Nucleic acids-based therapies have recently developed as next-generation agents for treating and preventing viral infection, cancer, and genetic disorders, but their use is still limited due to its relatively poor delivery into targeted cells. We designed and synthesized new amphiphilic amino acid derivatives (cysteine-based) of low molecular weight, formed by the same pentapeptide (AG2: WWCOO) N-acylated, with different hydrophobic chains containing from 12 to 18 carbons, named AG2-C n (N), which dimerize by oxidation in the presence of pLenti-CMV-GFP Puro plasmid (P) in the respective gemini . We determined transfection efficiency, critical micelle concentration, particle size, ζ-potential and cytotoxicity for the derivatives obtained. We found that all the synthesized compounds were active for DNA delivery and had greater ability to transfect CHO-K1 cells. In particular, AG2-C 18 is a promising carrier for gene delivery because it showed no cytotoxicity and its activity was greater than or equal to the commercial actives currently used.
Friedmann, T. (1999) The Development of Human Gene Therapy. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.
Thomas, C.E., Ehrhardt, A. and Kay, M.A. (2003) Progress and Problems with the Use of Viral Vectors for Gene Therapy. Nature Reviews Genetics, 4, 346-358. https://doi.org/10.1038/nrg1066
Ilies, M., Seitz, W.A. and Balaban, A.T. (2002) Cationic Lipids in Gene Delivery: Principles, Vector Design and Therapeutical Applications. Current Pharmaceutical Design, 8, 2441-2473. https://doi.org/10.2174/1381612023392748
Badea, I., Verrall, R. and Baca-Estrada, M. (2005) In Vivo Cutaneous Interferon-γ Gene Delivery Using Novel Dicationic (Gemini) Surfactant-Plasmid Complexes. The Journal of Gene Medicine, 7, 1200-1214. https://doi.org/10.1002/jgm.763
Singh, J., Yang, P., Michel, D., Verrall, R., Foldvari, M. and Badea, I. (2011) Amino Acid-Substituted Gemini Surfactant-Based Nanoparticles as Safe and Versatile Gene Delivery Agents. Current Drug Delivery, 8, 299-306. https://doi.org/10.2174/156720111795256200
Menger, F.M. and Littau, C. (1991) Gemini-Surfactants: Synthesis and Properties. Journal of the American Chemical Society, 113, 1451-1452. https://doi.org/10.1021/ja00004a077
Menger, F. and Littau, C. (1993) Gemini Surfactants: A New Class of Self-Assembling Molecules. Journal of the American Chemical Society, 115, 10083-10090. https://doi.org/10.1021/ja00075a025
Donkuru, M.D., Wettig, S.D., Verrall, R.E., Badea, I. and Foldvari, M. (2012) Designing pH-Sensitive Gemini Nanoparticles for Non-Viral Gene Delivery into Keratinocytes. Journal of Materials Chemistry, 22, 6232-6244. https://doi.org/10.1039/c2jm15719e
Yang, P., Singh, J., Wettig, S., Foldvari, M., Verrall, R.E. and Badea, I. (2010) Enhanced Gene Expression in Epitelial Cells Transfected with Amino Acid-Substituted Gemini Nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics, 75, 311-320.
