Enhanced cancer treatment by an acid-sensitive cytotoxic peptide-doxorubicin conjugate

Abstract Peptide-drug conjugates (PDCs) prepared by covalent attachment of specific peptides to a chemotherapeutic drug are receiving great attention for their significantly improved antitumor effects. Due to the unique properties of the tumor microenvironment, stimulus-responsive PDCs represent a promising strategy for improving the treatment of many types of cancers. In this study, we developed an acid-sensitive cytotoxic peptide-doxorubicin conjugate by linking doxorubicin (Dox) with a proapoptotic peptide (KLAK) via a hydrazone linker. The KLAK-Dox conjugate showed acid-sensitive release characteristics, while it was stable in neutral buffer. KLAK-Dox showed relatively lower uptake than free Dox but exhibited remarkably enhanced cytotoxicity toward HeLa cells. Moreover, drug distribution analysis indicated that tumor accumulation of KLAK-Dox was 3-fold higher than that of free Dox in a cervical carcinoma xenograft model. The conjugate also demonstrated remarkably improved antitumor efficacy in mice bearing cervical carcinoma xenografts. Our results suggested that cytotoxic peptide-doxorubicin conjugates may represent potential anticancer drugs for future cancer treatment.