Cancer-specific pro-oxidant therapy using low-toxic polypeptide micelles encapsulating piperlongumine

Eun Ji Hong; DaeYong Lee; Han Chang Kang; Yeu-Chun Kim; Min Suk Shim

Journal of Industrial and Engineering Chemistry, Vol.63, 57-64, July, 2018

DOI10.1016/j.jiec.2018.01.040 Export Citation

Cancer-specific pro-oxidant therapy using low-toxic polypeptide micelles encapsulating piperlongumine

Eun Ji Hong, DaeYong Lee¹, Han Chang Kang², Yeu-Chun Kim^{1, †}, and Min Suk Shim^†

Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
¹Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
²Department of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, and BK21 PLUS Team for Creative Leader Program for Pharmacomicsbased Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea

E-mail:,

Pro-oxidant therapy utilizing pro-oxidant drugs that can induce cytotoxic oxidative stress in cancer cells has attracted widespread attention for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent because it can exhibit cancer-specific cytotoxicity via elevation of intracellular reactive oxygen species (ROS) in cancer cells. However, its therapeutic efficacy has been limited by its poor water-solubility, which necessitates developing suitable drug carriers for PL delivery. In this study, low-toxic poly(ethylene glycol)-poly(histidine) [PEG-poly(His)] copolymer was developed for effective intracellular delivery of PL. Stable micelles composed of a PEG shell and a poly(His) core encapsulating PL were prepared. In vitro study revealed that plain PEG-poly(His) micelles without PL were low-toxic. Importantly, PL-PEG-poly(His) micelles showed superior cytotoxicity in cancer cells over normal cells due to the PL-induced, dramatic increase of intracellular ROS in cancer cells in comparison with normal cells. PL-PEG-poly(His) micelles were further modified with folic acid (FA) to enhance their cancer-specific pro-oxidant therapy. As compared to FA-free micelles, FA-PL-PEG-poly(His) micelles revealed more facilitated cellular uptake and anticancer efficacy in folate receptor-positive cancer cells. This study demonstrates that PL-PEG-poly(His) micelles are efficient and low-toxic carriers for PL delivery, thus leading to effective and cancer-targeted pro-oxidant therapy.

Keywords:Poly(histidine);Micelle;Piperlongumine;Cancer therapy;Pro-oxidant therapy

[References]

Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB, Free Radic. Biol. Med., 49, 1603 (2010)
Trachootham D, Alexandre J, Huang P, Nat. Rev. Drug Discov., 8, 579 (2009)
Schumacker PT, Cancer Cell, 10, 175 (2006)
Bezerra DP, Pessoa C, de Moraes MO, de Alencar NMN, Mesquita RO, Lima MW, Alves APNN, Pessoa ODL, Chaves JH, Silveira ER, Costa-Lotufo LV, Appl. Toxicol., 28, 599 (2008)
Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li XY, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW, Nature, 475(7355), 231 (2011)
Makhov P, Golovine K, Teper E, Kutikov A, Mehrazin R, Corcoran A, Tulin A, Uzzo RG, Kolenko VM, Br. J. Cancer, 110, 899 (2014)
Wang J, Yao K, Wang C, Tang C, Jiang X, J. Mater. Chem. B, 1, 2324 (2013)
Liu Y, Chang Y, Yang C, Sang Z, Yang T, Ang W, Ye W, Wei Y, Gong C, Luo Y, Nanoscale, 6, 4325 (2014)
Tian B, Tao X, Ren T, Weng Y, Lin X, Zhang Y, Tang X, J. Mater. Chem., 22, 17404 (2012)
Lee YJ, Kang HC, Hu J, Nichols JW, Jeon YS, Bae YH, Biomacromolecules, 13(9), 2945 (2012)
Zhao Z, Wang Y, Han J, Wang K, Yang D, Yang Y, Du Q, Song Y, Yin X, Int. J. Nanomed., 9, 5849 (2014)
Wu L, Fang S, Shi S, Deng J, Liu B, Cai L, Biomacromolecules, 14, 3027 (2013)
Lee ES, Gao Z, Bae YH, J. Control. Release, 132, 164 (2008)
Lee ES, Oh KT, Kim D, Youn YS, Bae YH, J. Control. Release, 123, 19 (2007)
Lee ES, Shin HJ, Na K, Bae YH, J. Control. Release, 90, 363 (2003)
Zhang XJ, Chen DW, Ba S, Zhu J, Zhang J, Hong W, Zhao XL, Hu HY, Qiao MX, Biomacromolecules, 15(11), 4032 (2014)
Hu J, Miura S, Na K, Bae YH, J. Control. Release, 172, 69 (2013)
Kim GM, Bae YH, Jo WH, Macromol. Biosci., 5, 1118 (2005)
Engin K, Leeper DB, Cater JR, Thistlethwaite AJ, Tupchong L, McFarlane JD, Int. J. Hyperth., 11, 211 (1995)
Chen CY, Kim TH, Wu WC, Huang CM, Wei H, Mount CW, Tian Y, Jang SH, Pun SH, Jen AK, Biomaterials, 34, 4501 (2013)
Kanayama N, Fukushima S, Nishiyama N, Itaka K, Jang WK, Miyata K, Yamasaki Y, Chung UI, Kataoka K, ChemMedChem, 1, 439 (2006)
Jhaveri AM, Torchilin VP, Front. Pharmacol., 5, 77 (2014)
Hamidi M, Azadi A, Rafiei P, Drug Deliv., 13, 399 (2006)
Pelaz B, del Pino P, Maffre P, Hartmann R, Gallego M, Rivera-Fernandez S, de la Fuente JM, Nienhaus GU, Parak WJ, ACS Nano, 9, 6996 (2015)
Venkatesan J, Alam MS, Hong EJ, Kim SK, Shim MS, RSC Adv., 6, 79307 (2016)
Dickinson BC, Chang CJ, Nat. Chem. Biol., 7, 504 (2011)
Roh JL, Kim EH, Park JY, Kim JW, Kwon M, Lee BH, Oncotarget, 5, 9227 (2014)
Wang Y, Cao X, Guo R, Shen M, Zhang M, Zhu M, Shi X, Polym. Chem., 2, 1754 (2011)
Zhang Y, Zhou J, Yang C, Wang W, Chu L, Huang F, Liu Q, Deng L, Kong D, Liu J, Liu J, Int. J. Nanomed., 11, 1119 (2016)

