Implication of multivalent aptamers in DNA and DNA.RNA hybrid structures for efficient drug delivery in vitro and in vivo

Yoon Young Kang; Jihyeon Song; Hee Sun Jung; Gijung Kwak; Gyeonghui Yu; Joong-Hoon Ahn; Sun Hwa Kim; Hyejung Mok

Journal of Industrial and Engineering Chemistry, Vol.60, 250-258, April, 2018

DOI10.1016/j.jiec.2017.11.011 Export Citation

Implication of multivalent aptamers in DNA and DNA.RNA hybrid structures for efficient drug delivery in vitro and in vivo

Yoon Young Kang¹, Jihyeon Song¹, Hee Sun Jung¹, Gijung Kwak^{2, 3}, Gyeonghui Yu¹, Joong-Hoon Ahn¹, Sun Hwa Kim^{2, †}, and Hyejung Mok^{1, †}

¹Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea
²Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea
³KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea

E-mail:,

To examine proper multivalency and type of aptamers in linear nucleic acid-based structures for efficient intracellular uptakes, we designed linear DNA structures with single and dual aptamers targeting guanosine-rich oligonucleotide 100 (AS1411) and mucin 1 (MUC-1). Multivalent linear DNA structures containing dual types of aptamers showed significantly superior cellular internalization. In addition, multivalent aptamer-immobilized DNA.RNA hybrid structures showed excellent tumor accumulation in vivo without liver toxicity and very low nonspecific cytokine induction. Thus, these multivalent nucleic acid based structures with dual types of aptamers can be specifically applied as carriers of therapeutic nucleic acids without inducing noticeable systemic toxicity.

Keywords:Multivalent;Aptamer;Nucleic acid structures;Delivery

[References]

