Tetrazine-mediated bioorthogonal removal of 3-isocyanopropyl groups enables the controlled release of nitric oxide in vivo
Tetrazine-mediated bioorthogonal removal of 3-isocyanopropyl groups enables the controlled release of nitric oxide in vivo
复制标题
四嗪介导的 3-异氰基丙基的生物正交去除能够实现体内一氧化氮的受控释放
DOI：
10.1039/d0bm01841d
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Huang Z
中科院分区：
文献类型：
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作者：
Wu J;Sun T;Yang C;Lv T;Bi Y;Xu Y;Ling Y;Zhao J;Cong R;Zhang Y;Wang J;Wen H;Jiang H;Li F;Huang Z
键断裂生物正交化学已被广泛用于恢复或活化蛋白质或前药。一氧化氮（NO）作为一种自由基分子，由于高水平的NO可产生抑制癌细胞生长的作用，已进入癌症治疗的临床竞技场。然而，NO的时空控制释放仍然是一个巨大的挑战，生物正交化学可能会打开一个新的窗口。本文中，我们描述了一类O2-3-异氰丙基二醇二氮烯鎓盐3a-f作为新的生物正交NO前体，其可以通过四嗪介导的键断裂反应有效地解开，以在活癌细胞中释放NO和丙烯醛，表现出有效的抗增殖活性。此外，3a和四嗪BTZ分别包封在两个脂质体中。结果发现，同时给予两种脂质体可以特异性地在斑马鱼中植入的癌细胞中释放大量的NO，从而在体内产生有效的肿瘤抑制活性。我们的研究结果表明，TZ-relabile NO前体可以在不久的将来扩展基于NO的智能疗法和生物正交化学在体内的应用范围。
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.