Disulfide and β-sheet stabilized poly(amino acid) nanovesicles for intracellular drug delivery

Chan Woo Park; Hee-Man Yang; Kwang Se Lee; Jong-Duk Kim

Journal of Industrial and Engineering Chemistry, Vol.56, 277-284, December, 2017

DOI10.1016/j.jiec.2017.07.020 Export Citation

Disulfide and β-sheet stabilized poly(amino acid) nanovesicles for intracellular drug delivery

Chan Woo Park^{1, 2, †}, Hee-Man Yang², Kwang Se Lee¹, and Jong-Duk Kim^{1, †}

¹Department of Chemical and Biomolecular Engineering (BK21 Graduate Program), Korea Advanced Institute of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea
²Decommissioning Technology Research Division, Korea Atomic Energy Research Institute, Daedeok-daero 989-111, Yuseong-gu, Daejeon, Republic of Korea

E-mail:,

We report the fabrication of redox-responsive poly(amino acid) vesicles containing bilayers highly stabilized by disulfide cross-links, β-sheets, and hydrophobic interactions. Tailor-made amphiphilic poly (amino acid)s, specifically poly(2-hydroxyethyl aspartamide)-g-oligo(L-cysteine) (P-g-OC), were used as building blocks for the formation of vesicles. The stable bilayer prematurely released hardly any of an encapsulated anticancer drug, doxorubicin, and the drug release was triggered only by millimolar concentrations of reducing agent, which mimic intracellular conditions. The vesicles demonstrated successful delivery of the drug to the inside of cells, triggered release of the drug after cellular uptake, and translocation of the drug to nuclei in cancer cells.

Keywords:Vesicle;Poly(amino acid)s;Disulfide;β-Sheet;Drug delivery

[References]

