Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death
Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death
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具有双重谷胱甘肽消耗特性的类过氧化物酶活性纳米药物可恢复奥沙利铂化学敏感性并促进程序性细胞死亡
DOI：
10.1021/acsnano.1c06777
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发表时间：
2022-03-22
期刊：
影响因子：
17.1
通讯作者：
Yang, Piaoping
中科院分区：
文献类型：
--
作者：
Wu, Feng;Du, Yaqian;Yang, Piaoping
纳米酶的纳米催化活性为肿瘤治疗提供了前景。然而，肿瘤微环境中过量GSH基础上形成的GSH相关抗氧化防御系统（ADS）限制了其催化活性。在这里，树枝状介孔二氧化硅纳米颗粒（DMSN）被用作纳米载体;超小的Fe 3 O 4纳米颗粒，Mn 2+离子，和脱氢酶抑制剂Telaglenastat（CB-839）随后被整合到DMSN的大介孔中，形成DMSN/Fe 3 O 4-Mn@CB-839（DFMC）纳米药物。这种纳米药物在酸性条件下表现出过氧化物酶模拟活性，催化过氧化氢（H2 O2）分解为羟基自由基（*OH）。这也促进了脂质过氧化物的形成，这是铁凋亡所必需的。此外，这种纳米药物可以有效地消耗现有的GSH，从而增强活性氧（ROS）介导的肿瘤催化治疗。此外，引入的CB-839阻断GSH的内源性合成，进一步增强GSH耗竭性能，从而减少肿瘤细胞中奥沙利铂的排泄（GSH相关耐药性），从而恢复奥沙利铂的化学敏感性。双重GSH耗竭特性显著减弱GSH相关的ADS并恢复奥沙利铂的化学敏感性，导致DFMC诱导的肿瘤细胞凋亡和铁凋亡增加。我们开发的基于纳米技术与临床药物相结合的纳米药物可能有助于肿瘤治疗的发展。
The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nano-particles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4-Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (*OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.