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

Abstract 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.