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Hamley IW, Soft Matter, 1(1), 36 (2005)
Palivan CG, Goers R, Najer A, Zhang X, Car A, Meier W, Chem. Soc. Rev., 45(2), 377 (2016)
Tian B, Tao X, Ren T, Weng Y, Lin X, Zhang Y, Tang X, J. Mater. Chem., 22(34), 17404 (2012)
Meng F, Hennink WE, Zhong Z, Biomaterials, 30(12), 2180 (2009)
Bae YH, Park K, J. Control. Release, 153(3), 198 (2011)
Lee HJ, Yang SR, An EJ, Kim JD, Macromolecules, 39(15), 4938 (2006)
Fujita K, Kimura S, Imanishi Y, Langmuir, 15(13), 4377 (1999)
Bellomo EG, Wyrsta MD, Pakstis L, Pochan DJ, Deming TJ, Nat. Mater., 3(4), 244 (2004)
Kukula H, Schlaad H, Antonietti M, Forster S, J. Am. Chem. Soc., 124(8), 1658 (2002)
Chilkoti A, Dreher MR, Meyer DE, Adv. Drug Deliv. Rev., 54(8), 1093 (2002)
Park CW, Lee HJ, Yang HM, Woo MA, Park HG, Kim JD, J. Polym. Sci. A: Polym. Chem., 49(1), 203 (2011)
Yang HM, Park CW, Lim S, Park SI, Chung BH, Kim JD, Chem. Commun., 47, 12518 (2011)
Smith CE, Kong H, Langmuir, 30(13), 3697 (2014)
Oba M, Aoyagi K, Miyata K, Matsumoto Y, Itaka K, Nishiyama N, Yamasaki Y, Koyama H, Kataoka K, Mol. Pharm., 5(6), 1080 (2008)
Li YL, Maciel D, Rodrigues J, Shi XY, Tomas H, Chem. Rev., 115(16), 8564 (2015)
Yan Y, Johnston APR, Dodds SJ, Kamphuis MMJ, Ferguson C, Parton RG, Nice EC, Heath JK, Caruso F, ACS Nano, 4(5), 2928 (2010)
Park CW, Yang HM, Woo MA, Lee KS, Kim JD, J. Ind. Eng. Chem., 45, 182 (2017)
Saito G, Swanson JA, Lee KD, Adv. Drug Deliv. Rev., 55(2), 199 (2003)
Wu X, Zhou L, Su Y, Dong CM, Polym. Chem., 6(38), 6857 (2015)
Sun J, Chen XS, Lu TC, Liu S, Tian HY, Guo ZP, Jing XB, Langmuir, 24(18), 10099 (2008)
Wang K, Luo GF, Liu Y, Li C, Cheng SX, Zhuo RX, Zhang XZ, Polym. Chem., 3(4), 1084 (2012)
Heitmann P, Eur. J. Biochem., 3(3), 346 (1968)
Neri P, Antoni G, Benvenuti F, Cocola F, Gazzei G, J. Med. Chem., 16(8), 893 (1973)
Yang SR, Lee HJ, Kim JD, J. Control. Release, 114(1), 60 (2006)
Deming TJ, Cha JN, Stucky GD, Morse DE, Nature, 403(6767), 289 (2000)
Daly WH, Poche D, Tetrahedron Lett., 29(46), 5859 (1988)
Tomida M, Nakato T, Matsunami S, Kakuchi T, Polymer, 38(18), 4733 (1997)
Kataoka K, Ishihara A, Harada A, Miyazaki H, Macromolecules, 31(18), 6071 (1998)
Jeong JH, Kang HS, Yang SR, Kim JD, Polymer, 44(3), 583 (2003)
Greenfield NJ, Nat. Protoc., 1(6), 2876 (2007)
Riddles PW, Blakeley RL, Zerner B, Anal. Biochem., 94(1), 75 (1979)
Nakaishi A, Maeda H, Tomiyama T, Ikeda S, Kobayashi Y, Kyogoku Y, J. Phys. Chem., 92, 6161 (1988)
Meng FH, Zhong ZY, Feijen J, Biomacromolecules, 10(2), 197 (2009)
Bermudez H, Brannan AK, Hammer DA, Bates FS, Discher DE, Macromolecules, 35(21), 8203 (2002)
Park CW, Yang HM, Seo BK, Kim JD, Colloids Surf. A: Physicochem. Eng. Asp., 500, 105 (2016)
Jeong JH, Cha C, Kaczmarowski A, Haan J, Oh S, Kong H, Soft Matter, 2012(8), 2237 (2012)
Lee HJ, Kwon SH, Jang KS, RSC Adv., 6, 86361 (2016)
Seidel C, Acta Polym., 37(7), 474 (1986)
Wen HY, Dong HQ, Xie W, Li YY, Wang K, Pauletti GM, Shi DL, Chem. Commun., 47(12), 3550 (2011)
Sahay G, Alakhova DY, Kabanov AV, J. Control. Release, 145(3), 182 (2010)

[Referenced By]

[1] Discher DE, Eisenberg A, Science, 297(5583) (2002)

[2] Hamley IW, Soft Matter, 1(1), 36 (2005)

[3] Palivan CG, Goers R, Najer A, Zhang X, Car A, Meier W, Chem. Soc. Rev., 45(2), 377 (2016)

[4] Tian B, Tao X, Ren T, Weng Y, Lin X, Zhang Y, Tang X, J. Mater. Chem., 22(34), 17404 (2012)

[5] Meng F, Hennink WE, Zhong Z, Biomaterials, 30(12), 2180 (2009)

[6] Bae YH, Park K, J. Control. Release, 153(3), 198 (2011)

[7] Lee HJ, Yang SR, An EJ, Kim JD, Macromolecules, 39(15), 4938 (2006)

[8] Fujita K, Kimura S, Imanishi Y, Langmuir, 15(13), 4377 (1999)

[9] Bellomo EG, Wyrsta MD, Pakstis L, Pochan DJ, Deming TJ, Nat. Mater., 3(4), 244 (2004)

[10] Kukula H, Schlaad H, Antonietti M, Forster S, J. Am. Chem. Soc., 124(8), 1658 (2002)

