澳门大学张宣军团队报道了用于自我报告的癌症光热疗法的自焚光敏剂。相关研究成果于2023年5月22日发表在《美国化学会杂志》。

光敏剂精确靶向并在光照下改变荧光，可以准确地自我报告光敏剂的工作地点和时间，使研究人员能够可视化治疗过程并精确调节治疗结果，这是对精准和个性化医疗的不懈追求。

该文中，研究人员报道了通过采用光操纵氧化切割C═C键策略的自焚光敏剂，可以产生活性氧的爆发，裂解释放自我报告的红色发射产物，并引发非凋亡细胞癌。通过研究结构-活性关系，研究人员发现强吸电子基团能有效抑制C═C活性和光毒性，它可以并通过不同的谷胱甘肽（GSH）反应基团暂时灭活光敏剂以及猝灭荧光制备NG1–NG5。其中，具有2-氰基-4-硝基苯-1-磺酰基的NG2比其他四种表现出优异的GSH响应性。令人惊讶的是，NG2在弱酸性条件下与GSH表现出更好的反应性，这激发了其在GSH升高的弱酸性肿瘤微环境中的应用。

为此，研究人员通过锚定整合素αvβ3结合环五肽（cRGD）来进一步合成NG-cRGD，用于肿瘤靶向。在A549异种移植的肿瘤小鼠中，由于肿瘤部位GSH升高，NG-cRGD成功地脱保护以恢复近红外荧光，随后GSH在光照射下被切割，释放出红色发光产物，以报告光敏剂的作用，同时通过触发的肿瘤有效消融肿瘤。先进的自焚有机光敏剂可能会加速未来精准肿瘤学中自我报告的光电疗法的发展。

附：英文原文

Title: Self-Immolative Photosensitizers for Self-Reported Cancer Phototheranostics

Author: Chunfei Wang, Yongjie Sun, Shaojuan Huang, Zixiang Wei, Jingyun Tan, Changfeng Wu, Qiang Chen, Xuanjun Zhang

Issue&Volume: May 22, 2023

Abstract: Photosensitizers to precise target and change fluorescence upon light illumination could accurately self-report where and when the photosensitizers work, enabling us to visualize the therapeutic process and precisely regulate treatment outcomes, which is the unremitting pursuit of precision and personalized medicine. Here, we report self-immolative photosensitizers by adopting a strategy of light-manipulated oxidative cleavage of C═C bonds that can generate a burst of reactive oxygen species, to cleave to release self-reported red-emitting products and trigger nonapoptotic cell oncosis. Strong electron-withdrawing groups are found to effectively suppress the C═C bond cleavage and phototoxicity via studying the structure–activity relationship, allowing us to elaborate NG1–NG5 that could temporarily inactivate the photosensitizer and quench the fluorescence by different glutathione (GSH)-responsive groups. Thereinto, NG2 with 2-cyano-4-nitrobenzene-1-sulfonyl group displays excellent GSH responsiveness than the other four. Surprisingly, NG2 shows better reactivity with GSH in weakly acidic condition, which inspires the application in weakly acidic tumor microenvironment where GSH elevates. To this end, we further synthesize NG-cRGD by anchoring integrin αvβ3 binding cyclic pentapeptide (cRGD) for tumor targeting. In A549 xenografted tumor mice, NG-cRGD successfully deprotects to restore near-infrared fluorescence because of elevated GSH in tumor site, which is subsequently cleaved upon light irradiation releasing red-emitting products to report photosensitizer working, while effectively ablating tumors via triggered oncosis. The advanced self-immolative organic photosensitizer may accelerate the development of self-reported phototheranostics in future precision oncology.

DOI: 10.1021/jacs.3c01666

Source: https://pubs.acs.org/doi/10.1021/jacs.3c01666