Xiao-Xiao Chen, Kun Peng, Xi Chen, Zheng-Yin Pan, Qing-Hua Shen, Yu-Yi Ling, Jian-Zhang Zhao, Cai-Ping Tan
{"title":"Microtubule polymerization induced by iridium-fullerene photosensitizers for cancer immunotherapy via dual-reactive oxygen species regulation strategy","authors":"Xiao-Xiao Chen, Kun Peng, Xi Chen, Zheng-Yin Pan, Qing-Hua Shen, Yu-Yi Ling, Jian-Zhang Zhao, Cai-Ping Tan","doi":"10.1002/agt2.623","DOIUrl":null,"url":null,"abstract":"<p>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 (C<sub>60</sub>)-functionalized Ir(III) complexes (<b>Ir-C<sub>60</sub>1</b> and <b>Ir-C<sub>60</sub>2</b>) are rationally designed as dual reactive oxygen species (ROS) regulators and MT-targeted Type I/II photosensitizers. In the dark, <b>Ir-C</b><b><sub>60</sub></b><b>1</b> and <b>Ir</b><b>-C</b><b><sub>60</sub></b><b>2</b> serve as ROS scavengers to eliminate O<sub>2</sub>•<sup>−</sup> and •OH, consequently reducing the dark cytotoxicity and reversing dysfunctional T cells. Due to the efficiently populated C<sub>60</sub>-localized intraligand triplet state, <b>Ir-C<sub>60</sub>1</b> and <b>I</b><b>r</b><b>-C</b><b><sub>60</sub></b><b>2</b> can be excited by green light (525 nm) to produce O<sub>2</sub>•<sup>−</sup> and •OONO<sup>−</sup> (Type I) and <sup>1</sup>O<sub>2</sub> (Type II) to overcome tumor hypoxia. Moreover, <b>Ir-C<sub>60</sub></b><b>1</b> is also able to photooxidize tubulin, consequently interfering with the cellular cytoskeleton structures, inducing immunogenic cell death and inhibiting cell proliferation and migration. Finally, <b>Ir-C</b><b><sub>60</sub></b><b>1</b> 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.</p>","PeriodicalId":72127,"journal":{"name":"Aggregate (Hoboken, N.J.)","volume":"5 6","pages":""},"PeriodicalIF":13.9000,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/agt2.623","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Aggregate (Hoboken, N.J.)","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/agt2.623","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
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.