Anticancer Effect of Intracellular-Delivered Doxorubicin Using a Redox-Responsive LMWSC-g-Lipoic Acid Micelles

Jun-Hyuk Anh; Gyeong-Won Jeong; Jae-Woon Nah

Macromolecular Research, Vol.26, No.7, 650-658, July, 2018

DOI10.1007/s13233-018-6113-1 Export Citation

Anticancer Effect of Intracellular-Delivered Doxorubicin Using a Redox-Responsive LMWSC-g-Lipoic Acid Micelles

Jun-Hyuk Anh, Gyeong-Won Jeong, and Jae-Woon Nah^†

Department of Polymer Science and Engineering, Sunchon National University, Jeonnam 57922, Korea

E-mail:

To induce a quick-drug release, lipoic acid (LA) was introduced to amine group of low molecular weight water-soluble chitosan (LMWSC) by coupling agent. The disulfide bond (-S-S-) of lipoyl group from LMWSC-grafted lipoic acid (LL) can response to glutathione (GSH) at cytoplasm with reducing environment, where LL can rapidly be disassembled via dissociation of disulfide bond (-S-S-) by GSH. The doxorubicin (DOX)-encapsulated LL (LLDOX) was prepared by dialysis method, which allowed quick release of DOX by destabilization of inner-hydrophobic core of LL when disulfide bond (-S-S-) was dissociated by GSH. To demonstrate a redox-responsive release behavior of LLDOX, its drug release was accomplished under PBS buffer (pH 7.4) and GSH (10 mM) condition. In addition, the particle size and morphology of LL and LLDOX were respectively confirmed by DLS and TEM. The particle sizes of LL30% and LL60% were indicated as 268.8±30.9 and 308.1±11.9 nm, respectively. In addition, particle size of LLDOX was decreased more than that of LL. Also, surface charge of LLDOX was displayed to strong positive charge (LLDOX30%: 12.6±0.5 mV, LLDOX60%: 9.6±1.1 mV). Moreover, their morphological structure has a spherical shape. The cytotoxicity LL and LLDOX was confirmed by using MTT assay. Besides, to investigate the intracellular uptake of DOX from LLDOX against HeLa and AGS cell lines, fluorescence image was observed by using fluorescence microscopy. These results suggest that LL is an excellent as a drug carrier due to high anticancer effect by rapid drug release with redox-responsive effect.

Keywords:LMWSC;lipoic acid;redox-responsive;glutathione;anticancer effect

[References]

