Wang Xiang, Shi Gaona, Wei Rao, Li Meng, Zhang Qingyang, Zhang Tiantai, Chen Chuan-Feng, Hu Hai-Yu
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100050 China
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences Beijing 100190 China
Chem Sci. 2024 Apr 3;15(17):6421-6431. doi: 10.1039/d3sc06826a. eCollection 2024 May 1.
Photodynamic immunotherapy (PDI) is an innovative approach to cancer treatment that utilizes photodynamic therapy (PDT) and photosensitizers (PSs) to induce immunogenic cell death (ICD). However, currently most commonly used PSs have restricted capabilities to generate reactive oxygen species (ROS) a type-II mechanism under hypoxic environments, which limits their effectiveness in PDI. To overcome this, we propose a novel approach for constructing oxygen independent PSs based on stable organic free-radical molecules. By fine-tuning the characteristics of tris(2,4,6-trichlorophenyl)-methyl (TTM) radicals through the incorporation of electron-donating moieties, we successfully found that TTMIndoOMe could produce substantial amounts of ROS even in hypoxic environments. experiments showed that TTMIndoOMe could effectively produce O˙, kill tumor cells and trigger ICD. Moreover, experiments also demonstrated that TTMIndoOMe could further trigger anti-tumor immune response and exhibit a superior therapeutic effect compared with PDT alone. Our study offers a promising approach towards the development of next-generation PSs functioning efficiently even under hypoxic conditions and also paves the way for the creation of more effective PSs for PDI.
光动力免疫疗法（PDI）是一种创新的癌症治疗方法，它利用光动力疗法（PDT）和光敏剂（PSs）诱导免疫原性细胞死亡（ICD）。然而，目前最常用的PSs在缺氧环境下产生活性氧（ROS）（一种II型机制）的能力有限，这限制了它们在PDI中的有效性。为了克服这一问题，我们提出了一种基于稳定有机自由基分子构建不依赖氧气的PSs的新方法。通过引入供电子基团来微调三（2,4,6-三氯苯基）-甲基（TTM）自由基的特性，我们成功发现TTMIndoOMe即使在缺氧环境中也能产生大量ROS。实验表明，TTMIndoOMe能有效产生O˙，杀死肿瘤细胞并触发ICD。此外，实验还证明TTMIndoOMe能进一步触发抗肿瘤免疫反应，与单独的PDT相比具有更好的治疗效果。我们的研究为开发即使在缺氧条件下也能有效发挥作用的下一代PSs提供了一种有前景的方法，也为创建更有效的PDI用PSs铺平了道路。
