Synthesis and Characterization of Dual-Sensitive PAMAM Derivatives Conjugated with Enzyme Cleavable Peptides as Gene Carriers

Jeil Lee; Seunghye Park; Yong-Eun Kwon; Eugeney Oh; Dong Woon Kim; Hwanuk Guim; Jehyeong Yeon; Jin-Cheol Kim; Joon Sig Choi

Macromolecular Research, Vol.29, No.9, 636-647, September, 2021

DOI10.1007/s13233-021-9078-4 Export Citation

Synthesis and Characterization of Dual-Sensitive PAMAM Derivatives Conjugated with Enzyme Cleavable Peptides as Gene Carriers

Jeil Lee, Seunghye Park, Yong-Eun Kwon¹, Eugeney Oh, Dong Woon Kim², Hwanuk Guim³, Jehyeong Yeon⁴, Jin-Cheol Kim⁴, and Joon Sig Choi^†

Department of Biochemistry, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea
¹Center for Scientific Instrumentation, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 34133, Korea
²Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
³Research Center for Materials Analysis, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 34133, Korea
⁴Department of Agricultural Chemistry, Institute of Environmentally Friendly Agriculture, College of Agriculture and Life Science, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea

E-mail:

Nonviral vectors have the potential for gene delivery comparable to viral vectors given their productive and economic advantages. However, the low transfection efficiency and specificity of nonviral vectors limit their application in gene medicine. To increase specificity, we selected cystamine core polyamidoamine (PAMAM) generation 3 (cPAMAM G3), a bioreducible polymer, and synthesized the FKFL sequence, as a cathepsin B-cleavable linker to cPAMAM G3. In addition, we simultaneously introduced RH dipeptides to FKFL-cPAMAM G3 to improve transfection efficiency. The synthesized RHFKFL-cPAMAM G3 showed similar transfection efficiency and low cytotoxicity compared with that of PEI 25 kDa in HepG2 and SW480 cells, which are cathepsin B enzyme overexpression cell lines. These results imply that a combination of enzyme- and reduction-responsive linkers can be used to solve the problems associated with the use of nonviral vectors.

Keywords:nonviral vector;polyamidoamine (PAMAM) dendrimer;cathepsin B;FKFL;transfection

[References]

Li J, Liang H, Liu J, Wang Z, Int. J. Pharm., 546, 215 (2018)
Hill AB, Chen M, Chen CK, Pfeifer BA, Jones CH, Trends Biotechnol., 34, 91 (2016)
Foldvari M, Chen DW, Nafissi N, Calderon D, Narsineni L, Rafiee A, J. Control. Release, 240, 165 (2016)
Akinc A, Thomas M, Klibanov AM, Langer R, J. Gene Med., 7, 657 (2005)
Freeman EC, Weiland LM, Meng WS, J. Biomater. Sci-Polym. E, 24, 398 (2013)
Brunner S, Sauer T, Cotton M, Saltik M, Wagner E, Gene Ther., 7, 401 (2000)
Eliyahu H, Barenholz Y, Domb A, Molecules, 10, 34 (2005)
Lachelt U, Wagner E, Chem. Rev., 115(19), 11043 (2015)
Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB, Emanuele AD, Int. J. Pharm., 252, 263 (2003)
Naha PC, Davoren M, Lyng FM, Byrne HJ, Toxicol. Appl. Pharmacol., 246, 91 (2010)
Breunig M, Lungwitz U, Liebl R, Goepferich A, P. Natl. Acad. Sci., 104, 14454 (2007)
Chu DS, Johnson RN, Pun SH, J. Control. Release, 157, 445 (2012)
Li X, Cao C, Wei P, Xu M, Liu Z, Liu L, Zhong Y, Li R, Zhou Y, Yi T, ACS Appl. Mater. Inter., 11, 12327 (2019)
Yoo J, Rejinold NS, Lee D, Jon S, Kim Y, J. Control. Release, 264, 89 (2017)
Bae Y, Green ES, Kim G, Song SJ, Mum JY, Lee S, Park J, Park J, Ko KS, Han J, Choi JS, Int. J. Pharm., 515, 186 (2016)
Thuy LT, Mallick S, Choi JS, Int. J. Pharm., 492, 233 (2015)
Lee M, Cho S, Jang H, Lim YS, You J, Park J, Suh H, Kim J, Park J, Kim D, Exp. Mol. Med., 34, 265 (2002)
Kurtoglu YE, Mishra MK, Kannan S, Kannan RM, Int. J. Pharm., 384, 189 (2010)
Han HS, Choi KY, Ko H, Jeon J, Saravanakumar G, Suh YD, Lee DS, Park JH, J. Control. Release, 200, 158 (2015)
Lee YS, Kim SW, J. Control. Release, 190, 424 (2014)
Sharma R, Sharma A, Kambhampati SP, Reddy RR, Zhang Z, Cleland JL, Kannan S, Kannan RM, Bioeng. Transl. Med., 3, 87 (2018)
Terasawa Y, Hotani T, Katayama Y, Tachibana M, Mizuguchi H, Sakurai F, Cancer Gene Ther., 22, 188 (2015)
Pantos A, Tsogas I, Paleos CM, Biochim. Biophys. Acta, 1778, 811 (2008)
Yadati T, Houben T, Bitorina A, Shiri-Sverdlov R, Cells, 9 (2020)
Li X, Hao S, Han A, Yang Y, Fang G, Liu J, Wang S, J. Mat. Chem. B, 7, 4008 (2019)
Lopaczynski W, Zeisel SH, Nutr. Res., 21, 295 (2001)
Kohen R, Yamamoto Y, Cundy KC, Ames BN, Proc. Natl. Acad. Sci., 85, 3175 (1988)
Wade AM, Tucker HN, J. Nutr. Biochem., 9, 308 (1998)