[Referenced By]

[1] Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB, Free Radic. Biol. Med., 49, 1603 (2010)

[2] Trachootham D, Alexandre J, Huang P, Nat. Rev. Drug Discov., 8, 579 (2009)

[3] Schumacker PT, Cancer Cell, 10, 175 (2006)

[4] Bezerra DP, Pessoa C, de Moraes MO, de Alencar NMN, Mesquita RO, Lima MW, Alves APNN, Pessoa ODL, Chaves JH, Silveira ER, Costa-Lotufo LV, Appl. Toxicol., 28, 599 (2008)

[5] Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li XY, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW, Nature, 475(7355), 231 (2011)

[6] Makhov P, Golovine K, Teper E, Kutikov A, Mehrazin R, Corcoran A, Tulin A, Uzzo RG, Kolenko VM, Br. J. Cancer, 110, 899 (2014)

[7] Wang J, Yao K, Wang C, Tang C, Jiang X, J. Mater. Chem. B, 1, 2324 (2013)

[8] Liu Y, Chang Y, Yang C, Sang Z, Yang T, Ang W, Ye W, Wei Y, Gong C, Luo Y, Nanoscale, 6, 4325 (2014)

[9] Tian B, Tao X, Ren T, Weng Y, Lin X, Zhang Y, Tang X, J. Mater. Chem., 22, 17404 (2012)

[10] Lee YJ, Kang HC, Hu J, Nichols JW, Jeon YS, Bae YH, Biomacromolecules, 13(9), 2945 (2012)

[11] Zhao Z, Wang Y, Han J, Wang K, Yang D, Yang Y, Du Q, Song Y, Yin X, Int. J. Nanomed., 9, 5849 (2014)

[12] Wu L, Fang S, Shi S, Deng J, Liu B, Cai L, Biomacromolecules, 14, 3027 (2013)

[13] Lee ES, Gao Z, Bae YH, J. Control. Release, 132, 164 (2008)

[14] Lee ES, Oh KT, Kim D, Youn YS, Bae YH, J. Control. Release, 123, 19 (2007)

[15] Lee ES, Shin HJ, Na K, Bae YH, J. Control. Release, 90, 363 (2003)

[16] Zhang XJ, Chen DW, Ba S, Zhu J, Zhang J, Hong W, Zhao XL, Hu HY, Qiao MX, Biomacromolecules, 15(11), 4032 (2014)

[17] Hu J, Miura S, Na K, Bae YH, J. Control. Release, 172, 69 (2013)

[18] Kim GM, Bae YH, Jo WH, Macromol. Biosci., 5, 1118 (2005)

[19] Engin K, Leeper DB, Cater JR, Thistlethwaite AJ, Tupchong L, McFarlane JD, Int. J. Hyperth., 11, 211 (1995)

[20] Chen CY, Kim TH, Wu WC, Huang CM, Wei H, Mount CW, Tian Y, Jang SH, Pun SH, Jen AK, Biomaterials, 34, 4501 (2013)

[21] Kanayama N, Fukushima S, Nishiyama N, Itaka K, Jang WK, Miyata K, Yamasaki Y, Chung UI, Kataoka K, ChemMedChem, 1, 439 (2006)

[22] Jhaveri AM, Torchilin VP, Front. Pharmacol., 5, 77 (2014)

[23] Hamidi M, Azadi A, Rafiei P, Drug Deliv., 13, 399 (2006)

[24] Pelaz B, del Pino P, Maffre P, Hartmann R, Gallego M, Rivera-Fernandez S, de la Fuente JM, Nienhaus GU, Parak WJ, ACS Nano, 9, 6996 (2015)

[25] Venkatesan J, Alam MS, Hong EJ, Kim SK, Shim MS, RSC Adv., 6, 79307 (2016)

[26] Dickinson BC, Chang CJ, Nat. Chem. Biol., 7, 504 (2011)

[27] Roh JL, Kim EH, Park JY, Kim JW, Kwon M, Lee BH, Oncotarget, 5, 9227 (2014)

[28] Wang Y, Cao X, Guo R, Shen M, Zhang M, Zhu M, Shi X, Polym. Chem., 2, 1754 (2011)

[29] Zhang Y, Zhou J, Yang C, Wang W, Chu L, Huang F, Liu Q, Deng L, Kong D, Liu J, Liu J, Int. J. Nanomed., 11, 1119 (2016)