Cationic Oligopeptide-Functionalized Mitochondria Targeting Sequence Show Mitochondria Targeting and Anticancer Activity

Mitochondrial drug delivery systems require development of highly selective mitochondria-targeting carriers. In this study, we report that mitochondria targeting sequence (MTS)-hybrid cationic oligopeptide, MTS-H 3 R 9 , shows the dual role of a mitochondria targeting vector along with anticancer effect for cancer therapy. In cytotoxicity assays, MTS-H 3 R 9 was shown to be more effective than MTS. MTS-H 3 R 9 showed significant cell penetration and internalization activity compared to that of MTS along with more efficient escape from lysosome to the cytosol. We showed efficient targeting of MTS-H 3 R 9 to mitochondria in HeLa cell line. Furthermore, we exhibited anticancer agent properties that mitochondrial-accumulated MTS-H 3 R 9 caused cell death by reactive oxygen species generation and loss of mitochondrial membrane potential. MTS-H 3 R 9 exhibited dramatically increased anticancer activity in 3D spheroids as well as in a 2D culture model. We demonstrated that MTS-H 3 R 9 provides dual potentials both as a vehicle for targeted delivery and as a cancer treatment agent for therapeutic applications.