Abstract
Hypoxia in the tumor microenvironment (TME) greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy (SDT); this phenomenon is further exacerbated by increased glutathione (GSH) levels in cancer cells. Simultaneously, cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation, but the efficacy of glucose oxidase (GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor. Glycer-aldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement. Here, we proposed thiol-ene click reactions based on a two-dimensional metal-organic framework (MOF) modification for tumor treatments to enable the combination of SDT and starvation therapy. Experimental studies demonstrated that the prepared material could consume GSH and GAPDH free from oxygen in TME, which benefited from the thiol-ene click reactions between the MOFs and thiol substances in cancer cells. Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently. This study is expected to create a promising avenue for thiol-ene click reactions in SDT and starvation therapy for cancer.
摘要
缺氧的肿瘤微环境(TME)限制了声动力疗法(SDT)杀灭癌细胞的 效果, 而且癌细胞中过量的谷胱甘肽(GSH)进一步加剧了这种疗效限 制. 同时, 癌症饥饿疗法作为一种有前途的临床治疗手段已得到越来越 多的认可, 但基于葡萄糖氧化酶(GOx)的饥饿疗法的疗效也因缺氧问题 而受到限制. 甘油醛-3-磷酸脱氢酶(GAPDH)是一种关键的糖酵解酶, 可作为缺氧情况下饥饿疗法的靶点. 本文提出利用二维金属有机框架 (MOF)实现巯基-烯点击反应, 达到对肿瘤进行SDT和饥饿疗法联合治 疗的目的. 实验结果表明, 因所制备的MOF材料和癌细胞中硫醇物质 发生巯基-烯点击反应, 该MOF可以在TME中无氧消耗GSH和GAPDH. 进一步的体外和体内实验表明, 所制备的MOF材料可以有效地杀死癌 细胞. 这项研究有望为巯基-烯点击反应在SDT疗法和癌症饥饿疗法的 应用中开辟一条前景广阔的道路.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (52172096) and the Classification Development of the Capital Normal University (009-2155091).
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Author contributions Jiang S, Zhang W, and Tian Y designed the experiments. Jiang S performed the experiments and prepared the manuscript. He Q, Ye L, and Zhang W helped analyze some data on biology. Li C and Dang K helped analyze the data of the materials. Tian Y supervised the project and revised the manuscript.
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Supplementary information Experimental details and supporting data are available in the online version of the paper.
Sen Jiang is a postgraduate student in Prof. Tian’s group and will receive his master degree from the Capital Normal University in 2022. His current research interest is synthesizing inorganic nanomaterials for tumor treatment.
Qijia He received her bachelor degree of biology from the Capital Normal University. Now she is pursuing a master degree at the College of Life Sciences, Capital Normal University. Her research focuses on cancer biology.
Kun Dang is a postgraduate student in Prof. Tian’s group and will receive his master degree from the Capital Normal University in 2022. His current research interest is synthesizing inorganic nanomaterials for catalysis.
Weiwei Zhang received her bachelor degree of medicine from Peking University and PhD degree of biology from the National University of Singapore. She is now a professor and doctoral supervisor of the College of Life Sciences, Capital Normal University. Her research focuses on exploring the mechanisms underlying stem cell differentiation and tumorigenesis.
Yang Tian received his BS degree in 2002 and PhD degree in 2007 both from Shandong University. He then joined the Department of Chemistry, Capital Normal University in 2007, and visited the University of Notre Dame as a visiting scholar in 2013–2014. His current research focuses on the design and synthesis of novel inorganic nanomaterials for the applications of MRI imaging and cancer therapy, as well as oxygen evolution catalysts.
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Employing the Thiol-Ene Click Reaction via Metal-Organic Framework for Integrated Sonodynamic-Starvation Therapy as an Oncology Treatment
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Jiang, S., He, Q., Li, C. et al. Employing the thiol-ene click reaction via metal-organic frameworks for integrated sonodynamic-starvation therapy as an oncology treatment. Sci. China Mater. 65, 1112–1121 (2022). https://doi.org/10.1007/s40843-021-1836-6
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DOI: https://doi.org/10.1007/s40843-021-1836-6