Bioreducible Polyspermine-Based Gene Carriers for Efficient siRNA Delivery: Effects of PEG Conjugation on Gene Silencing Efficiency

Suk Ho Bhang; Kyuwon Kim; Won Jong Rhee; Min Suk Shim

Macromolecular Research, Vol.26, No.12, 1135-1142, December, 2018

DOI10.1007/s13233-019-7027-2 Export Citation

Bioreducible Polyspermine-Based Gene Carriers for Efficient siRNA Delivery: Effects of PEG Conjugation on Gene Silencing Efficiency

Suk Ho Bhang, Kyuwon Kim¹, Won Jong Rhee², and Min Suk Shim^{2, †}

School of Chemical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Korea
¹Electrochemistry Laboratory for Sensors & Energy (ELSE), Department of Chemistry, Incheon National University, Incheon 22012, Korea
²Division of Bioengineering, Incheon National University, Incheon 22012, Korea

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A polyspermine-derived bioreducible polymer was synthesized as efficient siRNA carriers. Spermine was polymerized using disulfide-bearing cross-linkers, resulting in poly(disulfide spermine) (PDS). PDS was also conjugated with poly(ethylene glycol) (PEG) to tailor siRNA condensation efficiency of the polymer. PEG-conjugated PDS (PEG-PDS) was able to condense siRNA into nano-sized polyplexes at high N/P ratios. siRNA condensation efficiency of PDS was reduced by PEGylation due to its weakened interaction with siRNA caused by its decreased cationic charge density. An ethidium bromide exclusion assay demonstrated that siRNA was more efficiently released from the less stable PEG-PDS polyplexes compared to stable PDS polyplexes. In addition, bioreducible siRNA/PEG-PDS polyplexes were efficiently disassembled in the reductive conditions, leading to facilitated siRNA release into the cytoplasm. The lowered siRNA condensation but efficient cytoplasmic release of siRNA by PEG-PDS induced higher gene silencing efficiency in comparison with PDS. Moreover, PEG-PDS exhibited lower cytotoxicity compared to PDS and non-biodegradable branched polyethylenimine. These results suggest that siRNA delivery efficiency of cationic gene carriers can be improved by tailoring their siRNA complexation through PEG conjugation. This study demonstrates that bioreducible PEG-PDS is a promising candidate for safe and efficient siRNA delivery.

Keywords:bioreducible;poly(ethylene glycol);polyspermine;siRNA;targeted therapy

[References]

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[Referenced By]

[1] Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T, Nature, 411, 494 (2001)

[2] Kim DH, Rossi JJ, Nat. Rev. Genet., 8, 173 (2007)

[3] Whitehead KA, Langer R, Anderson DG, Nat. Rev. Drug Discov., 8, 129 (2009)

[4] Shim MS, Kwon YJ, FEBS J., 277, 4814 (2010)

[5] Gary DJ, Puri N, Won YY, J. Control. Release, 121, 64 (2007)

[6] Luo D, Saltzman WM, Nat. Biotechnol., 18, 33 (2000)

[7] Sarett SM, Nelson CE, Duvall CL, J. Control. Release, 218, 94 (2015)

[8] Zhang S, Zhao B, Jiang H, Wang B, Ma B, J. Control. Release, 123, 1 (2007)

[9] Howard KA, Kjems J, Expert Opin. Biol. Ther., 7, 1811 (2007)

[10] Choi C, Nam JP, Nah JW, J. Ind. Eng. Chem., 33, 1 (2016)

[11] Godbey WT, Wu KK, Mikos AG, J. Biomed. Mater. Res., 45, 268 (1999)

[12] Fischer D, Bieber T, Li Y, Elsasser H, Kissel T, Pharm. Res., 16, 1273 (1999)

[13] Alfei S, Castellaro S, Macromol. Res., 25(12), 1172 (2017)

[14] Jere D, Xu CX, Arote R, Yun CH, Cho MH, Cho CS, Biomaterials, 29, 2535 (2008)

[15] Shim MS, Kwon YJ, Polym. Chem., 3, 2570 (2012)

[16] Shim MS, Chang SS, Kwon YJ, Biomater. Sci., 2, 35 (2014)

[17] Piest M, Lin C, Mateos-Timoneda MA, Lok MC, Hennink WE, Feijen J, Engbersen JFJ, J. Control. Release, 130, 38 (2008)

[18] Nam K, Park JW, Bark H, Han J, Nah JW, Jang MK, Kim SW, Macromol. Res., 22(4), 370 (2014)

[19] Hardy JG, Kostiainen MA, Smith DK, Gabrielson NP, Pack DW, Bioconjug. Chem., 17, 172 (2006)

[20] Rejman J, Oberle V, Zuhorn IS, Hoekstra D, Biochem. J., 377, 159 (2004)

[21] Shim MS, Wang X, Ragan R, Kwon YJ, Microsc. Res. Tech., 73, 845 (2010)

[22] Kim C, Lee Y, Lee SH, Kim JS, Jeong JH, Park TG, Macromol. Res., 19(2), 166 (2011)

[23] Dominska M, Dykxhoorn DM, J. Cell Sci., 123, 1183 (2010)

[24] Dunlap DD, Maggi A, Soria MR, Monaco L, Nucleic Acids Res., 25, 3095 (1997)

[25] Detzer A, Overhoff M, Wunsche W, Rompf M, Turner JJ, Ivanova GD, Gait MJ, Sczakiel GS, RNA, 15, 627 (2009)

[26] Jones NA, Hill IRC, Stolnik S, Bignotti SF, Davis SS, Garnett MC, Biochim. Biophys. Acta, 1517, 1 (2000)

[27] Chen DJ, Majors BS, Zelikin A, Putnam D, J. Control. Release, 103, 273 (2005)

[28] Dearnley M, Reynolds NP, Cass P, Wei XH, Shi SN, Mohammed AA, Le T, Gunatillake P, Tizard ML, Thang SH, Hinton TM, Biomacromolecules, 17(11), 3532 (2016)

[29] Sato Y, Hatakeyama H, Hyodo M, Harashima H, Mol. Ther., 24, 788 (2016)

[30] Mao S, Neu M, Germershaus O, Merkel O, Sitterberg J, Bakowsky U, Kissel T, Bioconjug. Chem., 17, 1209 (2006)

[31] Frohlich E, Int. J. Nanomedicine, 7, 5577 (2012)