[11] Chilkoti A, Dreher MR, Meyer DE, Adv. Drug Deliv. Rev., 54(8), 1093 (2002)

[12] Park CW, Lee HJ, Yang HM, Woo MA, Park HG, Kim JD, J. Polym. Sci. A: Polym. Chem., 49(1), 203 (2011)

[13] Yang HM, Park CW, Lim S, Park SI, Chung BH, Kim JD, Chem. Commun., 47, 12518 (2011)

[14] Smith CE, Kong H, Langmuir, 30(13), 3697 (2014)

[15] Oba M, Aoyagi K, Miyata K, Matsumoto Y, Itaka K, Nishiyama N, Yamasaki Y, Koyama H, Kataoka K, Mol. Pharm., 5(6), 1080 (2008)

[16] Li YL, Maciel D, Rodrigues J, Shi XY, Tomas H, Chem. Rev., 115(16), 8564 (2015)

[17] Yan Y, Johnston APR, Dodds SJ, Kamphuis MMJ, Ferguson C, Parton RG, Nice EC, Heath JK, Caruso F, ACS Nano, 4(5), 2928 (2010)

[18] Park CW, Yang HM, Woo MA, Lee KS, Kim JD, J. Ind. Eng. Chem., 45, 182 (2017)

[19] Saito G, Swanson JA, Lee KD, Adv. Drug Deliv. Rev., 55(2), 199 (2003)

[20] Wu X, Zhou L, Su Y, Dong CM, Polym. Chem., 6(38), 6857 (2015)

[21] Sun J, Chen XS, Lu TC, Liu S, Tian HY, Guo ZP, Jing XB, Langmuir, 24(18), 10099 (2008)

[22] Wang K, Luo GF, Liu Y, Li C, Cheng SX, Zhuo RX, Zhang XZ, Polym. Chem., 3(4), 1084 (2012)

[23] Heitmann P, Eur. J. Biochem., 3(3), 346 (1968)

[24] Neri P, Antoni G, Benvenuti F, Cocola F, Gazzei G, J. Med. Chem., 16(8), 893 (1973)

[25] Yang SR, Lee HJ, Kim JD, J. Control. Release, 114(1), 60 (2006)

[26] Deming TJ, Cha JN, Stucky GD, Morse DE, Nature, 403(6767), 289 (2000)

[27] Daly WH, Poche D, Tetrahedron Lett., 29(46), 5859 (1988)

[28] Tomida M, Nakato T, Matsunami S, Kakuchi T, Polymer, 38(18), 4733 (1997)

[29] Kataoka K, Ishihara A, Harada A, Miyazaki H, Macromolecules, 31(18), 6071 (1998)

[30] Jeong JH, Kang HS, Yang SR, Kim JD, Polymer, 44(3), 583 (2003)

[31] Greenfield NJ, Nat. Protoc., 1(6), 2876 (2007)

[32] Riddles PW, Blakeley RL, Zerner B, Anal. Biochem., 94(1), 75 (1979)

[33] Nakaishi A, Maeda H, Tomiyama T, Ikeda S, Kobayashi Y, Kyogoku Y, J. Phys. Chem., 92, 6161 (1988)

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

[35] Bermudez H, Brannan AK, Hammer DA, Bates FS, Discher DE, Macromolecules, 35(21), 8203 (2002)

[36] Park CW, Yang HM, Seo BK, Kim JD, Colloids Surf. A: Physicochem. Eng. Asp., 500, 105 (2016)

[37] Jeong JH, Cha C, Kaczmarowski A, Haan J, Oh S, Kong H, Soft Matter, 2012(8), 2237 (2012)

[38] Lee HJ, Kwon SH, Jang KS, RSC Adv., 6, 86361 (2016)

[39] Seidel C, Acta Polym., 37(7), 474 (1986)

[40] Wen HY, Dong HQ, Xie W, Li YY, Wang K, Pauletti GM, Shi DL, Chem. Commun., 47(12), 3550 (2011)

[41] Sahay G, Alakhova DY, Kabanov AV, J. Control. Release, 145(3), 182 (2010)