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Novel antibody-drug conjugate with UV-controlled cleavage mechanism for cytotoxin release
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-11-16 , DOI: 10.1016/j.bioorg.2020.104475
Jiaguo Li 1 , Dian Xiao 2 , Fei Xie 2 , Wei Li 2 , Lei Zhao 2 , Wei Sun 3 , Xiaohong Yang 3 , Xinbo Zhou 2
Affiliation  

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.



中文翻译:

具有用于细胞毒素释放的紫外线控制裂解机制的新型抗体药物偶联物

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。

更新日期:2020-11-16
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