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A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-10-15 , DOI: 10.1021/jacs.8b08014 Timothy A Su 1 , Diyala S Shihadih 2 , Wendy Cao 1 , Tyler C Detomasi 1 , Marie C Heffern 1 , Shang Jia 1 , Andreas Stahl 2 , Christopher J Chang 1, 3, 4, 5
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-10-15 , DOI: 10.1021/jacs.8b08014 Timothy A Su 1 , Diyala S Shihadih 2 , Wendy Cao 1 , Tyler C Detomasi 1 , Marie C Heffern 1 , Shang Jia 1 , Andreas Stahl 2 , Christopher J Chang 1, 3, 4, 5
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Copper deficiency is implicated in a variety of genetic, neurological, cardiovascular, and metabolic diseases. Current approaches for addressing copper deficiency rely on generic copper supplementation, which can potentially lead to detrimental off-target metal accumulation in unwanted tissues and subsequently trigger oxidative stress and damage cascades. Here we present a new modular platform for delivering metal ions in a tissue-specific manner and demonstrate liver-targeted copper supplementation as a proof of concept of this strategy. Specifically, we designed and synthesized an N-acetylgalactosamine-functionalized ionophore, Gal-Cu(gtsm), to serve as a copper-carrying "Trojan Horse" that targets liver-localized asialoglycoprotein receptors (ASGPRs) and releases copper only after being taken up by cells, where the reducing intracellular environment triggers copper release from the ionophore. We utilized a combination of bioluminescence imaging and inductively coupled plasma mass spectrometry assays to establish ASGPR-dependent copper accumulation with this reagent in both liver cell culture and mouse models with minimal toxicity. The modular nature of our synthetic approach presages that this platform can be expanded to deliver a broader range of metals to specific cells, tissues, and organs in a more directed manner to treat metal deficiency in disease.
中文翻译：
用于细胞和动物肝脏定向铜补充的模块化离子载体平台
铜缺乏与多种遗传、神经、心血管和代谢疾病有关。目前解决铜缺乏症的方法依赖于普通的铜补充剂，这可能会导致有害的脱靶金属在不需要的组织中积累，从而引发氧化应激和损伤级联。在这里，我们提出了一种新的模块化平台，用于以组织特异性方式输送金属离子，并展示针对肝脏的铜补充剂作为该策略的概念证明。具体来说，我们设计并合成了一种N-乙酰半乳糖胺功能化离子载体Gal-Cu(gtsm)，作为携带铜的“特洛伊木马”，靶向肝脏局部脱唾液酸糖蛋白受体(ASGPR)，并仅在被吸收后释放铜通过细胞，减少的细胞内环境触发铜从离子载体中释放。我们结合生物发光成像和电感耦合等离子体质谱分析，用该试剂在肝细胞培养物和小鼠模型中建立了 ASGPR 依赖性铜积累，且毒性最小。我们的合成方法的模块化性质预示着该平台可以扩展，以更直接的方式向特定细胞、组织和器官提供更广泛的金属，以治疗疾病中的金属缺乏。
更新日期：2018-10-15
中文翻译：
用于细胞和动物肝脏定向铜补充的模块化离子载体平台
铜缺乏与多种遗传、神经、心血管和代谢疾病有关。目前解决铜缺乏症的方法依赖于普通的铜补充剂，这可能会导致有害的脱靶金属在不需要的组织中积累，从而引发氧化应激和损伤级联。在这里，我们提出了一种新的模块化平台，用于以组织特异性方式输送金属离子，并展示针对肝脏的铜补充剂作为该策略的概念证明。具体来说，我们设计并合成了一种N-乙酰半乳糖胺功能化离子载体Gal-Cu(gtsm)，作为携带铜的“特洛伊木马”，靶向肝脏局部脱唾液酸糖蛋白受体(ASGPR)，并仅在被吸收后释放铜通过细胞，减少的细胞内环境触发铜从离子载体中释放。我们结合生物发光成像和电感耦合等离子体质谱分析，用该试剂在肝细胞培养物和小鼠模型中建立了 ASGPR 依赖性铜积累，且毒性最小。我们的合成方法的模块化性质预示着该平台可以扩展，以更直接的方式向特定细胞、组织和器官提供更广泛的金属，以治疗疾病中的金属缺乏。
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