School of Materials and Energy, Southwest University, Chongqing, 400715, China.
Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
Biomaterials. 2022 Jul;286:121572. doi: 10.1016/j.biomaterials.2022.121572. Epub 2022 May 11.
Endogenous HO sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable HO supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and HO-rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O replenishment through Pt-catalyzed decomposition of HO. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular HO level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular HO balance during HO-depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.
内源性 HO 牺牲用于对抗肿瘤的多样化治疗反应。然而，由于肿瘤微环境 (TME) 中 HO 的供应不可持续，治疗效果并不总是令人满意。在此，通过表面接枝葡萄糖氧化酶 (GOx) 封端的锰羰基 (MnCO) 和负载 3-氨基-1,2,4-三唑 (3-AT)，建立了一种基于铂 (Pt) 纳米笼的多酶平台 (简称 PGMA)。温和的酸性和富含 HO 的 TME 可导致 MnCO 降解，随后触发 CO 气体、3-AT 和 Mn 的释放。由此产生的 GOx 暴露引发肿瘤内葡萄糖耗竭，通过 Pt 催化分解 HO 补充 O 来促进这一过程。同时，通过 Mn 偶联介导的芬顿样反应，细胞内活性氧 (ROS) 水平升高。因此，CO 释放引发的气体治疗、葡萄糖耗尽引起的肿瘤饥饿和 ROS 触发的化学动力学治疗致力于实现对线粒体功能的联合破坏效应。重要的是，释放的 3-AT 可以抑制内源性过氧化氢酶的活性，这有效地提高了细胞内 HO 水平，以补偿其消耗，并为级联利用提供额外的反应物。总之，本研究旨在强调 HO 耗竭治疗过程中细胞内 HO 平衡的重要性，并为通过线粒体功能障碍应用该策略进行肿瘤治疗提供了一个范例。
