Zang Chuanlong, Wang Huawei, Li Tiantian, Zhang Yingqian, Li Jiahui, Shang Mengdi, Du Juanjuan, Xi Zhen, Zhou Chuanzheng
State Key Laboratory of Elemento-Organic Chemistry , Department of Chemical Biology , College of Chemistry , Nankai University , Tianjin 300071 , China . Email:
School of Pharmaceutical Sciences , Tsinghua University , 30 Shuangqing Rd. , Beijing 100084 , China.
Chem Sci. 2019 Aug 19;10(39):8973-8980. doi: 10.1039/c9sc03016f. eCollection 2019 Oct 21.
When designing prodrugs, choosing an appropriate linker is the key to achieving efficient, controlled drug delivery. Herein, we report the use of a photocaged C4'-oxidized abasic site (PC4AP) as a light-responsive, self-immolative linker. Any amine- or hydroxyl-bearing drug can be loaded onto the linker a carbamate or carbonate bond, and the linker is then conjugated to a carrier peptide or protein an alkyl chain. The PC4AP linker is stable under physiologically relevant conditions. However, photodecaging of the linker generates an active intermediate that reacts intramolecularly with a primary amine (the ε-amine of a lysine residue and the N-terminal amine) on the carrier, leading to rapid and efficient release of the drug an addition-elimination cascade, without generating any toxic side products. We demonstrated that the use of this self-immolative linker to conjugate the anticancer drug doxorubicin to a cell-penetrating peptide or an antibody enabled targeted, controlled delivery of the drug to cells. Our results suggest that the linker can be used with a broad range of carriers, such as cell-penetrating peptides, proteins, antibodies, and amine-functionalized polymers, and thus will find a wide range of practical applications.
在设计前药时，选择合适的连接子是实现高效、可控药物递送的关键。在此，我们报道了使用光笼蔽的C4'-氧化无碱基位点（PC4AP）作为光响应性、自牺牲连接子。任何带有胺基或羟基的药物都可以通过氨基甲酸酯或碳酸酯键连接到该连接子上，然后该连接子通过烷基链与载体肽或蛋白质缀合。PC4AP连接子在生理相关条件下是稳定的。然而，连接子的光脱笼反应会产生一种活性中间体，该中间体与载体上的伯胺（赖氨酸残基的ε-胺和N端胺）发生分子内反应，通过加成-消除级联反应导致药物快速、高效释放，且不会产生任何有毒副产物。我们证明，使用这种自牺牲连接子将抗癌药物阿霉素与细胞穿透肽或抗体缀合，能够实现药物向细胞的靶向、可控递送。我们的结果表明，该连接子可与多种载体一起使用，如细胞穿透肽、蛋白质、抗体和胺功能化聚合物，因此将有广泛的实际应用。
