An Endoplasmic Reticulum Targeting Type I Photosensitizer for Effective Photodynamic Therapy against Hypoxic Tumor Cells

• Published in: Chemistry : a European journal 2022-12, Vol.28 (72), p.e202202680-n/a
• Main Authors: Li, Shumeng, Chen, Yuncong, Wu, Yanping, Yao, Shankun, Yuan, Hao, Tan, Yehong, Qi, Fen, He, Weijiang, Guo, Zijian
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; benzophenothiazine; Cell Line, Tumor; Chemistry; Damage accumulation; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Homeostasis; Hypoxia; Hypoxia - metabolism; I.R. radiation; Irradiation; lysosome damage; Mice; Microenvironments; Neoplasms - drug therapy; Neoplasms - metabolism; Photochemotherapy - methods; Photodynamic therapy; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Phototoxicity; Protein folding; Reactive oxygen species; Reactive Oxygen Species - metabolism; Solid tumors; superoxide anion radicals; Toxicity; Tumor cells; Tumor Microenvironment; Tumors; type I photodynamic therapy
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202202680

Organelle‐targeted type I photodynamic therapy (PDT) shows great potential to overcome the hypoxic microenvironment in solid tumors. The endoplasmic reticulum (ER) is an indispensable organelle in cells with important biological functions. When the ER is damaged due to the production of reactive oxygen species (ROS), the accumulation of misfolded proteins will interfere with ER homeostasis, resulting in ER stress. Here, an ER‐targeted benzophenothiazine‐based photosensitizer NBS‐ER was presented. ER targeting modification significantly reduced the dark toxicity and improved phototoxicity index (PI). NBS‐ER could effectively produce O2−⋅ with near‐infrared irradiation, making its phototoxicity under hypoxia close to that under normoxia. Meanwhile, the photoinduced ROS triggered ER stress and induced apoptosis. In addition, NBS‐ER possessed excellent photodynamic therapeutic effect in 4T1‐tumor‐bearing mice. An ER‐targeted benzophenothiazine‐based photosensitizer NBS‐ER was constructed, which triggered ER stress and induced apoptosis with significantly reduced dark toxicity and improved phototoxicity index (PI). In addition, excellent photodynamic therapeutic effect of NBS‐ER was demonstrated in 4T1‐tumor‐bearing mice.