Wu Jianbing, Sun Tao, Yang Chenxi, Lv Tian, Bi Yuyang, Xu Yuan, Ling Yong, Zhao Jun, Cong Rigang, Zhang Yihua, Wang Jianhua, Wen Hao, Jiang Hulin, Li Fei, Huang Zhangjian
State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, 830054, P.R. China and State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P.R. China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, P.R. China.
Biomater Sci. 2021 Mar 10;9(5):1816-1825. doi: 10.1039/d0bm01841d.
Bond cleavage bioorthogonal chemistry has been widely employed to restore or activate proteins or prodrugs. Nitric oxide (NO), as a free radical molecule, has joined the clinical arena of cancer therapy, since high levels of NO could produce a cancer cell growth inhibitory effect. However, the spatiotemporal controlled release of NO remains a great challenge, and bioorthogonal chemistry may open a new window. Herein, we described a class of O2-3-isocyanopropyl diazeniumdiolates 3a-f as new bioorthogonal NO precursors, which can be effectively uncaged via tetrazine-mediated bond cleavage reactions to liberate NO and acrolein in living cancer cells, exhibiting potent antiproliferative activity. Furthermore, 3a and tetrazine BTZ were respectively encapsulated into two liposomes. It was found that simultaneous administrations of the two liposomes could specifically release large amounts of NO in the implanted cancer cells in zebrafish, thus generating potent tumor suppression activity in vivo. Our findings indicate that the TZ-labile NO precursors could serve to expand the NO-based smart therapeutics and the scope of bioorthogonal chemistry utility in vivo in the near future.
键断裂生物正交化学已被广泛用于恢复或激活蛋白质或前药。一氧化氮（NO）作为一种自由基分子，已进入癌症治疗的临床领域，因为高水平的NO可产生癌细胞生长抑制作用。然而，NO的时空控制释放仍然是一个巨大的挑战，而生物正交化学可能会打开一扇新的窗口。在此，我们描述了一类O2-3-异氰基丙基二氮烯二醇盐3a-f作为新型生物正交NO前体，它们可以通过四嗪介导的键断裂反应在活癌细胞中有效地释放出NO和丙烯醛，表现出强大的抗增殖活性。此外，将3a和四嗪BTZ分别包裹在两个脂质体中。发现同时给予这两种脂质体可以在斑马鱼植入的癌细胞中特异性地释放大量NO，从而在体内产生强大的肿瘤抑制活性。我们的研究结果表明，在不久的将来，对四嗪不稳定的NO前体可用于扩展基于NO的智能疗法以及生物正交化学在体内的应用范围。
