Anti-glycolysis is well-recognized for inhibition of tumor proliferation. However, tumor metabolic heterogeneity confers great challenges in the therapeutic efficacy of glycolysis inhibitors. Here, a metabolic trapping strategy was employed to avoid metabolism heterogeneity in tumors. Unlike usual glycolysis inhibition, the glycolysis level was first promoted. Then excessive metabolite of lactate was transformed into H₂O₂ and hydroxyl radical by lactate oxidase (LOX) and MIL-101 (Fe) nanoparticles (MF). Finally, the ATP production was inhibited, and the tumor was suppressed by the generation of toxic reactive oxygen species (ROS). We realized this strategy via methacrylated gelatin (GelMA) hydrogel microspheres, co-loaded with metformin (MET) and LOX@MF. The results showed that MET was completely released within 2 h, followed by most LOX@MF released within 72 h. LOX@MF and MET synergistically suppressed tumor proliferation and angiogenesis both in vitro and in vivo. Compared with control, the primary tumor volume was reduced by 75.7 %, and the average number of lung metastasis nodules decreased from 15.5 to 1.0. Regarding the metabolism, higher glycolytic enzymes expressions were observed initially, followed by lower lactate and vascular endothelial growth factor (VEGF), and finally elevated ROS levels. Overall, our study provides new insights to improve metabolism heterogeneity-limited metabolic cancer therapy.

中文翻译：

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通过代谢捕获策略实现抗肿瘤和抗转移联合策略的局部糖酵解调节水凝胶微球


抗糖酵解对抑制肿瘤增殖是公认的。然而，肿瘤代谢异质性给糖酵解抑制剂的治疗效果带来了巨大挑战。在这里，采用了一种代谢捕获策略来避免肿瘤中的代谢异质性。与通常的糖酵解抑制不同，糖酵解水平首先得到提升。然后乳酸过量代谢物被乳酸氧化酶 （LOX） 和 MIL-101 （Fe） 纳米颗粒 （MF） 转化为 H₂O₂ 和羟基自由基。最后，ATP 的产生受到抑制，肿瘤通过产生有毒活性氧 （ROS） 而受到抑制。我们通过甲基丙烯酸明胶 （GelMA） 水凝胶微球实现了这一策略，该微球与二甲双胍 （MET） 和 LOX@MF 共同加载。结果显示，MET 在 2 小时内完全释放，其次是大部分 LOX@MF 在 72 小时内释放。LOX@MF 和 MET 在体外和体内协同抑制肿瘤增殖和血管生成。与对照组相比，原发肿瘤体积减少了 75.7 %，肺转移结节的平均数量从 15.5 个减少到 1.0 个。关于代谢，最初观察到较高的糖酵解酶表达，其次是较低的乳酸和血管内皮生长因子 （VEGF），最后是 ROS 水平升高。总体而言，我们的研究为改善代谢异质性限制代谢癌症治疗提供了新的见解。