Zhu Zifan, Feng Yun, Tian Qiufen, Li Jiawen, Liu Chencong, Cheng Yuchi, Zhang Sanjun, Dang Yijing, Gao Jing, Lai Yi, Zhang Fan, Yu Haijun, Zhang Wen, Xu Zhiai
School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
JACS Au. 2024 Oct 3;4(10):4032-4042. doi: 10.1021/jacsau.4c00787. eCollection 2024 Oct 28.
The precise theranostic strategy of fluorescence imaging-guided photodynamic therapy (PDT) can effectively mitigate the adverse effect of photosensitizers in normal cells and tissues. However, low tumor enrichment and high diffusivity of photosensitizers significantly compromise the imaging accuracy and PDT effect. In this study, we have developed a nitroreductase (NTR)-activated and self-immobilizing photosensitizer CyNT-F, which showed enhanced enrichment in tumor tissues and facilitated precise and sustained imaging as well as PDT for hypoxia tumors. mPEG--PDPA nanomicelles encapsulating photosensitizers underwent dissociation and released CyNT-F in tumor cells. CyNT-F and NTR enzymatically reacted in situ to generate highly reactive quinone methide, subsequently covalently binding to adjacent proteins for fluorescence and PDT activation. CyNT-F exhibited longer intracellular retention (7 days) and effectively inhibited the tumor growth of solid hypoxia tumor. We believe the activatable and self-immobilizing strategy of PDT presents a novel methodology for minimizing the adverse effect and enabling spatiotemporally accurate ablation of diseased cells and tissues.
荧光成像引导的光动力疗法（PDT）精确的诊疗策略能够有效减轻光敏剂对正常细胞和组织的不良影响。然而，光敏剂的低肿瘤富集性和高扩散性显著影响成像准确性和PDT效果。在本研究中，我们开发了一种硝基还原酶（NTR）激活的自固定化光敏剂CyNT-F，其在肿瘤组织中的富集增强，有助于对缺氧肿瘤进行精确且持续的成像以及PDT。包裹光敏剂的mPEG-PDPA纳米胶束在肿瘤细胞中解离并释放出CyNT-F。CyNT-F与NTR在原位发生酶促反应生成高活性的亚甲基醌，随后与相邻蛋白质共价结合以激活荧光和PDT。CyNT-F表现出更长的细胞内保留时间（7天），并有效抑制实体缺氧肿瘤的生长。我们认为，可激活的自固定化PDT策略为最大限度减少不良影响以及实现对病变细胞和组织进行时空精确消融提供了一种新方法。
