우선민 (계명대학교 의과대학)

한빛사논문

조회70

계명대학교 의과대학

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Biomaterials, Jul 30 2024, 312 S0142-9612(24)00267-9 | https://doi.org/10.1016/j.biomaterials.2024.122733 Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer

Thoa Thi Kim Nguyen ^a,b,1, Seon Min Woo ^c,1, Seung Un Seo ^c, Asmita Banstola ^d, Haesoo Kim ^a, Ramesh Duwa^e,f, An Thi Thanh Vu ^a, In-Sun Hong ^g, Taeg Kyu Kwon ^c,h, Simmyung Yook^e,i

^aCollege of Pharmacy, Keimyung University, Daegu, 42602, Republic of Korea

^bDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea

^cDepartment of Immunology, School of medicine, Keimyung University, Daegu, Republic of Korea

^dDepartment of Dermatology, Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA

^eDepartment of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea

^fDepartment of Radiology, Molecular Imaging Program at Stanford (MIPS), School of medicine, Stanford University, Stanford, CA, 94305, USA

^gDepartment of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea

^hCenter for Forensic Pharmaceutical Science, Keimyung University, Daegu, 42601, Republic of Korea

ⁱSchool of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors: Taeg Kyu Kwon, Simmyung Yook

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.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-08-07)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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