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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Synthesis, Characterization, and Evaluation of Sulfonium Lipids as Potential Nonviral Gene Vectors

Author(s): Jing Li*, Ying Zhang, Yanjie Lu, Lei Zhang, Guinan Shen and Chenghao Jin

Volume 21, Issue 2, 2024

Published on: 21 October, 2022

Page: [339 - 348] Pages: 10

DOI: 10.2174/1570180819666220926140957

Price: $65

Abstract

Background: Non-viral gene vectors have attracted much attention in the last few decades because of their potential activity and fewer side effects. Headgroup chemistry is a key aspect of lipid design.

Methods: In this study, a group of sulfonium lipids were designed and constructed by combining tetrahydrothiophene or tetrahydrothiopyran with an ethoxy linker and carbon aliphatic chains and were evaluated in terms of their ability as potential gene vectors. The sulfonium lipids were synthesized and characterized by 1H NMR, 13C NMR, and Mass. Condensates of sulfonium lipids (SL) and DNA were examined by gel electrophoresis and particle size and zeta potential were measured. Sulfonium compounds were tested on HepG2 cells for cytotoxicity. SL/DNA condensates were studied in cellular uptake and distribution using fluorescent microscopy.

Results: 12 sulfonium lipids were obtained. Gel electrophoresis experiments showed that sulfonium cation can effectively interact with phosphorous in DNA. Compounds containing longer lipid chains can effectively retard DNA at an S/P ratio higher than 10/1 and can condense DNA into nano size particles with particle size in the range of 150 nm ~ 300 nm and zeta potential in the range of +20~+40. Sulfonium compounds were calculated against HepG2 cells in the range of 0.035 μg/mL to 1.64 μg/mL. The intracellular uptake experiments revealed that SL/DNA nanoparticle was taken into the cell at low efficiency.

Conclusion: Sulfonium head group can interact with the phosphates of DNA. The structural environment of sulfonium ions influences the DNA bonding effect. The designed cyclic sulfonium ion was buried in the middle of the structure and thus hindered interaction with DNA. This type of molecule is worthy of further modification to increase DNA capacity and reduce cell cytotoxicity.

Keywords: Sulfonium, Cationic lipids, Non-viral gene vector, DNA, Organic synthesis, Delivery

