Reactive Oxygen Species‐Responsive Peptide‐Drug Conjugate for Mitochondria‐Specific Chemotherapy

Chemotherapy is one of the main means in clinical cancer treatment, but the efficient and precise delivery of chemotherapeutic drugs remains a key bottleneck. The precise delivery of nanomedicines to the mitochondria may achieve unexpected therapeutic effect, and peptides are considered as a promising class of mitochondrial targeting molecules. In this paper, we reported a reactive oxygen species (ROS)-responsive peptide-drug conjugate (PDC, CPT-TK-KLAK) self-delivery system, where a mitochondria-targeted peptide (KLAK, sequence: (KLAKLAK)(2)) is linked to the anticancer drug camptothecin (CPT) via a ROS responsive unit. The release amount of CPT from CPT-TK-KLAK in the 1 mM H2O2 solution was ca. 90% in 24 h, while CPT-CC-KLAK barely released CPT in 1 mM H2O2 solution. Therefore, after targeting to the mitochondria of HeLa cells, CPT-TK-KLAK can specifically release CPT under overproduced ROS, which in turn destroys mitochondria and induces ROS burst, causing HeLa cells apoptosis. As a result, CPT-TK-KLAK exhibits high cytotoxicity to HeLa cells with an IC50 of 0.37 mu M, which is 9-fold lower than free CPT. This ROS-responsive PDC can also be applied for the targeted delivery of other chemotherapeutic agents, thereby enhancing therapeutic efficacy.