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Detachable MOF-Based Core/Shell Nanoreactor for Cancer Dual-Starvation Therapy With Reversing Glucose and Glutamine Metabolisms
Small ( IF 13.0 ) Pub Date : 2023-06-17 , DOI: 10.1002/smll.202303253 Huiping Du 1 , Siyu Meng 1 , Meijuan Geng 1 , Pan Zhao 1 , Liyang Gong 1 , Xinmin Zheng 2 , Xiang Li 2 , Zhang Yuan 1 , Hui Yang 2 , Yanli Zhao 3 , Liangliang Dai 1
Small ( IF 13.0 ) Pub Date : 2023-06-17 , DOI: 10.1002/smll.202303253 Huiping Du 1 , Siyu Meng 1 , Meijuan Geng 1 , Pan Zhao 1 , Liyang Gong 1 , Xinmin Zheng 2 , Xiang Li 2 , Zhang Yuan 1 , Hui Yang 2 , Yanli Zhao 3 , Liangliang Dai 1
Affiliation
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Tumor-dependent glucose and glutamine metabolisms are essential for maintaining survival, while the accordingly metabolic suppressive therapy is limited by the compensatory metabolism and inefficient delivery efficiency. Herein, a functional metal–organic framework (MOF)-based nanosystem composed of the weakly acidic tumor microenvironment-activated detachable shell and reactive oxygen species (ROS)-responsive disassembled MOF nanoreactor core is designed to co-load glycolysis and glutamine metabolism inhibitors glucose oxidase (GOD) and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES) for tumor dual-starvation therapy. The nanosystem excitingly improves tumor penetration and cellular uptake efficiency via integrating the pH-responsive size reduction and charge reversal and ROS-sensitive MOF disintegration and drug release strategy. Furthermore, the degradation of MOF and cargoes release can be self-amplified via additional self-generation H2O2 mediated by GOD. Last, the released GOD and BPTES collaboratively cut off the energy supply of tumors and induce significant mitochondrial damage and cell cycle arrest via simultaneous restriction of glycolysis and compensatory glutamine metabolism pathways, consequently realizing the remarkable triple negative breast cancer killing effect in vivo with good biosafety via the dual starvation therapy.
中文翻译：
可拆卸的基于 MOF 的核/壳纳米反应器用于逆转葡萄糖和谷氨酰胺代谢的癌症双饥饿疗法
肿瘤依赖性葡萄糖和谷氨酰胺代谢对于维持生存至关重要，而相应的代谢抑制治疗则受到代偿性代谢和低效递送效率的限制。在此，一种基于功能性金属有机框架（MOF）的纳米系统由弱酸性肿瘤微环境激活的可拆卸外壳和活性氧（ROS）响应的可拆卸MOF纳米反应器核心组成，旨在共同负载糖酵解和谷氨酰胺代谢抑制剂葡萄糖氧化酶（GOD）和双-2-（5-苯基乙酰氨基-1,2,4-噻二唑-2-基）乙基硫醚（BPTES）用于肿瘤双重饥饿疗法。该纳米系统通过整合 pH 响应性尺寸减小和电荷反转以及 ROS 敏感 MOF 崩解和药物释放策略，令人兴奋地提高了肿瘤渗透和细胞摄取效率。此外，MOF 的降解和货物释放可以通过GOD 介导的额外自生成 H 2 O 2来自我放大。最后，释放的GOD和BPTES协同切断肿瘤的能量供应，通过同时限制糖酵解和代偿性谷氨酰胺代谢途径，诱导显着的线粒体损伤和细胞周期阻滞，从而在体内实现显着的三阴性乳腺癌杀伤作用，且具有良好的生物安全性通过双重饥饿疗法。
更新日期：2023-06-17
中文翻译：
可拆卸的基于 MOF 的核/壳纳米反应器用于逆转葡萄糖和谷氨酰胺代谢的癌症双饥饿疗法
肿瘤依赖性葡萄糖和谷氨酰胺代谢对于维持生存至关重要，而相应的代谢抑制治疗则受到代偿性代谢和低效递送效率的限制。在此，一种基于功能性金属有机框架（MOF）的纳米系统由弱酸性肿瘤微环境激活的可拆卸外壳和活性氧（ROS）响应的可拆卸MOF纳米反应器核心组成，旨在共同负载糖酵解和谷氨酰胺代谢抑制剂葡萄糖氧化酶（GOD）和双-2-（5-苯基乙酰氨基-1,2,4-噻二唑-2-基）乙基硫醚（BPTES）用于肿瘤双重饥饿疗法。该纳米系统通过整合 pH 响应性尺寸减小和电荷反转以及 ROS 敏感 MOF 崩解和药物释放策略，令人兴奋地提高了肿瘤渗透和细胞摄取效率。此外，MOF 的降解和货物释放可以通过GOD 介导的额外自生成 H 2 O 2来自我放大。最后，释放的GOD和BPTES协同切断肿瘤的能量供应，通过同时限制糖酵解和代偿性谷氨酰胺代谢途径，诱导显着的线粒体损伤和细胞周期阻滞，从而在体内实现显着的三阴性乳腺癌杀伤作用，且具有良好的生物安全性通过双重饥饿疗法。
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