Targeted prodrugs exploiting cleavable linkers capable of responding to endogenous stimuli have increasingly been explored for cancer therapy. Successful application of these prodrug designs relies on the manipulation of both stability and responsiveness of the cleavable linkers, which, however, are difficult to be finely regulated, particularly for acid-responsive acylhydrazone bonds. Here we developed a new class of peptide-bridged twin-acylhydrazone linkers (PTA linkers) displaying both an ultrahigh stability and a rapid responsiveness—highly stable in neutral and acidic conditions due to the effect of cooperativity between the two acylhydrazone bonds, easily cleavable in acidic conditions after enzymatically triggered unlocking of the two bonds. Moreover, our study shows the design of PTA-linked prodrugs and the proof-of-concept application of the PTA linkers for site-specific release of anticancer drugs into cancer cells.

中文翻译：

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蛋白水解解锁超稳定双酰基Ac接头溶酶体酸触发释放的抗癌药物。

利用能够响应内源性刺激的可裂解接头的靶向前药已被越来越多地用于癌症治疗。这些前药设计的成功应用取决于对可裂解连接子的稳定性和响应性的操纵，但是，很难对其进行精细调节，尤其是对于酸响应性酰基hydr键而言。在这里，我们开发了新型的肽桥联双酰基zone连接子（PTA连接子），显示了超高的稳定性和快速的响应性-由于两个酰基hydr键之间的协同作用，在中性和酸性条件下都非常稳定，在其中容易裂解酶促触发两个键的解锁后处于酸性条件。而且，