Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. However, off-target toxicity caused by the instability of linkers remains one of the main issues to be resolved. Developing a novel photocontrol-ADC with good stability and photocontrolled release seemed to be an attractive and practical solution. In this study, we designed, for the first time, a novel ultraviolet (UV) light-controlled ADC by carefully integrating the UV-cleavable o-nitro-benzyl structure into the linker. Our preliminary work indicated that the ADC exhibited good stability and photocontrollability while maintaining a targeting effect similar to that of the naked antibody. Upon irradiation with UV light, the ADC rapidly released free cytotoxins and exerted significant cytotoxicity toward drug-resistant tumor cells. Compared to those of the unirradiated cells, the EC₅₀ values of ADCs increased by up to 50-fold. Furthermore, our research confirmed that the degradation products of unirradiated ADC, Cys-1a, were relatively less toxic, thus potentially reducing the off-target toxicity caused by nonspecific uptake of ADCs. The novel design strategy of UV light-controlled ADCs may provide new perspectives for future research on ADCs and promote the development of photocontrol systems.

抗体-药物偶联物 (ADC) 正在世界范围内开发，有可能彻底改变当前的癌症治疗策略。然而，由接头不稳定引起的脱靶毒性仍然是有待解决的主要问题之一。开发一种具有良好稳定性和光控释放的新型光控制-ADC 似乎是一个有吸引力且实用的解决方案。在这项研究中，我们首次设计了一种新型的紫外线 (UV) 光控制 ADC，通过精心整合紫外线可裂解的o-硝基-苄基结构进入接头。我们的初步工作表明，ADC 表现出良好的稳定性和光控性，同时保持与裸抗体相似的靶向作用。在紫外线照射下，ADC 迅速释放游离细胞毒素，并对耐药肿瘤细胞发挥显着的细胞毒性。与未经辐照的细胞相比，ADC的 EC ₅₀值增加了 50 倍。此外，我们的研究证实，未经辐照的 ADC 的降解产物 Cys- 1a，毒性相对较小，因此有可能降低非特异性摄取 ADC 引起的脱靶毒性。UV光控ADC的新颖设计策略可能为未来ADC的研究提供新的视角，促进光控系统的发展。