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

Yoonhee Bae; Chanyang Joo; Goo-Young Kim; Kyung Soo Ko; Kang Moo Huh; Jin Han; Joon Sig Choi

Macromolecular Research, Vol.27, No.11, 1071-1080, November, 2019

DOI10.1007/s13233-019-7153-x Export Citation

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

Yoonhee Bae, Chanyang Joo¹, Goo-Young Kim², Kyung Soo Ko³, Kang Moo Huh¹, Jin Han^†, and Joon Sig Choi^{4, †}

Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea
¹Department of Polymer Science and Engineering, Chungnam National University, Daejeon 34134, Korea
²Department of Biology and Clinical Pharmacology, R&D Center, Samyang Biopharmaceuticals Corporation, Seongnam 13480, Korea
³Department of Internal Medicine, Sanggye Paik Hospital, Cardiovascular and Metabolic Disease Center, Inje University, Seoul 01757, Korea
⁴Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Korea

E-mail:,

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-H3R9, shows the dual role of a mitochondria targeting vector along with anticancer effect for cancer therapy. In cytotoxicity assays, MTS-H3R9 was shown to be more effective than MTS. MTS-H3R9 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-H3R9 to mitochondria in HeLa cell line. Furthermore, we exhibited anticancer agent properties that mitochondrial-accumulated MTS-H3R9 caused cell death by reactive oxygen species generation and loss of mitochondrial membrane potential. MTS-H3R9 exhibited dramatically increased anticancer activity in 3D spheroids as well as in a 2D culture model. We demonstrated that MTS-H3R9 provides dual potentials both as a vehicle for targeted delivery and as a cancer treatment agent for therapeutic applications.

Keywords:Mitochondria targeting;MTS-H3R9;3D spheroids;anticancer activity

[References]

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[Referenced By]

[1] Jurj A, Braicu C, Pop LA, Tomuleasa C, Gherman CD, Berindan-Neagoe I, Drug. Des. Devel. Ther., 11, 2871 (2017)

[2] Zhao CY, Cheng R, Yang Z, Tian ZM, Molecules, 23 (2018)

[3] Zhang E, Zhang C, Su Y, Cheng T, Shi C, Drug Discov. Today, 16, 140 (2011)

[4] Farokhzad OC, Langer R, ACS Nano, 3, 16 (2009)

[5] Truong NP, Whittaker MR, Mak CW, Davis TP, Expert. Opin. Drug Deliv., 12, 129 (2015)

[6] Biswas S, Torchilin VP, Adv. Drug Deliv. Rev., 66, 26 (2014)

[7] Youle RJ, van der Bliek AM, Science, 337(6098), 1062 (2012)

[8] Lackner LL, BMC Biol., 12, 35 (2014)

[9] Grandemange S, Herzig S, Martinou JC, Semin. Cancer Biol., 19, 50 (2009)

[10] Heller A, Brockhoff G, Goepferich A, Eur. J. Pharm. Biopharm., 82, 1 (2012)

[11] Modica-Napolitano JS, Weissig V, Int. J. Mol. Sci., 16(8), 17394 (2015)

[12] Yamada Y, Akita H, Kogure K, Kamiya H, Harashima H, Mitochondrion, 7, 63 (2007)

[13] Jean SR, Ahmed M, Lei EK, Wisnovsky SP, Kelley SO, Accounts Chem. Res., 49, 1893 (2016)

[14] Horton KL, Kelley SO, J. Med. Chem., 52, 3293 (2009)

[15] Lin R, Zhang P, Cheetham AG, Walston J, Abadir P, Cui H, Bioconjug. Chem., 26, 71 (2015)

[16] von Heijne G, Embo J., 5, 1335 (1986)

[17] Yu GS, Han J, Ko KS, Choi JS, Macromol. Res., 22(1), 42 (2014)

[18] Schmidt N, Mishra A, Lai GH, Wong GC, Febs Lett., 584, 1806 (2010)

[19] Thoma CR, Zimmermann M, Agarkova I, Kelm JM, Krek W, Adv. Drug Deliv. Rev., 29, 69 (2014)

[20] Huang BW, Gao JQ, J. Control. Release, 270, 246 (2018)

[21] Cho MO, Li Z, Shim HE, Cho IS, Nurunnabi M, Park H, Lee KY, Moon SH, Kim KS, Kang SW, Huh KM, NPG Asia Mater., 8, e309 (2016)

[22] Bae Y, Green ES, Kim GY, Song SJ, Mun JY, Lee S, Park JI, Park JS, Ko KS, Han J, Choi JS, Int. J. Pharm., 515, 186 (2016)

[23] Bae Y, Jung MK, Lee S, Song SJ, Mun JY, Green ES, Han J, Ko KS, Choi JS, Eur. J. Pharm. Biopharm., 124, 104 (2018)

[24] Hunter AC, Adv. Drug Deliv. Rev., 58, 1523 (2006)

[25] Holder AL, Goth-Goldstein R, Lucas D, Koshland CP, Chem. Res. Toxicol., 25, 1885 (2012)

[26] Jain A, Chugh A, Febs Lett., 590, 2896 (2016)

[27] Yang Y, Xiang Y, Xu M, Sci. Rep., 5, 18583 (2015)

[28] Varkouhi AK, Scholte M, Storm G, Haisma HJ, J. Control. Release, 151, 220 (2011)

[29] Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J, Wieckowski MR, Methods Mol. Biol., 810, 183 (2012)

[30] Park J, Lee J, Choi C, PloS One, 6, e23211 (2011)

[31] Hu C, Chen X, Huang Y, Chen Y, Sci. Rep., 8, 2274 (2018)

[32] Xiang L, Xie G, Liu C, Zhou J, Chen J, Yu S, Li J, Pang X, Shi H, Liang H, Biochim. Biophys. Acta, 1833, 2996 (2013)

[33] Zhang X, Wang C, Wu J, Liu Y, Yang Z, Zhang Y, Sui X, Li M, Feng M, J. Control. Release, 262, 305 (2017)

[34] Lin RZ, Chang HY, Biotechnol. J., 3, 1172 (2008)