Abstract
In the study of triple-negative breast cancer (TNBC) therapeutic approaches, researchers have recently focused on exploiting P-glycoprotein (P-gp) and hypoxia-inducible factor (HIF) inhibitors to enhance the effectiveness of chemotherapeutic agents, which are often limited by poor specificity and high toxicity. Additionally, herbal medicines have shown promising results as non-toxic P-gp and HIF inhibitors. However, the co-administration of chemotherapeutic agents with natural P-gp inhibitors, such as curcumin (CUR) or HIF-inhibitors like 6-aminoflavon (AF), remains challenging due to pharmacokinetic constraints. In the present work, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are employed as drug delivery systems. CUR, AF, and a lipophilic doxorubicin (DOXO) ester (C12-DOXO) were individually loaded into both systems and subsequently used in combination. SLNs, both naked and hyaluronic acid (HA)-decorated, and NLCs were prepared and characterized. Given that NLCs have not yielded fully satisfactory results regarding drug entrapment and recovery, we have, for the time being, focused further characterization studies and cell line experiments exclusively on SLNs. SLNs were therefore tested on DOXO-sensitive and DOXO-resistant TNBC cell lines (MDA-MB-231 and MDA-MB-231/DX cells, respectively). HA-decorated SLNs showed effective C12-DOXO accumulation in P-gp-expressing cells, significantly reducing cell viability, including in DOXO-resistant cells. The combination of HA-decorated SLNs containing C12-DOXO (SLN-C12-DOXO-HA) with HA-decorated SLNs containing CUR (SLN-CUR-HA) or AF (SLN-AF-HA) demonstrated a significant reduction in cell viability across all concentrations, exceeding the cytotoxicity noted in the application of SLN-C12-DOXO-HA alone, especially at higher concentrations in both DOXO sensitive and resistant cell lines.
Published Version
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