Srinivasarao M, Galliford CV, Low PS, Nat. Rev. Drug Discov., 14, 203 (2015)
Xu S, Olenyuk BZ, Okamoto CT, Hamm-Alvarez SF, Adv. Drug Deliv. Rev., 65, 121 (2013)
Bareford LM, Swaan PW, Adv. Drug Deliv. Rev., 59, 748 (2007)
Lale SV, Aswathy RG, Aravind A, Kumar DS, Koul V, Biomacromolecules, 15(5), 1737 (2014)
Moore NM, Sakiyama-Elbert SE, IEEE Trans. Nanobioscience, 11, 54 (2012)
Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown PA, Hanna TN, Liu JW, Phillips B, Carter MB, Carroll NJ, Jiang XM, Dunphy DR, Willman CL, Petsev DN, Evans DG, Parikh AN, Chackerian B, Wharton W, Peabody DS, Brinker CJ, Nat. Mater., 10(5), 389 (2011)
Vorobyeva M, Vorobjev P, Venyaminova A, Molecules, 21 (2016)
Curk T, Dobnikar J, Frenkel D, Proc. Natl. Acad. Sci. U. S. A., 114, 7210 (2017)
Zhdanov VP, Phys. Rev. E, 96 (2017)
Kim J, Lee E, Kang YY, Mok H, Chem. Commun., 51, 9038 (2015)
Ouyang X, Li J, Liu H, Zhao B, Yan J, Ma Y, Xiao S, Song S, Huang Q, Chao J, Fan C, Small, 9, 3082 (2013)
Zhu G, Zheng J, Song E, Donovan M, Zhang K, Liu C, Tan W, Proc. Natl. Acad. Sci. U. S. A., 110, 7998 (2013)
Ouyang X, Li J, Liu H, Zhao B, Yan J, He D, Fan C, Chao J, Methods, 67, 198 (2014)
Nimjee SM, Rusconi CP, Sullenger BA, Annu. Rev. Med., 56, 555 (2005)
Li X, Zhao Q, Qiu L, J. Control. Release, 171, 152 (2013)
Jo H, Ban C, Exp. Mol. Med., 48 (2016)
Santosh B, Yadava PK, Biomed. Res. Int., 2014, 1 (2014)
Nimjee SM, White RR, Becker RC, Sullenger BA, Annu. Rev. Pharmacol., 57, 61 (2017)
Zhu Q, Liu G, Kai M, Molecules, 20, 20979 (2015)
Hong CA, Jang B, Jeong EH, Jeong H, Lee H, Chem. Commun., 50, 13049 (2014)
Roh YH, Lee JB, Shopsowitz KE, Dreaden EC, Morton SW, Poon Z, Hong J, Yamin I, Bonner DK, Hammond PT, ACS Nano, 8, 9767 (2014)
Zhu GZ, Hu R, Zhao ZL, Chen Z, Zhang XB, Tan WH, J. Am. Chem. Soc., 135(44), 16438 (2013)
Klinov D, Dwir B, Kapon E, Borovok N, Molotsky T, Kotlyar A, Nanotechnology, 18 (2007)
Yoo H, Jung H, Kim SA, Mok H, Chem. Commun., 50, 6765 (2014)
Mok H, Lee SH, Park JW, Park TG, Nat. Mater., 9(3), 272 (2010)
Hu Y, Duan JH, Zhan QM, Wang FD, Lu X, Yang XD, PLoS One, 7 (2012)
Wang L, Ta HS, Ullal C, Wang F, Wang CY, Dong GH, RSC Adv., 7, 11821 (2017)
Mandelkern M, Elias JG, Eden D, Crothers DM, J. Mol. Biol., 152, 153 (1981)
Sachse M, Strous GJ, Klumperman J, J. Cell Sci., 117, 1699 (2004)
Wang W, Zhou S, Guo L, Zhi W, Li X, Weng J, Int. J. Nanomed., 5, 557 (2010)
Zhang Z, Ali MM, Eckert MA, Kang DK, Chen YY, Sender LS, Fruman DA, Zhao W, Biomaterials, 34, 9728 (2013)
He ZY, Deng F, Wei XW, Ma CC, Luo M, Zhang P, Sang YX, Liang X, Liu L, Qin HX, Shen YL, Liu T, Liu YT, Wang W, Wen YJ, Zhao X, Zhang XN, Qian ZY, Wei YQ, Sci. Rep., 6, 23764 (2016)
Huang F, Zhang W, Gong G, Yuan C, Yan Y, Yang S, Cui L, Zhu J, Yang Z, Hua X, BMC Infect. Dis., 9, 93 (2009)
Hong J, Wang H, Shen G, Lin D, Lin Y, Ye N, Guo Y, Li Q, Deng C, Meng C, Sci. Rep., 6, 24397 (2016)
Qi H, Liu C, Long L, Ren Y, Zhang S, Chang X, Qian X, Jia H, Zhao J, Sun J, Hou X, Yuan X, Kang C, ACS Nano, 10, 3323 (2016)
Huang JL, Jiang G, Song QX, Gu X, Hu M, Wang XL, Song HH, Chen LP, Lin YY, Jiang D, Chen J, Feng JF, Qiu YM, Jiang JY, Jiang XG, Chen HZ, Gao XL, Nat. Commun., 8, 15144 (2017)
Meng H, Mai WX, Zhang HY, Xue M, Xia T, Lin SJ, Wang X, Zhao Y, Ji ZX, Zink JI, Nel AE, ACS Nano, 7, 994 (2013)
Xiao WC, Ren M, Zhang C, Li SL, An W, Am. J. Physiol. Cell Ph., 309, C215 (2015)
Arumugam A, Lissner EA, Lakshmanaswamy R, Reprod. Biol. Endocrinol., 12 (2014)

[1] Srinivasarao M, Galliford CV, Low PS, Nat. Rev. Drug Discov., 14, 203 (2015)

[2] Xu S, Olenyuk BZ, Okamoto CT, Hamm-Alvarez SF, Adv. Drug Deliv. Rev., 65, 121 (2013)

[3] Bareford LM, Swaan PW, Adv. Drug Deliv. Rev., 59, 748 (2007)

[4] Lale SV, Aswathy RG, Aravind A, Kumar DS, Koul V, Biomacromolecules, 15(5), 1737 (2014)

[5] Moore NM, Sakiyama-Elbert SE, IEEE Trans. Nanobioscience, 11, 54 (2012)

[6] Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown PA, Hanna TN, Liu JW, Phillips B, Carter MB, Carroll NJ, Jiang XM, Dunphy DR, Willman CL, Petsev DN, Evans DG, Parikh AN, Chackerian B, Wharton W, Peabody DS, Brinker CJ, Nat. Mater., 10(5), 389 (2011)

[7] Vorobyeva M, Vorobjev P, Venyaminova A, Molecules, 21 (2016)

[8] Curk T, Dobnikar J, Frenkel D, Proc. Natl. Acad. Sci. U. S. A., 114, 7210 (2017)

[9] Zhdanov VP, Phys. Rev. E, 96 (2017)

[10] Kim J, Lee E, Kang YY, Mok H, Chem. Commun., 51, 9038 (2015)

[11] Ouyang X, Li J, Liu H, Zhao B, Yan J, Ma Y, Xiao S, Song S, Huang Q, Chao J, Fan C, Small, 9, 3082 (2013)

