Nano-enabled tumor systematic energy exhaustion via zinc (II) interference mediated glycolysis inhibition and specific GLUT1 depletion
【作者】Sixuan Wu, Kaixiang Zhang, Yan Liang, Yongbin Wei, Jingyi An, Yifei Wang, Jiali Yang, Hongling Zhang, Zhenzhong Zhang, Junjie Liu, Jinjin Shi.
【期刊名】Advanced Science
【影响因子】 2021年:16.806
【作者单位】School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China
【年，卷(期)：页码】2021, 2103534. https://doi.org./10.1002/advs.202103534
【关键词】starvation therapy, zinc (II) interference, glycolysis inhibition, GLUT1 depletion, systematic energy exhaustion
【摘要】Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the “Zn2+ interference”-mediated glycolysis inhibition and Zn2+-activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. We discovered that ZIF-8 (zinc imidazolate metal-organic frameworks) could induce abrupt intracellular Zn2+ elevation preferentially in melanoma cells, and then achieved effective glycolysis blockade through “Zn2+ interference”-triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, we designed Zn2+-activating DNAzymes for specifically cleaving GLUT1 mRNA. This DNAzyme could only be activated under intracellular Zn2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up-regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes were loaded in ZIF-8 concurrently tethered by hyaluronic acid (HA), constructing a “nano-enabled energy interrupter”. Such a rational design presented a preferential accumulation tendency to tumor sites due to the active CD44-targeting mechanisms, specifically achieved remarkable systematic energy exhaustion in melanoma cells, and afforded 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verified a fascinating therapeutic platform enabling ion interference-inductive starvation strategy for effective tumor therapy.
【全文链接】
https://doi.org./10.1002/advs.202103534 (DOI)