« Previous Next »
[1]
Cao, H.; Molday, R.S.; Hu, J. Gene therapy: Light is finally in the tunnel. Protein Cell, 2011, 2(12), 973-989.
[http://dx.doi.org/10.1007/s13238-011-1126-y] [PMID: 22231356]
[2]
Yin, H.; Kanasty, R.L.; Eltoukhy, A.A.; Vegas, A.J.; Dorkin, J.R.; Anderson, D.G. Non-viral vectors for gene-based therapy. Nat. Rev. Genet., 2014, 15(8), 541-555.
[http://dx.doi.org/10.1038/nrg3763] [PMID: 25022906]
[3]
Katz, M.G.; Fargnoli, A.S.; Williams, R.D.; Bridges, C.R. Gene therapy delivery systems for enhancing viral and nonviral vectors for cardiac diseases: Current concepts and future applications. Hum. Gene Ther., 2013, 24(11), 914-927.
[http://dx.doi.org/10.1089/hum.2013.2517] [PMID: 24164239]
[4]
Draghici, B.; Ilies, M.A. Synthetic nucleic acid delivery systems: Present and perspectives. J. Med. Chem., 2015, 58(10), 4091-4130.
[http://dx.doi.org/10.1021/jm500330k] [PMID: 25658858]
[5]
Wang, T.; Upponi, J.R.; Torchilin, V.P. Design of multifunctional non-viral gene vectors to overcome physiological barriers: Dilemmas and strategies. Int. J. Pharm., 2012, 427(1), 3-20.
[http://dx.doi.org/10.1016/j.ijpharm.2011.07.013] [PMID: 21798324]
[6]
Hardee, C.; Arévalo-Soliz, L.; Hornstein, B.; Zechiedrich, L. Advances in non-viral DNA vectors for gene therapy. Genes (Basel), 2017, 8(2), 65.
[http://dx.doi.org/10.3390/genes8020065] [PMID: 28208635]
[7]
Pack, D.W.; Hoffman, A.S.; Pun, S.; Stayton, P.S. Design and development of polymers for gene delivery. Nat. Rev. Drug Discov., 2005, 4(7), 581-593.
[http://dx.doi.org/10.1038/nrd1775] [PMID: 16052241]
[8]
Quijano, E.; Bahal, R.; Ricciardi, A.; Saltzman, W.M.; Glazer, P.M. Therapeutic peptide nucleic acids: Principles, limitations, and opportunities. Yale J. Biol. Med., 2017, 90(4), 583-598.
[PMID: 29259523]
[9]
Junquera, E.; Aicart, E. Cationic lipids as transfecting agents of DNA in gene therapy. Curr. Top. Med. Chem., 2014, 14(5), 649-663.
[http://dx.doi.org/10.2174/1568026614666140118203128] [PMID: 24444161]
[10]
Hart, S. Lipid carriers for gene therapy. Curr. Drug Deliv., 2005, 2(4), 423-428.
[http://dx.doi.org/10.2174/156720105774370230] [PMID: 16305445]
[11]
Samal, S.K.; Dash, M.; Van Vlierberghe, S.; Kaplan, D.L.; Chiellini, E.; van Blitterswijk, C.; Moroni, L.; Dubruel, P. Cationic polymers and their therapeutic potential. Chem. Soc. Rev., 2012, 41(21), 7147-7194.
[http://dx.doi.org/10.1039/c2cs35094g] [PMID: 22885409]
[12]
Wahane, A.; Waghmode, A.; Kapphahn, A.; Dhuri, K.; Gupta, A.; Bahal, R. Role of lipid-based and polymer-based non-viral vectors in nucleic acid delivery for next-generation gene therapy. Molecules, 2020, 25(12), 2866.
[http://dx.doi.org/10.3390/molecules25122866] [PMID: 32580326]
[13]
Ghosh, S.; Ray, A.; Pramanik, N. Self-assembly of surfactants: An overview on general aspects of amphiphiles. Biophys. Chem., 2020, 265, 106429.
[http://dx.doi.org/10.1016/j.bpc.2020.106429] [PMID: 32693319]
[14]
Ponti, F.; Campolungo, M.; Melchiori, C.; Bono, N.; Candiani, G. Cationic lipids for gene delivery: Many players, one goal. Chem. Phys. Lipids, 2021, 235, 105032.
[http://dx.doi.org/10.1016/j.chemphyslip.2020.105032] [PMID: 33359210]
[15]
Koynova, R.; Tenchov, B. Recent patents in cationic lipid carriers for delivery of nucleic acids. Recent Pat. DNA Gene Seq., 2011, 5, 8-27.
[http://dx.doi.org/10.2174/187221511794839255]
[16]
Sun, Y.; Migueliz, I.; Navarro, G.; de Ilarduya, C. Structural and morphological studies of cationicliposomes-DNA complexes. Lett. Drug Des. Discov., 2009, 6(1), 33-37.
[http://dx.doi.org/10.2174/157018009787158571]
[17]
Ivanova, E.A.; Maslov, M.A.; Kabilova, T.O.; Puchkov, P.A.; Alekseeva, A.S.; Boldyrev, I.A.; Vlassov, V.V.; Serebrennikova, G.A.; Morozova, N.G.; Zenkova, M.A. Structure–transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups. Org. Biomol. Chem., 2013, 11(41), 7164-7178.
[http://dx.doi.org/10.1039/c3ob40442k] [PMID: 24057052]