[12] Zhu G, Zheng J, Song E, Donovan M, Zhang K, Liu C, Tan W, Proc. Natl. Acad. Sci. U. S. A., 110, 7998 (2013)

[13] Ouyang X, Li J, Liu H, Zhao B, Yan J, He D, Fan C, Chao J, Methods, 67, 198 (2014)

[14] Nimjee SM, Rusconi CP, Sullenger BA, Annu. Rev. Med., 56, 555 (2005)

[15] Li X, Zhao Q, Qiu L, J. Control. Release, 171, 152 (2013)

[16] Jo H, Ban C, Exp. Mol. Med., 48 (2016)

[17] Santosh B, Yadava PK, Biomed. Res. Int., 2014, 1 (2014)

[18] Nimjee SM, White RR, Becker RC, Sullenger BA, Annu. Rev. Pharmacol., 57, 61 (2017)

[19] Zhu Q, Liu G, Kai M, Molecules, 20, 20979 (2015)

[20] Hong CA, Jang B, Jeong EH, Jeong H, Lee H, Chem. Commun., 50, 13049 (2014)

[21] Roh YH, Lee JB, Shopsowitz KE, Dreaden EC, Morton SW, Poon Z, Hong J, Yamin I, Bonner DK, Hammond PT, ACS Nano, 8, 9767 (2014)

[22] Zhu GZ, Hu R, Zhao ZL, Chen Z, Zhang XB, Tan WH, J. Am. Chem. Soc., 135(44), 16438 (2013)

[23] Klinov D, Dwir B, Kapon E, Borovok N, Molotsky T, Kotlyar A, Nanotechnology, 18 (2007)

[24] Yoo H, Jung H, Kim SA, Mok H, Chem. Commun., 50, 6765 (2014)

[25] Mok H, Lee SH, Park JW, Park TG, Nat. Mater., 9(3), 272 (2010)

[26] Hu Y, Duan JH, Zhan QM, Wang FD, Lu X, Yang XD, PLoS One, 7 (2012)

[27] Wang L, Ta HS, Ullal C, Wang F, Wang CY, Dong GH, RSC Adv., 7, 11821 (2017)

[28] Mandelkern M, Elias JG, Eden D, Crothers DM, J. Mol. Biol., 152, 153 (1981)

[29] Sachse M, Strous GJ, Klumperman J, J. Cell Sci., 117, 1699 (2004)

[30] Wang W, Zhou S, Guo L, Zhi W, Li X, Weng J, Int. J. Nanomed., 5, 557 (2010)

[31] Zhang Z, Ali MM, Eckert MA, Kang DK, Chen YY, Sender LS, Fruman DA, Zhao W, Biomaterials, 34, 9728 (2013)

[32] He ZY, Deng F, Wei XW, Ma CC, Luo M, Zhang P, Sang YX, Liang X, Liu L, Qin HX, Shen YL, Liu T, Liu YT, Wang W, Wen YJ, Zhao X, Zhang XN, Qian ZY, Wei YQ, Sci. Rep., 6, 23764 (2016)

[33] Huang F, Zhang W, Gong G, Yuan C, Yan Y, Yang S, Cui L, Zhu J, Yang Z, Hua X, BMC Infect. Dis., 9, 93 (2009)

[34] Hong J, Wang H, Shen G, Lin D, Lin Y, Ye N, Guo Y, Li Q, Deng C, Meng C, Sci. Rep., 6, 24397 (2016)

[35] Qi H, Liu C, Long L, Ren Y, Zhang S, Chang X, Qian X, Jia H, Zhao J, Sun J, Hou X, Yuan X, Kang C, ACS Nano, 10, 3323 (2016)

[36] Huang JL, Jiang G, Song QX, Gu X, Hu M, Wang XL, Song HH, Chen LP, Lin YY, Jiang D, Chen J, Feng JF, Qiu YM, Jiang JY, Jiang XG, Chen HZ, Gao XL, Nat. Commun., 8, 15144 (2017)

[37] Meng H, Mai WX, Zhang HY, Xue M, Xia T, Lin SJ, Wang X, Zhao Y, Ji ZX, Zink JI, Nel AE, ACS Nano, 7, 994 (2013)

[38] Xiao WC, Ren M, Zhang C, Li SL, An W, Am. J. Physiol. Cell Ph., 309, C215 (2015)

[39] Arumugam A, Lissner EA, Lakshmanaswamy R, Reprod. Biol. Endocrinol., 12 (2014)