Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer.

Autor: Nguyen TTK; College of Pharmacy, Keimyung University, Daegu, 42602, Republic of Korea; Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea., Woo SM; Department of Immunology, School of medicine, Keimyung University, Daegu, Republic of Korea., Seo SU; Department of Immunology, School of medicine, Keimyung University, Daegu, Republic of Korea., Banstola A; Department of Dermatology, Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA., Kim H; College of Pharmacy, Keimyung University, Daegu, 42602, Republic of Korea., Duwa R; Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Radiology, Molecular Imaging Program at Stanford (MIPS), School of medicine, Stanford University, Stanford, CA, 94305, USA., Vu ATT; College of Pharmacy, Keimyung University, Daegu, 42602, Republic of Korea., Hong IS; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea., Kwon TK; Department of Immunology, School of medicine, Keimyung University, Daegu, Republic of Korea; Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, 42601, Republic of Korea. Electronic address: kwontk@dsmc.or.kr., Yook S; Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: ysimmyung@skku.edu.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2025 Jan; Vol. 312, pp. 122733. Date of Electronic Publication: 2024 Jul 30.
DOI: 10.1016/j.biomaterials.2024.122733
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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