[18]
Zhi, D.; Zhang, S.; Wang, B.; Zhao, Y.; Yang, B.; Yu, S. Transfection efficiency of cationic lipids with different hydrophobic domains in gene delivery. Bioconjug. Chem., 2010, 21(4), 563-577.
[http://dx.doi.org/10.1021/bc900393r] [PMID: 20121120]
[19]
Zhi, D.; Zhang, S.; Cui, S.; Zhao, Y.; Wang, Y.; Zhao, D. The headgroup evolution of cationic lipids for gene delivery. Bioconjug. Chem., 2013, 24(4), 487-519.
[http://dx.doi.org/10.1021/bc300381s] [PMID: 23461774]
[20]
Hirayama, M. The antimicrobial activity, hydrophobicity and toxicity of sulfonium compounds, and their relationship. Biocontrol Sci., 2011, 16(1), 23-31.
[http://dx.doi.org/10.4265/bio.16.23] [PMID: 21467626]
[21]
Kaiser, D.; Klose, I.; Oost, R.; Neuhaus, J.; Maulide, N. Bond-forming and -breaking reactions at sulfur(IV): Sulfoxides, sulfonium salts, sulfur ylides, and sulfinate salts. Chem. Rev., 2019, 119(14), 8701-8780.
[http://dx.doi.org/10.1021/acs.chemrev.9b00111] [PMID: 31243998]
[22]
Wang, X.; Wang, G.; Zhao, J.; Zhu, Z.; Rao, J. Main-chain sulfonium-containing homopolymers with negligible hemolytic toxicity for eradication of bacterial and fungal biofilms. ACS Macro Lett., 2021, 10(12), 1643-1649.
[http://dx.doi.org/10.1021/acsmacrolett.1c00698] [PMID: 35549147]
[23]
Sun, J.; Li, M.; Lin, M.; Zhang, B.; Chen, X. High Antibacterial activity and selectivity of the versatile polysulfoniums that combat drug resistance. Adv. Mater., 2021, 33(41), 2104402.
[http://dx.doi.org/10.1002/adma.202104402] [PMID: 34436803]
[24]
Park, Y.S.; Kim, Y.H.; Kim, S.K.; Choi, S.J. A new antitumor agent: Methyl sulfonium perchlorate of echinomycin. Bioorg. Med. Chem. Lett., 1998, 8(7), 731-734.
[http://dx.doi.org/10.1016/S0960-894X(98)00113-9] [PMID: 9871531]
[25]
Lu, L.; Li, X.; Yang, Y.; Xie, W. Recent progress in the construction of natural de-O-sulfonatedsulfoniumsugars with antidiabeticactivities. Chemistry, 2019, 25(59), 13458-13471.
[http://dx.doi.org/10.1002/chem.201902562] [PMID: 31314135]
[26]
Guan, D.; Chen, F.; Qiu, Y.; Jiang, B.; Gong, L.; Lan, L.; Huang, W. Sulfonium, an underestimated moiety for structural modification, alters the antibacterial profile of vancomycin against multidrug-resistant bacteria. Angew. Chem. Int. Ed., 2019, 58(20), 6678-6682.
[http://dx.doi.org/10.1002/anie.201902210] [PMID: 30908776]
[27]
Anstee, Q.M.; Day, C.P. S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility. J. Hepatol., 2012, 57(5), 1097-1109.
[http://dx.doi.org/10.1016/j.jhep.2012.04.041] [PMID: 22659519]
[28]
Rhodes, D.; Hanson, A.D. Quaternary ammonium and tertiary sulfoniumcompounds in higher plants. Annu. Rev. Plant Physiol. Plant Mol. Biol., 1993, 44(1), 357-384.
[http://dx.doi.org/10.1146/annurev.pp.44.060193.002041]
[29]
Hemp, S.T.; Allen, M.H., Jr; Smith, A.E.; Long, T.E. Synthesis and properties of sulfonium polyelectrolytes for biological applications. ACS Macro Lett., 2013, 2(8), 731-735.
[http://dx.doi.org/10.1021/mz4002172] [PMID: 35606959]
[30]
Mackenzie, M.C.; Shrivats, A.R.; Konkolewicz, D.; Averick, S.E.; McDermott, M.C.; Hollinger, J.O.; Matyjaszewski, K. Synthesis of poly(meth)acrylates with thioether and tertiary sulfonium groups by ARGET ATRP and their use as siRNA delivery agents. Biomacromolecules, 2015, 16(1), 236-245.
[http://dx.doi.org/10.1021/bm501449a] [PMID: 25515324]
[31]
Zhu, D.; Yan, H.; Liu, X.; Xiang, J.; Zhou, Z.; Tang, J.; Liu, X.; Shen, Y. Intracellular lydis integratable poly sulfoniums for efficient gene delivery. Adv. Funct. Mater., 2017, 27(16), 1606826.
[http://dx.doi.org/10.1002/adfm.201606826]
[32]
Xu, F.; Xue, R.; Yang, F.; Liu, H.; Zhang, X.; Luan, S.; Tang, H. Preparation and solution properties of helical sulfonium-based polypeptides and their polyelectrolyte complexes. Eur. Polym. J., 2021, 149, 110390.
[http://dx.doi.org/10.1016/j.eurpolymj.2021.110390]

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