivery, overcoming resistance mechanisms, and enabling targeted combination therapies. The research demonstrates the versatility of nanoparticles in addressing various aspects of breast cancer biology, from bypassing drug efflux pumps to modulating gene expression and targeting specific cell surface receptors. These findings contribute significantly to the field of nanomedicine and offer promising avenues for personalized breast cancer treatment strategies, paving the way for more effective, targeted, and less toxic therapeutic interventions.