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 μM, 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. A reactive oxygen species (ROS)‐responsive peptide‐drug conjugate (PDC, CPT‐TK‐KLAK) self‐delivery system was designed to improve chemotherapy of tumors.