Quercetin-loaded solid lipid nanoparticles enhance the anticancer efficacy of doxorubicin and celecoxib in breast cancer cells by modulation of apoptosis, angiogenesis, and miRNA signaling

Background: Chemotherapy resistance and treatment-related toxicity remain major barriers to successful breast cancer management. Nanotechnology-based delivery systems, particularly solid lipid nanoparticles, offer an effective strategy to overcome these limitations. To the best of our knowledge, the combined therapeutic potential of quercetin-loaded solid lipid nanoparticles (Q-SLNs) with doxorubicin (DOX) and celecoxib (CXB) with the involvement of miRNA that regulate tumor suppressor gene expression has not been comprehensively investigated in breast cancer. Objective: This study aimed to evaluate the ability of Q-SLNs to enhance the anticancer efficacy of DOX and CXB in MCF-7 and MDA-MB-231 cells through modulation of proliferation, autophagy, angiogene­sis, apoptosis and miRNA-associated signaling pathways. Methods: Q-SLNs were prepared using a microemulsification technique, employing glyceryl monostearate as the lipid matrix and Poloxamer 407 as the stabilizing surfactant. The morphology of the particles was examined using scanning electron microscopy and transmission electron microscopy. Particle size, polydispersity index, and zeta potential were determined by dynamic light scattering. Human breast cancer cell lines MCF-7 and MDA-MB-231 were used in experiments. Cells were assigned to five groups: control (0.1% DMSO), Q-treated, Q-SLN-treated, DOX+CXB-treated, and Q-SLNs+DOX+CXB-treated groups. Cell viability was evaluated with MTT assay. Treatment was administered at the respective IC50 values for 48 h. Levels of HSP90, caspase-9, VEGF, Beclin-1, and Ki67 were quantified by ELISA. Apoptosis was assessed by Annexin V-FITC/PI staining. The expression levels of miR-21 and miR-34a were quantified by qRT-PCR Results: Q-SLNs exhibited favorable nanoscale characteristics and enhanced cytotoxicity against breast cancer cells compared with free quercetin. The combination of Q-SLNs, DOX, and CXB exerted the strongest antiproliferative and pro-apoptotic effects, particularly in MDA-MB-231 cells. These effects were associated with downregulation of miR-21, VEGF, HSP90 and Ki67, alongside with upregulation of miR-34a and caspase-9, indicating suppression of tumor-promoting pathways and apoptosis activation. Conclusions: Overall, Q-SLNs significantly enhanced the therapeutic activity of DOX and CXB and represent a promising nanoplatform for improving breast cancer treatment by modulation of apoptosis, angiogenesis, and miRNA signaling.