Zhang Jiayao, Liang Chen, Wei Ziye, Yang Wanlan, Ge Wei, Qu Xinyu, Si Weili, Wang Wenjun, Mou Xiaozhou, Dong Xiaochen
Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, China.
Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
Biomaterials. 2022 Aug;287:121682. doi: 10.1016/j.biomaterials.2022.121682. Epub 2022 Jul 18.
Adenosine triphosphate (ATP) is an essential substance for maintaining tumor cell survival and proliferation. Inhibiting the ATP-producing pathways has emerged as a promising cancer treatment strategy. However, the antitumor efficiency of ATP inhibitors is compromised by the inter-compensation of multiple ATP-producing pathways in tumor cells and biological barriers in the complex tumor microenvironment (TME). Herein, we developed metformin (Met) and glucose oxidase (GOx) co-loaded manganese silicon nanoplatform MnSiO@Met@GOx (MMG) for TME-responsive ATP dual inhibited starvation/chemodynamic synergistic therapy. Under the mildly acidic conditions in TME, MMG was decomposed, releasing Met and GOx for effective ATP suppression by inhibiting oxidative phosphorylation (OXPHOS) and aerobic glycolysis pathways, respectively. Meanwhile, GOx-catalyzed glucose oxidation increased tumor acidity and hydrogen peroxide (HO) concentration in tumors, which not only accelerated MMG decomposition and drug release but also promoted manganese ions-mediated Fenton-like reaction. In vitro and in vivo experiments further demonstrated the effectiveness and biosafety of MMG-based synergistic therapy. This study provides a novel strategy for tumor treatment based on tumor metabolism regulation.
三磷酸腺苷（ATP）是维持肿瘤细胞存活和增殖的必需物质。抑制ATP生成途径已成为一种有前景的癌症治疗策略。然而，ATP抑制剂的抗肿瘤效率受到肿瘤细胞中多种ATP生成途径的相互补偿以及复杂肿瘤微环境（TME）中的生物屏障的影响。在此，我们开发了负载二甲双胍（Met）和葡萄糖氧化酶（GOx）的锰硅纳米平台MnSiO@Met@GOx（MMG），用于TME响应性ATP双重抑制饥饿/化学动力学协同治疗。在TME的轻度酸性条件下，MMG分解，释放出Met和GOx，分别通过抑制氧化磷酸化（OXPHOS）和好氧糖酵解途径有效抑制ATP。同时，GOx催化的葡萄糖氧化增加了肿瘤酸度和肿瘤中的过氧化氢（HO）浓度，这不仅加速了MMG分解和药物释放，还促进了锰离子介导的类芬顿反应。体外和体内实验进一步证明了基于MMG的协同治疗的有效性和生物安全性。本研究为基于肿瘤代谢调控的肿瘤治疗提供了一种新策略。
