Bioorthogonal chemistry provides a new avenue for disease treatment by generating therapeutic agents in situ. However, two crucial issues have to be considered for future practical applications. One is the prevention of metabolic inactivation of the in situ-synthesized drug molecules. The other is enhancing the biocompatibility and tumour cell selectivity of the bioorthogonal catalyst. Here, to tackle the above issues, we design a biocompatible hydrogen-bonded organic framework-based dual prodrugs activation platform (namely Apt@E-F@PHOF-1). The ferric porphyrin ligands of hydrogen-bonded organic framework-based bioorthogonal pre-catalyst are reduced to ferrous porphyrin by the abundant glutathione in tumour, which then catalyses the cleavage reaction to synthesize 5-fluorouracil (5FU) and 5-ethynyluracil. The 5FU catabolic enzyme inhibitor 5-ethynyluracil prevents 5FU metabolic inactivation. As an example of hydrogen-bonded organic framework-based bioorthogonal prodrug activation, this work provides insights into prevention of drug inactivation by using bioorthogonal chemistry, thus enhancing tumour inhibition and reducing therapeutic side effects demonstrated by both in vitro and orthotopic metastatic mouse model experiments.

生物正交化学通过原位产生治疗剂为疾病治疗提供了新途径。然而，对于未来的实际应用，必须考虑两个关键问题。一是防止原位合成药物分子的代谢失活。另一个是增强生物正交催化剂的生物相容性和肿瘤细胞选择性。在这里，为了解决上述问题，我们设计了一种基于生物相容性氢键有机框架的双前药激活平台（即Apt@EF@PHOF-1）。氢键有机骨架生物正交预催化剂的铁卟啉配体被肿瘤中丰富的谷胱甘肽还原为铁卟啉，然后催化裂解反应合成5-氟尿嘧啶（5FU）和5-乙炔基尿嘧啶。5FU 分解代谢酶抑制剂 5-乙炔尿嘧啶可防止 5FU 代谢失活。作为基于氢键有机框架的生物正交前药激活的一个例子，这项工作提供了利用生物正交化学预防药物失活的见解，从而增强肿瘤抑制并减少体外和原位转移小鼠模型实验所证明的治疗副作用。