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A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H2O2 self-supply, GSH depletion and calcium overload
Nanoscale ( IF 6.7 ) Pub Date : 2024-04-03 , DOI: 10.1039/d3nr06422k Yong Li , Jing Wang , Tao Zhu , Ying Zhan , Xiaoli Tang , Jianying Xi , Xiaohui Zhu , Yong Zhang , Jinliang Liu
Nanoscale ( IF 6.7 ) Pub Date : 2024-04-03 , DOI: 10.1039/d3nr06422k Yong Li , Jing Wang , Tao Zhu , Ying Zhan , Xiaoli Tang , Jianying Xi , Xiaohui Zhu , Yong Zhang , Jinliang Liu
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Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H2O2 and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO2-based multifunctional nanocomposite with a surface coating of Cu2+ and L-buthionine sulfoximine (BSO) (named CaO2@Cu–BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO2 nanoparticles subsequently decompose to produce H2O2, alleviating the insufficient supply of endogenous H2O2 in the tumor microenvironment (TME). Furthermore, Cu2+ detached from the surface of CaO2 is reduced by H2O2 and GSH to Cu+ and ROS. Then, Cu+ catalyzes H2O2 to generate highly cytotoxic ˙OH and Cu2+, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu2+ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO2 by TME releases a large amount of free Ca2+, resulting in the accumulation and overload of Ca2+ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.
中文翻译:
一种产生 ROS 风暴的纳米复合材料,通过 H2O2 自供应、GSH 消耗和钙超载来增强化学动力学治疗
从过氧化氢(H 2 O 2 )催化产生有毒羟基自由基(˙OH)是化学动力学疗法(CDT)中肿瘤治疗的有效策略。然而,实体瘤微环境的固有特征(以有限的H 2 O 2和过度表达的谷胱甘肽(GSH)为特征)严重阻碍了细胞内˙OH的积累,带来了重大挑战。为了规避这些关键问题,在这项工作中,设计了一种具有 Cu 2+和L-丁硫氨酸亚砜亚胺 (BSO)表面涂层的CaO 2基多功能纳米复合材料(命名为 CaO 2 @Cu–BSO),用于增强 CDT。利用肿瘤的弱酸性环境,纳米复合材料逐渐崩解,暴露的CaO 2纳米颗粒随后分解产生H 2 O 2 ,缓解肿瘤微环境(TME)内源性H 2 O 2供应不足。此外,从CaO 2表面脱离的Cu 2+被H 2 O 2和GSH还原为Cu +和ROS。然后,Cu +催化H 2 O 2生成高细胞毒性的˙OH和Cu 2+,形成有效CDT的循环催化作用。同时,GSH 被 Cu 2+离子耗尽,以消除可能的 ˙OH 清除作用。此外,TME分解CaO 2释放出大量游离Ca 2+ ,导致肿瘤细胞内Ca 2+积累和超载以及线粒体损伤,进一步提高CDT疗效并加速肿瘤细胞凋亡。此外,BSO 是一种分子抑制剂,通过阻断 γ-谷氨酰半胱氨酸合成酶来减少 GSH 的产生。总之,该策略可以通过肿瘤治疗中的 ROS 风暴生成策略来提高 CDT 效率。实验结果证实并证明了体外和体内良好的肿瘤抑制效果。
更新日期:2024-04-03
中文翻译:
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一种产生 ROS 风暴的纳米复合材料,通过 H2O2 自供应、GSH 消耗和钙超载来增强化学动力学治疗
从过氧化氢(H 2 O 2 )催化产生有毒羟基自由基(˙OH)是化学动力学疗法(CDT)中肿瘤治疗的有效策略。然而,实体瘤微环境的固有特征(以有限的H 2 O 2和过度表达的谷胱甘肽(GSH)为特征)严重阻碍了细胞内˙OH的积累,带来了重大挑战。为了规避这些关键问题,在这项工作中,设计了一种具有 Cu 2+和L-丁硫氨酸亚砜亚胺 (BSO)表面涂层的CaO 2基多功能纳米复合材料(命名为 CaO 2 @Cu–BSO),用于增强 CDT。利用肿瘤的弱酸性环境,纳米复合材料逐渐崩解,暴露的CaO 2纳米颗粒随后分解产生H 2 O 2 ,缓解肿瘤微环境(TME)内源性H 2 O 2供应不足。此外,从CaO 2表面脱离的Cu 2+被H 2 O 2和GSH还原为Cu +和ROS。然后,Cu +催化H 2 O 2生成高细胞毒性的˙OH和Cu 2+,形成有效CDT的循环催化作用。同时,GSH 被 Cu 2+离子耗尽,以消除可能的 ˙OH 清除作用。此外,TME分解CaO 2释放出大量游离Ca 2+ ,导致肿瘤细胞内Ca 2+积累和超载以及线粒体损伤,进一步提高CDT疗效并加速肿瘤细胞凋亡。此外,BSO 是一种分子抑制剂,通过阻断 γ-谷氨酰半胱氨酸合成酶来减少 GSH 的产生。总之,该策略可以通过肿瘤治疗中的 ROS 风暴生成策略来提高 CDT 效率。实验结果证实并证明了体外和体内良好的肿瘤抑制效果。