Qian Manping, Wang Ke, Yang Peng, Liu Yu, Li Meng, Zhang Chengxiao, Qi Honglan
Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, 710062, P. R. China.
Chem Biomed Imaging. 2024 Aug 1;2(12):808-816. doi: 10.1021/cbmi.4c00042. eCollection 2024 Dec 23.
Photodynamic therapy (PDT) has long been receiving increasing attention for the minimally invasive treatment of cancer. The performance of PDT depends on the photophysical and biological properties of photosensitizers (PSs). The always-on fluorescence signal of conventional PSs makes it difficult to real-time monitor phototherapeutic efficacy in the PDT process. Therefore, functional PSs with good photodynamic therapy effect and self-reporting properties are highly desired. Here, two nonemissive iridium(III) solvent complexes, [(dfppy)Ir(DMSO)]Cl (Ir-DMSO, dfppy = 2,4-difluorophenyl)pyridine, DMSO = dimethyl sulfoxide) and [(dfppy)Ir(ACN)]Cl (Ir-ACN, ACN = acetonitrile) as PSs, were synthesized. Both of them exhibit intense high-energy absorption bands, low photoluminescence (PL) emission, and low dark toxicity. Thanks to the lower dark toxicity of Ir-DMSO, we chose it as a PS for further PDT. In this work, Ir-DMSO functions as a specific PL "signal on" PS for self-reporting therapeutic efficacy during its own PDT process. Colocalization experiments indicated that Ir-DMSO accumulated in the endoplasmic reticulum and mitochondria. Under light irradiation, Ir-DMSO not only exhibited the ability to kill cancer cells but also presented a "signal on" PL response toward cell death. During Ir-DMSO-induced PDT, cell death modality was further investigated and immunogenic cell death was revealed, in which main hallmarks, including ROS generation, upregulation of surface-exposed calreticulin, high-mobility group box 1, and adenosine triphosphate secretion, were observed. Thanks to the specific coordination reaction between Ir-DMSO and histidine (His)/His-containing proteins, the phototherapeutic efficacy can be monitored in real time without other signal probes. This work provides a new and promising strategy for the development of PSs with self-reporting ability, which is of great importance for imaging-guided PDT.
光动力疗法（PDT）长期以来一直因癌症的微创治疗而受到越来越多的关注。PDT的性能取决于光敏剂（PSs）的光物理和生物学特性。传统PSs持续存在的荧光信号使得在PDT过程中难以实时监测光治疗效果。因此，非常需要具有良好光动力治疗效果和自我报告特性的功能性PSs。在此，合成了两种无发射铱（III）溶剂配合物，即[(dfppy)Ir(DMSO)]Cl（Ir-DMSO，dfppy = 2,4-二氟苯基吡啶，DMSO = 二甲基亚砜）和[(dfppy)Ir(ACN)]Cl（Ir-ACN，ACN = 乙腈）作为PSs。它们都表现出强烈的高能吸收带、低光致发光（PL）发射和低暗毒性。由于Ir-DMSO的暗毒性较低，我们选择它作为进一步PDT的PS。在这项工作中，Ir-DMSO在其自身的PDT过程中作为一种特定的PL“信号开启”PS用于自我报告治疗效果。共定位实验表明Ir-DMSO在内质网和线粒体中积累。在光照下，Ir-DMSO不仅表现出杀死癌细胞的能力，还对细胞死亡呈现出“信号开启”的PL响应。在Ir-DMSO诱导的PDT过程中，进一步研究了细胞死亡方式并揭示了免疫原性细胞死亡，其中观察到了包括活性氧生成、表面暴露的钙网蛋白上调、高迁移率族蛋白盒1和三磷酸腺苷分泌等主要特征。由于Ir-DMSO与组氨酸（His）/含His的蛋白质之间的特定配位反应，可以在无需其他信号探针的情况下实时监测光治疗效果。这项工作为开发具有自我报告能力的PSs提供了一种新的且有前景的策略，这对于成像引导的PDT非常重要。
