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Development of silver-based hybrid nanoparticles loaded with eEF2 K-siRNA and quercetin against triple-negative
Orhan Burak Eksi1,2, Ahsen Guler3,4, Munevver Akdeniz2,5
1ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Turkey.
Abstract:
Breast cancer is the most common cancer among women, with approximately 2.3 million new cases globally. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, making it unresponsive to traditional therapies. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is overexpressed in TNBC, promoting cell survival by inhibiting apoptosis through phosphorylation of eEF2. Recently, eEF2K has been targeted for cancer therapy, and siRNA-based gene therapy has emerged as an effective approach to silence overexpressed genes. However, siRNA delivery is challenging due to its instability and susceptibility to degradation. In this study, we developed a novel hybrid nanoparticle (HNP) using a Layer-by-Layer (LbL) method for siRNA delivery targeting eEF2K in TNBC. The HNPs consist of a silver nanoparticle (AgNP) core, coated with poly (allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS), and loaded with eEF2K-siRNA and quercetin (QU), a chemotherapeutic agent, in separate layers. The nanoparticles also incorporated 4-ATP molecules for Raman traceability. In vitro experiments on TNBC cell lines (MDA-MB-231, BT-549, 4T1) showed that the combination therapy of eEF2K-siRNA and QU reduced cell viability, inhibited colony formation, and suppressed cell migration. At high 120 nM of siRNA concentration, 3D spheroid disintegration, activation of apoptotic pathways, and eventual necrotic cell death were observed. The results demonstrate that the developed HNPs are non-toxic, effective, and offer potential as a theranostic platform for TNBC treatment.
Insights
This study introduces novel hybrid nanoparticles for triple-negative breast cancer (TNBC) treatment. These nanoparticles effectively deliver siRNA targeting eEF2K and quercetin, reducing cancer cell viability and promoting apoptosis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking standard therapeutic targets.
- Eukaryotic Elongation Factor 2 Kinase (eEF2K) is overexpressed in TNBC, promoting cancer cell survival.
- Effective siRNA delivery for gene silencing in TNBC remains a significant challenge.
Purpose of the Study:
- To develop a novel hybrid nanoparticle (HNP) system for targeted siRNA delivery against eEF2K in TNBC.
- To evaluate the combined therapeutic effect of eEF2K-siRNA and quercetin (QU) loaded HNPs on TNBC cells.
- To assess the potential of HNPs as a theranostic platform for TNBC treatment.
Main Methods:
- Fabrication of HNPs using a Layer-by-Layer (LbL) method with a silver nanoparticle (AgNP) core, PAH/PSS coatings, eEF2K-siRNA, quercetin, and 4-ATP for Raman traceability.
- In vitro evaluation of HNPs on TNBC cell lines (MDA-MB-231, BT-549, 4T1) including cell viability, colony formation, and migration assays.
- Assessment of apoptotic pathway activation and cell death mechanisms at high siRNA concentrations.
Main Results:
- The developed HNPs demonstrated significant reduction in TNBC cell viability, colony formation, and migration.
- High concentrations of eEF2K-siRNA within HNPs induced 3D spheroid disintegration and activated apoptotic pathways.
- The combination therapy showed synergistic effects, leading to necrotic cell death and suppressed tumor growth.
- The HNPs were found to be non-toxic to TNBC cells, indicating a favorable safety profile.
Conclusions:
- The novel LbL-assembled HNPs offer an effective and non-toxic platform for co-delivery of eEF2K-siRNA and quercetin in TNBC.
- This theranostic approach shows promise for overcoming treatment resistance in aggressive TNBC subtypes.
- Further investigation into in vivo efficacy and theranostic applications of these HNPs is warranted.