How SC, Chen YF, Hsieh PL, Wang SS, Jan JS, Colloids Surf. B: Biointerfaces, 153, 244 (2017)
Gu X, Wang H, Camden JP, Chem. Sci., 8, 5902 (2017)
Yoshida C, Uchida Y, Ito T, Takami T, Murakami Y, Materials, 10 (2017)
Dong F, Dong X, Zhou L, Xiao H, Ho PY, Wong MS, Wang Y, Colloids Surf. B: Biointerfaces, 140, 324 (2016)
Li YL, Zhu L, Liu Z, Cheng R, Meng F, Cui JH, Ji SJ, Zhong Z, Angew. Chem.-Int. Edit., 48, 9914 (2009)
Nirei T, Ishihara S, Tanaka T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Watanabe T, J. Surg. Res., 218, 334 (2017)
Wang Y, Qin F, Tan H, Zhang Y, Jiang M, Lu M, Yao X, Int. J. Nanomedicine, 10, 7359 (2015)
Wei RR, Cheng L, Zheng M, Cheng R, Meng FH, Deng C, Zhong ZY, Biomacromolecules, 13(8), 2429 (2012)
Zhong Y, Zhang J, Cheng R, Deng C, Meng F, Xie F, Zhong Z, J. Control. Release, 205, 144 (2015)
Huo M, Liu Y, Wang L, Yin T, Qin C, Xiao Y, Yin L, Liu J, Zhou J, Mol. Pharm., 13, 1750 (2016)
Li J, Huo M, Wang J, Zhou J, Mohammad JM, Zhang Y, Zhu Q, Waddad AY, Zhang Q, Biomaterials, 33, 2310 (2012)
Li F, Chen WL, You BG, Liu Y, Yang SD, Yuan ZQ, Zhu WJ, Li JZ, Qu CX, Zhou YJ, Zhou XF, Liu C, Zhang XN, ACS Appl. Mater. Interfaces, 8, 32146 (2016)
Yang S, Wang Y, Ren Z, Chen M, Chen W, Zhang X, Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 82, 234 (2018)
Jang KW, Seol D, Ding L, Heo DN, Lee SJ, Martin JA, Kwon IK, Int. J. Biol. Macromol., 106, 1211 (2018)
Liu P, Zhang R, Pei M, Colloids Surf. B: Biointerfaces, 160, 455 (2017)
Qin B, Liu L, Wu X, Liang F, Hou T, Pan Y, Song S, Acta Biomater., 64, 211 (2017)
Bar-Zeev M, Livney YD, Assaraf YG, Drug Resist Updat., 31, 15 (2017)
Hu Y, Chen J, Li X, Sun Y, Huang S, Li Y, Liu H, Xu J, Zhong S, Nanotechnology, 28, 375101 (2017)
Nagesetti A, Srinivasan S, McGoron AJ, J. Photochem. Photobiol. B-Biol., 174, 209 (2017)
Gu F, Hu C, Tai Z, Yao C, Tian J, Zhang L, Xia Q, Gong C, Gao Y, Gao S, Sci. Rep., 6, 36281 (2016)
Jeong GW, Nah JW, Carbohydr. Polym., 178, 322 (2017)
Chen Y, Su M, Li Y, Gao J, Zhang C, Cao Z, Zhou J, Liu J, Jiang Z, ACS Appl. Mater. Interfaces, 9, 30519 (2017)
Sun B, Deng C, Meng F, Zhang J, Zhong Z, Acta Biomater., 45, 223 (2016)
Zheng M, Zhong Y, Meng F, Peng R, Zhong Z, Mol. Pharm., 8, 2434 (2011)
Huang J, Wu F, Yu Y, Huang H, Zhang S, You J, Org. Biomol. Chem., 15, 4798 (2017)
Turcu I, Zarafu I, Popa M, Chifiriuc MC, Bleotu C, Culita D, Ghica C, Ionita P, Nanomaterials, 7, 43 (2017)
Yang SD, Zhu WJ, Zhu QL, Chen WL, Ren ZX, Li F, Yuan ZQ, Li JZ, Liu Y, Zhou XF, Liu C, Zhang XN, J. Biomed. Mater. Res. B: Appl. Biomater., 105, 1114 (2017)
Vivek R, Thangam R, NipunBabu V, Rejeeth C, Sivasubramanian S, Gunasekaran P, Muthuchelian K, Kannan S, ACS Appl. Mater. Interfaces, 6, 6469 (2014)
Zhou T, Luo T, Song J, Qu J, Anal. Chem., 90, 2170 (2018)
Liu G, Li K, Wang H, J. Biomater. Appl., 31, 1039 (2017)
Uchegbu IF, Schatzlein AG, Tetley L, Gray AI, Sludden J, Siddique S, Mosha E, J. Pharm. Pharmacol., 50, 453 (1998)
Yuan H, Lu LJ, Du YZ, Hu FQ, Mol. Pharm, 8, 225 (2011)
Jeong GW, Park SC, Choi C, Nam JP, Kim TH, Choi SK, Park JK, Nah JW, Int. J. Pharm., 488, 165 (2015)

[1] How SC, Chen YF, Hsieh PL, Wang SS, Jan JS, Colloids Surf. B: Biointerfaces, 153, 244 (2017)

[2] Gu X, Wang H, Camden JP, Chem. Sci., 8, 5902 (2017)

[3] Yoshida C, Uchida Y, Ito T, Takami T, Murakami Y, Materials, 10 (2017)

[4] Dong F, Dong X, Zhou L, Xiao H, Ho PY, Wong MS, Wang Y, Colloids Surf. B: Biointerfaces, 140, 324 (2016)

[5] Li YL, Zhu L, Liu Z, Cheng R, Meng F, Cui JH, Ji SJ, Zhong Z, Angew. Chem.-Int. Edit., 48, 9914 (2009)

[6] Nirei T, Ishihara S, Tanaka T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Watanabe T, J. Surg. Res., 218, 334 (2017)

[7] Wang Y, Qin F, Tan H, Zhang Y, Jiang M, Lu M, Yao X, Int. J. Nanomedicine, 10, 7359 (2015)