[1] Li J, Liang H, Liu J, Wang Z, Int. J. Pharm., 546, 215 (2018)

[2] Hill AB, Chen M, Chen CK, Pfeifer BA, Jones CH, Trends Biotechnol., 34, 91 (2016)

[3] Foldvari M, Chen DW, Nafissi N, Calderon D, Narsineni L, Rafiee A, J. Control. Release, 240, 165 (2016)

[4] Akinc A, Thomas M, Klibanov AM, Langer R, J. Gene Med., 7, 657 (2005)

[5] Freeman EC, Weiland LM, Meng WS, J. Biomater. Sci-Polym. E, 24, 398 (2013)

[6] Brunner S, Sauer T, Cotton M, Saltik M, Wagner E, Gene Ther., 7, 401 (2000)

[7] Eliyahu H, Barenholz Y, Domb A, Molecules, 10, 34 (2005)

[8] Lachelt U, Wagner E, Chem. Rev., 115(19), 11043 (2015)

[9] Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB, Emanuele AD, Int. J. Pharm., 252, 263 (2003)

[10] Naha PC, Davoren M, Lyng FM, Byrne HJ, Toxicol. Appl. Pharmacol., 246, 91 (2010)

[11] Breunig M, Lungwitz U, Liebl R, Goepferich A, P. Natl. Acad. Sci., 104, 14454 (2007)

[12] Chu DS, Johnson RN, Pun SH, J. Control. Release, 157, 445 (2012)

[13] Li X, Cao C, Wei P, Xu M, Liu Z, Liu L, Zhong Y, Li R, Zhou Y, Yi T, ACS Appl. Mater. Inter., 11, 12327 (2019)

[14] Yoo J, Rejinold NS, Lee D, Jon S, Kim Y, J. Control. Release, 264, 89 (2017)

[15] Bae Y, Green ES, Kim G, Song SJ, Mum JY, Lee S, Park J, Park J, Ko KS, Han J, Choi JS, Int. J. Pharm., 515, 186 (2016)

[16] Thuy LT, Mallick S, Choi JS, Int. J. Pharm., 492, 233 (2015)

[17] Lee M, Cho S, Jang H, Lim YS, You J, Park J, Suh H, Kim J, Park J, Kim D, Exp. Mol. Med., 34, 265 (2002)

[18] Kurtoglu YE, Mishra MK, Kannan S, Kannan RM, Int. J. Pharm., 384, 189 (2010)

[19] Han HS, Choi KY, Ko H, Jeon J, Saravanakumar G, Suh YD, Lee DS, Park JH, J. Control. Release, 200, 158 (2015)

[20] Lee YS, Kim SW, J. Control. Release, 190, 424 (2014)

[21] Sharma R, Sharma A, Kambhampati SP, Reddy RR, Zhang Z, Cleland JL, Kannan S, Kannan RM, Bioeng. Transl. Med., 3, 87 (2018)

[22] Terasawa Y, Hotani T, Katayama Y, Tachibana M, Mizuguchi H, Sakurai F, Cancer Gene Ther., 22, 188 (2015)

[23] Pantos A, Tsogas I, Paleos CM, Biochim. Biophys. Acta, 1778, 811 (2008)

[24] Yadati T, Houben T, Bitorina A, Shiri-Sverdlov R, Cells, 9 (2020)

[25] Li X, Hao S, Han A, Yang Y, Fang G, Liu J, Wang S, J. Mat. Chem. B, 7, 4008 (2019)

[26] Lopaczynski W, Zeisel SH, Nutr. Res., 21, 295 (2001)

[27] Kohen R, Yamamoto Y, Cundy KC, Ames BN, Proc. Natl. Acad. Sci., 85, 3175 (1988)

[28] Wade AM, Tucker HN, J. Nutr. Biochem., 9, 308 (1998)