Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated remarkable anti-tumor effects by blocking tumor glutamine metabolism, but their use is frequently causing toxicity. Despite the existence of multiple glutamine antagonist prodrug designs, a tumor-selective prodrug has yet to be developed. Herein, a novel prodrug of DON, Azo-DON, has been developed, which remains stable and inactive in normal tissues with sufficient oxygen levels, while can be selectively reduced to DON by highly expressed azo-reductase in hypoxic tumor environments. This leads to blockade of glutamine metabolism in cancer cells and promotes cell death without affecting T cell proliferation. In a high-hypoxic H22 hepatoma cancer model, Azo-DON showed a 1.8-fold enhancement in glutamine blockade compared to the control group, resulting in a tumor suppression rate (TSR) of 84.2% in vivo with no significant weight loss. In a low-hypoxic CT26 colon cancer model, when combined with vascular disrupting agent nanoparticles (CBP) to induce a hypoxic environment, Azo-DON exhibited a 4.6-fold enhancement in glutamine blockade over the control group, resulted in a remarkable TSR of 96.6% in vivo. This innovative approach represents a promising strategy for the application of broad-spectrum metabolic inhibitors in the field of precision cancer treatment.

中文翻译：

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偶氮基缺氧激活的6-重氮-5-氧代-L-正亮氨酸（DON）前药与血管破坏剂纳米颗粒联合用于肿瘤选择性谷氨酰胺代谢阻断


谷氨酰胺拮抗剂，如 6-重氮-5-氧代-L-正亮氨酸 (DON)，通过阻断肿瘤谷氨酰胺代谢而表现出显着的抗肿瘤作用，但它们的使用经常引起毒性。尽管存在多种谷氨酰胺拮抗剂前药设计，但尚未开发出肿瘤选择性前药。在此，我们开发了一种新型的 DON 前药 Azo-DON，它在氧气水平充足的正常组织中保持稳定和无活性，而在缺氧肿瘤环境中可以被高表达的偶氮还原酶选择性还原为 DON。这会导致癌细胞中谷氨酰胺代谢受阻并促进细胞死亡，而不影响 T 细胞增殖。在高氧 H22 肝癌模型中，与对照组相比，Azo-DON 的谷氨酰胺阻断作用增强了 1.8 倍，体内肿瘤抑制率 (TSR) 达到 84.2%，且体重没有明显下降。在低氧 CT26 结肠癌模型中，当与血管破坏剂纳米颗粒 (CBP) 结合诱导低氧环境时，Azo-DON 的谷氨酰胺阻断效果比对照组增强 4.6 倍，TSR 显着达到 96.6 ％体内。这种创新方法代表了广谱代谢抑制剂在精准癌症治疗领域应用的一种有前景的策略。