Synthesis and physicochemical characterization of reduction-sensitive block copolymer for intracellular delivery of doxorubicin

Thavasyappan Thambi; Gurusamy Saravanakumar; Jun-Uk Chu; Roun Heo; Hyewon Ko; Veerasikku Gopal Deepagan; Jong-Ho Kim; Jae Hyung Park

Macromolecular Research, Vol.21, No.1, 100-107, January, 2013

DOI10.1007/s13233-013-1014-9 Export Citation

Synthesis and physicochemical characterization of reduction-sensitive block copolymer for intracellular delivery of doxorubicin

Thavasyappan Thambi¹, Gurusamy Saravanakumar¹, Jun-Uk Chu², Roun Heo³, Hyewon Ko¹, Veerasikku Gopal Deepagan¹, Jong-Ho Kim^{4, †}, and Jae Hyung Park^{1, 3, †}

¹Department of Polymer Science and Engineering, College of Engineering, Sungkyunkwan University, Gyeonggi, 440-746, Korea
²Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 136-791, Korea
³Graduate School of Health Sciences and Technology, Sungkyunkwan University, Gyeonggi, 440-746, Korea
⁴Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Korea

E-mail:,

An amphiphilic diblock copolymer bearing the reduction-sensitive linker, composed of poly(ethylene glycol) (PEG) and hydrophobic poly(γ-benzyl L-glutamate) (PBLG), was prepared as the potential carrier of doxorubicin (DOX) via a facile synthetic method in the presence of a shell-sheddable PEG macroinitiator (PEG-SS-NH2). Owing to its amphiphilic nature, the copolymer (PEG-SS-PBLG) formed spherical micelles (137 nm in diameter) in aqueous conditions. The micelles were stable under the physiologic condition (pH 7.4) and were readily cleaved in the presence of glutathione (GSH), a tripeptide reducing the disulfide bond in the cytoplasm of the cell. DOX, chosen as a model anticancer drug, was effectively encapsulated into the hydrophobic core of the micelle with high loading efficiency (>75%). The micelle released DOX completely within 18 h at 10 mM GSH mimicking the intracellular condition, whereas only 34% of the drug was released from the micelle at 2 μM GSH. In vitro cytotoxicity tests revealed that DOX-loaded reduction-sensitive micelles are more toxic to SCC7 cells than reduction-insensitive control micelles. These results suggest that PEG-SS-PBLG is the promising carrier for the intracellular delivery of DOX.

Keywords:reduction-sensitive micelle;amphiphilic block copolymer;glutathione;doxorubicin

[References]

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Daly WH, Poche D, Tetrahedron Lett., 29, 5859 (1988)
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[Referenced By]

[1] Kataoka K, Harada A, Nagasaki Y, Adv. Drug Deliv. Rev., 47, 113 (2001)

[2] Rosler A, Vandermeulen GWM, Klok HA, Adv. Drug Deliv. Rev., 53, 95 (2001)

[3] Matsumura Y, Maeda H, Cancer Res., 46, 6387 (1986)

[4] Maeda H, Wu J, Sawa T, Matsumura Y, Hori K, J.Control. Release., 65, 271 (2000)

[5] Nakada Y, Tudomi R, Sakurai K, Takahashi Y, Int. J.Pharm., 175, 109 (1998)

[6] Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R, Science, 263(5153), 1600 (1994)

[7] Shuai X, Ai H, Nasongkla N, Kim S, Gao J, J. Control. Release., 98, 415 (2004)

[8] Machida Y, Onishi H, Kurita A, Hata H, Morikawa A, J. Control. Release., 66, 159 (2000)

[9] Dong Y, Feng SS, Biomaterials., 25, 2843 (2004)

[10] Stuart MAC, Huck WTS, Genzer J, Muller M, Ober C, Stamm M, Sukhorukov GB, Szleifer I, Tsukruk VV, Urban M, Winnik F, Zauscher S, Luzinov I, Minko S, Nat. Mater., 9(2), 101 (2010)

[11] Meng F, Hennink WE, Zhong Z, Biomaterials., 30, 2180 (2009)

[12] Natalya R, Prog. Polym. Sci., 32, 962 (2007)

[13] Meng FH, Zhong ZY, Feijen J, Biomacromolecules, 10(2), 197 (2009)

[14] Shamay Y, Adar L, Ashkenasy G, David A, Biomaterials., 32, 1377 (2011)

[15] Zhang H, Xia H, Wang J, Li Y, J. Control. Release., 139, 31 (2009)

[16] Thambi T, Deepagan VG, Yoo CK, Park JH, Polymer, 52(21), 4753 (2011)

[17] Min KH, Kim JH, Bae SM, Shin H, Kim MS, Park S, Lee H, Park RW, Kim IS, Kim K, Kwon IC, Jeong SY, Lee DS, J. Control. Release., 144, 259 (2010)

[18] Lu JS, Li NJ, Xu QF, Ge JF, Lu JM, Xia XW, Polymer, 51(8), 1709 (2010)

[19] Liu SQ, Tong YW, Yang YY, Biomaterials., 26, 5064 (2005)

[20] Cerritelli S, Velluto D, Hubbell JA, Biomacromolecules, 8(6), 1966 (2007)

[21] Koo AN, Lee HJ, Kim SE, Chang JH, Park C, Kim C, Park JH, Lee SC, Chem. Commun., 6570 (2008)

[22] Ren TB, Feng Y, Zhang ZH, Li L, Li YY, Soft Matter., 7, 2329 (2011)

[23] Sun H, Guo B, Cheng R, Meng F, Liu H, Zhong Z, Biomaterials., 30, 6358 (2009)

[24] Thambi T, Yoon HY, Kim K, Kwon IC, Yoo CK, Park JH, Bioconjug. Chem., 22, 1924 (2011)

[25] Jones DP, Carlson JL, Samiec PS, Sternberg P, Mody VC, Reed RL, Brown LA, Clin. Chim. Acta., 275, 175 (1998)

[26] Sun Y, Yan X, Yuan T, Liang J, Fan Y, Gu Z, Zhang X, Biomaterials., 31, 7124 (2010)

[27] Stolnik S, Illum L, Davis SS, Adv. Drug Deliv. Rev., 16, 195 (1995)

[28] Romberg B, Hennink W, Storm G, Pharm. Res., 25, 55 (2008)

[29] Lee Y, Park SY, Kim C, Park TG, J. Control.Release., 135, 89 (2009)

[30] Daly WH, Poche D, Tetrahedron Lett., 29, 5859 (1988)

[31] Wilhelm M, Zhao CL, Wang Y, Xu R, Winnik MA, Mura JL, Riess G, Croucher MD, Macromolecules., 24, 1033 (1991)

[32] Tang LY, Wang YC, Li Y, Du ZH, Wang J, Bioconjug.Chem., 20, 1095 (2009)

[33] Yoo HS, Lee EA, Park TG, J. Control. Release., 82, 17 (2002)

[34] Choi KY, Chung H, Min KH, Yoon HY, Kim K, Park JH, Kwon IC, Jeong SY, Biomaterials., 31, 106 (2010)

[35] Kim C, Lee SC, Kang SW, Kwon IC, Kim YH, Jeong SY, Langmuir, 16(11), 4792 (2000)

[36] Kwon S, Park JH, Chung H, Kwon IC, Jeong SY, Kim IS, Langmuir, 19(24), 10188 (2003)

[37] Li Y, Tong R, Xia H, Zhang H, Xuan J, Chem. Commun., 46, 7739 (2010)