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Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination

BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and h...

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Autores principales: Rao, Zhiping, Xia, Yutian, Jia, Qian, Zhu, Yutong, Wang, Lexuan, Liu, Guohuan, Liu, Xuelan, Yang, Peng, Ning, Pengbo, Zhang, Ruili, Zhang, Xianghan, Qiao, Chaoqiang, Wang, Zhongliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416514/
https://www.ncbi.nlm.nih.gov/pubmed/37563614
http://dx.doi.org/10.1186/s12951-023-01998-w
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author Rao, Zhiping
Xia, Yutian
Jia, Qian
Zhu, Yutong
Wang, Lexuan
Liu, Guohuan
Liu, Xuelan
Yang, Peng
Ning, Pengbo
Zhang, Ruili
Zhang, Xianghan
Qiao, Chaoqiang
Wang, Zhongliang
author_facet Rao, Zhiping
Xia, Yutian
Jia, Qian
Zhu, Yutong
Wang, Lexuan
Liu, Guohuan
Liu, Xuelan
Yang, Peng
Ning, Pengbo
Zhang, Ruili
Zhang, Xianghan
Qiao, Chaoqiang
Wang, Zhongliang
author_sort Rao, Zhiping
collection PubMed
description BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-023-01998-w.
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spelling pubmed-104165142023-08-12 Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination Rao, Zhiping Xia, Yutian Jia, Qian Zhu, Yutong Wang, Lexuan Liu, Guohuan Liu, Xuelan Yang, Peng Ning, Pengbo Zhang, Ruili Zhang, Xianghan Qiao, Chaoqiang Wang, Zhongliang J Nanobiotechnology Research BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-023-01998-w. BioMed Central 2023-08-10 /pmc/articles/PMC10416514/ /pubmed/37563614 http://dx.doi.org/10.1186/s12951-023-01998-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Rao, Zhiping
Xia, Yutian
Jia, Qian
Zhu, Yutong
Wang, Lexuan
Liu, Guohuan
Liu, Xuelan
Yang, Peng
Ning, Pengbo
Zhang, Ruili
Zhang, Xianghan
Qiao, Chaoqiang
Wang, Zhongliang
Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title_full Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title_fullStr Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title_full_unstemmed Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title_short Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
title_sort iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416514/
https://www.ncbi.nlm.nih.gov/pubmed/37563614
http://dx.doi.org/10.1186/s12951-023-01998-w
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