Microtubule polymerization induced by iridium-fullerene photosensitizers for cancer immunotherapy via dual-reactive oxygen species regulation strategy

IF 13.9 Q1 CHEMISTRY, MULTIDISCIPLINARY
Xiao-Xiao Chen, Kun Peng, Xi Chen, Zheng-Yin Pan, Qing-Hua Shen, Yu-Yi Ling, Jian-Zhang Zhao, Cai-Ping Tan
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Abstract

Microtubules (MTs) are key players in cell division, migration, and signaling, and they are regarded as important targets for cancer treatment. In this work, two fullerene (C60)-functionalized Ir(III) complexes (Ir-C601 and Ir-C602) are rationally designed as dual reactive oxygen species (ROS) regulators and MT-targeted Type I/II photosensitizers. In the dark, Ir-C601 and Ir-C602 serve as ROS scavengers to eliminate O2 and •OH, consequently reducing the dark cytotoxicity and reversing dysfunctional T cells. Due to the efficiently populated C60-localized intraligand triplet state, Ir-C601 and Ir-C602 can be excited by green light (525 nm) to produce O2 and •OONO (Type I) and 1O2 (Type II) to overcome tumor hypoxia. Moreover, Ir-C601 is also able to photooxidize tubulin, consequently interfering with the cellular cytoskeleton structures, inducing immunogenic cell death and inhibiting cell proliferation and migration. Finally, Ir-C601 exhibits promising photo-immunotherapeutic effects both in vitro and in vivo. In all, we report here the first MT stabilizing photosensitizer performing through Type I/II photodynamic therapy pathways, which provides insights into the rational design of new photo-immunotherapeutic agents targeting specific biomolecules.

Abstract Image

Abstract Image

铱-富勒烯光敏剂通过双重活性氧调节策略诱导微管聚合,用于癌症免疫疗法
微管(MT)是细胞分裂、迁移和信号传递的关键角色,被视为癌症治疗的重要靶标。在这项研究中,我们合理地设计了两种富勒烯(C60)功能化的Ir(III)复合物(Ir-C601和Ir-C602),作为双重活性氧(ROS)调节剂和MT靶向I/II型光敏剂。在黑暗中,Ir-C601 和 Ir-C602 可作为 ROS 清除剂消除 O2- 和 -OH,从而降低黑暗细胞毒性并逆转功能失调的 T 细胞。Ir-C601 和 Ir-C602 在绿光(525 nm)下可被激发产生 O2--和 -OONO--(Ⅰ型)和 1O2(Ⅱ型),从而克服肿瘤缺氧。此外,Ir-C601 还能使微管蛋白光氧化,从而干扰细胞的细胞骨架结构,诱导免疫性细胞死亡,抑制细胞增殖和迁移。最后,Ir-C601 在体外和体内都表现出良好的光免疫治疗效果。总之,我们在此报告了首个通过 I/II 型光动力疗法途径发挥作用的 MT 稳定光敏剂,这为合理设计针对特定生物大分子的新型光免疫治疗药物提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
17.40
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审稿时长
7 weeks
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