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Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer
Thoa Thi Kim Nguyen1, Seon Min Woo2, Seung Un Seo2
1College of Pharmacy, Keimyung University, Daegu, 42602, Republic of Korea; Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.
Insights
This study developed novel nanoparticles combining Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and Odanacatib (ODN) to overcome cancer cell resistance. The TRAIL-ODN-PLGA-NPs formulation demonstrated synergistic anticancer effects in vitro and in vivo.
Area of Science:
- Nanotechnology in Cancer Therapy
- Molecular Oncology
- Drug Delivery Systems
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but faces resistance.
- Odanacatib (ODN), a cathepsin K inhibitor, shows potential as a sensitizer to enhance TRAIL efficacy.
- Combination therapy is a promising strategy to improve TRAIL-based cancer treatments.
Purpose of the Study:
- To develop and evaluate ODN-loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs).
- To investigate the efficacy of TRAIL-ODN-PLGA-NPs in targeting and treating TRAIL-resistant cancers.
- To explore the synergistic effects of combined TRAIL and ODN delivery via nanoparticles.
Main Methods:
- Formulation of ODN-loaded PLGA nanoparticles conjugated with GST-TRAIL.
- Assessment of cellular uptake via death receptors (DR4/DR5) on cancer cells.
- In vitro and in vivo evaluation of TRAIL-resistant and TRAIL-sensitive cancer models.
- Analysis of molecular mechanisms including protein expression (Raptor, Bim, Bax) and reactive oxygen species (ROS) generation.
- Biodistribution studies in tumor-bearing animal models.
Main Results:
- TRAIL-ODN-PLGA-NPs significantly increased cellular uptake and selectively killed TRAIL-resistant cancer cells.
- The nanoparticles enhanced TRAIL-induced apoptosis by downregulating Raptor, stabilizing Bim, and increasing mitochondrial ROS.
- In vivo studies showed preferential tumor accumulation and significant inhibition of xenograft tumor growth.
- The formulation modulated the tumor microenvironment by increasing TNF-α and decreasing IL-6 levels.
Conclusions:
- TRAIL-ODN-PLGA-NPs exhibit synergistic anticancer effects superior to free drug combinations.
- This novel nanoparticle formulation represents a promising therapeutic candidate for overcoming TRAIL resistance in cancer treatment.
- The study highlights the potential of targeted nanoparticle delivery for enhancing TRAIL-based apoptosis induction.
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