Smac Gene Delivery by the Glycol Chitosan with Low Molecular Weight Polyethylenimine Induces Apoptosis of Cancer Cells for Combination Therapy with Etoposide

Yoonhee Bae; Young Hwa Lee; Kyung Soo Ko; Jin Han; Joon Sig Choi

Macromolecular Research, Vol.27, No.10, 944-954, October, 2019

DOI10.1007/s13233-019-7130-4 Export Citation

Smac Gene Delivery by the Glycol Chitosan with Low Molecular Weight Polyethylenimine Induces Apoptosis of Cancer Cells for Combination Therapy with Etoposide

Yoonhee Bae, Young Hwa Lee¹, Kyung Soo Ko², Jin Han^†, and Joon Sig Choi^{1, †}

Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea
¹Department of Biochemistry, College of Natural Science, Chungnam National University, Daejeon 34134, Korea
²Department of internal Medicine, Sanggye Paik Hospital, Cardiovascular and Metabolic Disease Center, Inje University, Seoul 01757, Korea

E-mail:,

We developed polymer-based nanoparticle carriers for gene delivery, glycol chitosan (GC)-methyl acrylate-low molecular weight polyethylenimine (800Da PEI), GMP, and investigated their ability to deliver second mitochondria-activation of caspase (Smac) gene into cancer cell lines. We analyzed cytotoxicity level and gene transfection efficiency in GBL-14, U373-MG, MDA-MB-231, and dermal fibroblasts (HDF) cell lines. GMP exhibited significantly lower cytotoxicity level, as compared with PEI25KD. Also, it showed high transfection efficiency in these cell lines. We treated these cells with a complex of GMP and Smac, and investigated their facilitated cellular uptake by flow cytometry. Also, analyses using cell cycle distribution, Annexin V staining, JC-1, and caspase-3 activity, indicated that apoptosis was induced by GMP/FLAG-Smac combined with etoposide in MDA-MB-231 cell line. This study demonstrates that combining the GMP/FLAG-Smac complex with chemotherapeutic agents could potentially be an effective approach for cancer therapy.

Keywords:Smac;nanoparticle;GMP;apoptosis;etoposide

[References]

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[1] Gmeiner WH, Ghosh S, Nanotechnol. Rev., 3, 111 (2015)

[2] Jeong K, Kang CS, Kim Y, Lee YD, Kwon IC, Kim S, Cancer Lett., 374, 31 (2016)

[3] Bae KH, Chung HJ, Park TG, Mol. Cells, 31, 295 (2011)

[4] Peer D, Karp JM, Hong S, FaroKHzad OC, Margalit R, Langer R, Nat. Nanotechnol., 2(12), 751 (2007)

[5] Chira S, Jackson CS, Oprea I, Ozturk F, Pepper MS, Diaconu I, Braicu C, Raduly LZ, Calin GA, Berindan-Neagoe I, Oncotarget, 6, 30675 (2015)

[6] Paleos CM, Tziveleka LA, Sideratou Z, Tsiourvas D, Expert Opin. Drug Deliv., 6, 27 (2009)

[7] Jones CH, Chen CK, Ravikrishnan A, Rane S, Pfeifer BA, Molecular pharmaceutics, 10, 4082 (2013)

[8] Pathak A, Patnaik S, Gupta KC, Biotechnol. J., 4, 1559 (2009)

[9] Al-Dosari MS, Gao X, AAPS J., 11, 671 (2009)

[10] Ahsan SM, Thomas M, Reddy KK, Sooraparaju SG, Asthana A, Bhatnagar I, Int. J. Biol. Macromol., 110, 97 (2018)

[11] Mansouri S, Lavigne P, Corsi K, Benderdour M, Beaumont E, Fernandes JC, Eur. J. Pharm. Biopharm., 57, 1 (2004)

[12] Liu WG, Yao KD, J. Control. Release, 83, 1 (2002)

[13] Nam HY, Kwon SM, Chung H, Lee SY, Kwon SH, Jeon H, Kim Y, Park JH, Kim J, Her S, Oh YK, Kwon IC, Kim K, Jeonge SY, J. Control. Release, 135, 259 (2009)

[14] Koo H, Min KH, Lee SC, Park JH, Park K, Jeong SY, Choi K, Kwon IC, Kim K, J. Control. Release, 172, 823 (2013)

[15] Koo H, Huh MS, Sun IC, Yuk SH, Choi K, Kim K, Kwon IC, Accounts Chem. Res., 44, 1018 (2011)

[16] Sun IC, Na JH, Jeong SY, Kim DE, Kwon IC, Choi K, Ahn CH, Kim K, Pharm. Res., 31, 1418 (2014)

[17] Yoo HS, Lee JR, Chung H, Kwon IC, Jeong SY, J. Control. Release, 103, 235 (2005)

[18] Adrain C, Creagh EM, Martin SJ, Embo J., 20, 6627 (2001)

[19] Mao HL, Pang Y, Zhang X, Yang F, Zheng J, Wang Y, Liu P, Oncol. Rep., 29, 515 (2013)

[20] Bae Y, Kho CW, Lee SY, Rhim H, Kang S, Biochem. Biophys. Res. Commun., 397(4), 718 (2010)

[21] Bockbrader KM, Tan M, Sun Y, Oncogene, 24, 7381 (2005)

[22] Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JPR, Melendez-Zajgla J, J. Exp. Clin. Cancer Res., 27, 48 (2008)

[23] Bae Y, Lee YH, Lee S, Han J, Ko KS, Choi JS, Carbohydr. Polym., 153, 379 (2016)

[24] Lee YH, Park HI, Choi JS, Carbohydr. Polym., 137, 669 (2016)

[25] 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)

[26] 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)

[27] Bae Y, Rhim HS, Lee S, Ko KS, Han J, Choi JS, J. Pharm. Sci., 106, 1618 (2017)

[28] Sun Y, Li Y, Liu X, Jin M, Zhang L, Du Z, Guo C, Huang P, Sun Z, Toxicol. In vitro, 25, 1619 (2011)

[29] Theodossiou TA, Sideratou Z, Katsarou ME, Tsiourvas D, Pharm. Res., 30, 2832 (2013)

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

[31] Silver N, Best S, Jiang J, Thein SL, BMC Mol. Biol., 7, 33 (2006)

[32] Zhao J, Jin J, Zhang X, Shi M, Dai J, Wu M, Wang R, Guo Y, Cancer Gene Therapy, 13, 420 (2006)

[33] Ceballos-Cancino G, Espinosa M, Maldonado V, Melendez-Zajgla J, Oncogene, 26, 7569 (2007)

[34] Pietkiewicz S, Schmidt JH, Lavrik IN, J. Immunol. Methods, 423, 99 (2015)

[35] Sun Q, Zheng X, Zhang L, Yu J, Clin. Cancer Res., 17, 2361 (2011)

[36] Shah BP, Pasquale N, De G, Tan T, Ma J, Lee KB, ACS Nano, 8, 9379 (2014)

[37] Ma X, Zhang LH, Wang LR, Xue X, Sun JH, Wu Y, Zou G, Wu X, Wang PC, Wamer WG, Yin JJ, Zheng K, Liang XJ, ACS Nano, 6, 10486 (2012)