[8] Wei RR, Cheng L, Zheng M, Cheng R, Meng FH, Deng C, Zhong ZY, Biomacromolecules, 13(8), 2429 (2012)

[9] Zhong Y, Zhang J, Cheng R, Deng C, Meng F, Xie F, Zhong Z, J. Control. Release, 205, 144 (2015)

[10] Huo M, Liu Y, Wang L, Yin T, Qin C, Xiao Y, Yin L, Liu J, Zhou J, Mol. Pharm., 13, 1750 (2016)

[11] Li J, Huo M, Wang J, Zhou J, Mohammad JM, Zhang Y, Zhu Q, Waddad AY, Zhang Q, Biomaterials, 33, 2310 (2012)

[12] Li F, Chen WL, You BG, Liu Y, Yang SD, Yuan ZQ, Zhu WJ, Li JZ, Qu CX, Zhou YJ, Zhou XF, Liu C, Zhang XN, ACS Appl. Mater. Interfaces, 8, 32146 (2016)

[13] Yang S, Wang Y, Ren Z, Chen M, Chen W, Zhang X, Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 82, 234 (2018)

[14] Jang KW, Seol D, Ding L, Heo DN, Lee SJ, Martin JA, Kwon IK, Int. J. Biol. Macromol., 106, 1211 (2018)

[15] Liu P, Zhang R, Pei M, Colloids Surf. B: Biointerfaces, 160, 455 (2017)

[16] Qin B, Liu L, Wu X, Liang F, Hou T, Pan Y, Song S, Acta Biomater., 64, 211 (2017)

[17] Bar-Zeev M, Livney YD, Assaraf YG, Drug Resist Updat., 31, 15 (2017)

[18] Hu Y, Chen J, Li X, Sun Y, Huang S, Li Y, Liu H, Xu J, Zhong S, Nanotechnology, 28, 375101 (2017)

[19] Nagesetti A, Srinivasan S, McGoron AJ, J. Photochem. Photobiol. B-Biol., 174, 209 (2017)

[20] Gu F, Hu C, Tai Z, Yao C, Tian J, Zhang L, Xia Q, Gong C, Gao Y, Gao S, Sci. Rep., 6, 36281 (2016)

[21] Jeong GW, Nah JW, Carbohydr. Polym., 178, 322 (2017)

[22] Chen Y, Su M, Li Y, Gao J, Zhang C, Cao Z, Zhou J, Liu J, Jiang Z, ACS Appl. Mater. Interfaces, 9, 30519 (2017)

[23] Sun B, Deng C, Meng F, Zhang J, Zhong Z, Acta Biomater., 45, 223 (2016)

[24] Zheng M, Zhong Y, Meng F, Peng R, Zhong Z, Mol. Pharm., 8, 2434 (2011)

[25] Huang J, Wu F, Yu Y, Huang H, Zhang S, You J, Org. Biomol. Chem., 15, 4798 (2017)

[26] Turcu I, Zarafu I, Popa M, Chifiriuc MC, Bleotu C, Culita D, Ghica C, Ionita P, Nanomaterials, 7, 43 (2017)

[27] Yang SD, Zhu WJ, Zhu QL, Chen WL, Ren ZX, Li F, Yuan ZQ, Li JZ, Liu Y, Zhou XF, Liu C, Zhang XN, J. Biomed. Mater. Res. B: Appl. Biomater., 105, 1114 (2017)

[28] Vivek R, Thangam R, NipunBabu V, Rejeeth C, Sivasubramanian S, Gunasekaran P, Muthuchelian K, Kannan S, ACS Appl. Mater. Interfaces, 6, 6469 (2014)

[29] Zhou T, Luo T, Song J, Qu J, Anal. Chem., 90, 2170 (2018)

[30] Liu G, Li K, Wang H, J. Biomater. Appl., 31, 1039 (2017)

[31] Uchegbu IF, Schatzlein AG, Tetley L, Gray AI, Sludden J, Siddique S, Mosha E, J. Pharm. Pharmacol., 50, 453 (1998)

[32] Yuan H, Lu LJ, Du YZ, Hu FQ, Mol. Pharm, 8, 225 (2011)

[33] Jeong GW, Park SC, Choi C, Nam JP, Kim TH, Choi SK, Park JK, Nah JW, Int. J. Pharm., 488, 165 (2015)