Kirby, A.J., Camilleri, P., Engberts, J.B.F.N., Feiters, M.C., Nolte, R.J.M., et al. (2003) Gemini Surfactants: New Synthetic Vectors for Gene Transfection. Angewandte Chemie International Edition, 42, 1448-1457. https://doi.org/10.1002/anie.200201597
Wettig, S.D., Verrall, R.E. and Foldvari, M. (2008) Gemini Surfactants: A New Family of Building Blocks for Non-Viral Gene Delivery Systems. Current Gene Therapy, 8, 9-23. https://doi.org/10.2174/156652308783688491
Dauty, E., Remy, J.S., Blessing, T. and Behr, J.P. (2001) Gemini Surfactants Structurally Related to 1, Derived from the Oxidative Dimerization of Cysteine-Based Monomers, Have Been Reported by the Strasbourg Group to Show Interesting Transfection Capabilities. Journal of the American Chemical Society, 123, 9227-9234. https://doi.org/10.1021/ja015867r
Ronsin, G., Perrin, C., Guédat, P., Kremer, A., Camilleri, P. and Kirby, A.J. (2001) Novel Spermine-Based Cationic Geminisurfactants for Gene Delivery. Chemical Communications, No. 21, 2234-2235. https://doi.org/10.1039/b105936j
Fielden, M.L., Perrin, C., Kremer, A., Bergsma, M., Stuart, M.C. and Camilleri, P. (2001) Sugar-Based Tertiary Amino Gemini Surfactants with a Vesicle-to-Micelle-transition in the Endosomal pH Range Mediate Efficient Transfection in Vitro. The FEBS Journal, 268, 1269-1279. https://doi.org/10.1046/j.1432-1327.2001.01995.x
Candiani, G., Frigerio, M., Viani, F., Verpelli, C., Sala, C. and Chiamenti, L. (2007) Dimerizable Redox-Sensitive Triazine-Based Cationic Lipids for in Vitro Gene Delivery. ChemMedChem, 2, 292-296.
Pérez, L., Pinazo, A., Pons, R. and Infante, M.R. (2014) Gemini Surfactants from Natural Amino Acids. Advances in Colloid and Interface Science, 205, 134-155.
Yoshimura, T., Sakato, A., Tsuchiya, K., Ohkubo, T., Sakai, H. and Abe, M. (2007) Adsorption and Aggregation Properties of Amino Acid-Based N-Alkyl Cysteine Monomeric and N,N’-Dialkyl Cystine Gemini Surfactants. Journal of Colloid and Interface Science, 308, 466-473.
Faustino, C.M.C., Calado, A.R.T. and Garcia-Rio, L. (2010) Dimeric and Monomeric Surfactants Derived from Sulfur-Containing Amino Acids. Journal of Colloid and Interface Science, 351, 472-477. https://doi.org/10.1016/j.jcis.2010.08.007
Jennings, K., Marshall, I., Birrell, H., Edwards, A., Haskins, N., Sodermann, O. and Kirby, A.J. (1998) The Synthesis and Aggregation Properties of a Novel Anionic Gemini Surfactant. Chemical Communications, 18, 1951-1952.
Miller, A.J. (1998) Cationic Liposomes for Gene Therapy. Angewandte Chemie International Edition, 37, 1768-1785. https://doi.org/10.1002/(SICI)1521-3773(19980803)37:13/14 3.0.CO;2-4
Bechara, C. and Sagan, S. (2014) Cell-Penetrating Peptides: 20 Years Later, Where Do We Stand? Historical Perspective. Advances in Colloid and Interface Science, 205, 134-155.
Müller, D.M., Ingaramo, M.C., Arganará, M.F. and Murguía, M.C. (2011) Síntesis y actividad biológica de nuevos surfactantes peptídicos tipo gemini. CIT, 22, 11-20. https://doi.org/10.4067/S0718-07642011000500003
Garello, C.P., Ingaramo, M.C., Argaraná, M.F., Murguía, M.C. and Müller, D.M. (2012) Estudios de relación estructura—Actividad sobre surfactantes gemini con actividad antimicrobiana. http://www.grupomontevideo.edu.uy/index.php/programas/jovenes-investigadores http://issuu.com/ufprdigital/docs/xx_jornadas_completo
Chang, W.C. (2004) Fmoc Solid Phase Peptide Synthesis: A Practical Approach. Oxford University Press, Oxford.
Campeau, E., Ruhl, V.E., Rodier, F., et al. (2009) A Versatile Viral System for Expression and Depletion of Proteins in Mammalian Cells. PLoS ONE, 4, e6529. https://doi.org/10.1371/journal.pone.0006529
Wang, C., Li, X., Wettig, S.D., Badea, I., Foldvarid, M. and Verral, R.E. (2007) Investigation of Complexes Formed by Interaction of Cationic Gemini Surfactants with Deoxyribonucleic Acid. Physical Chemistry Chemical Physics, 9, 1616-1628. https://doi.org/10.1039/b618579g
Tagg, J.R. and Mcgiven, A.R. (1971) Assay Systems for Bacteriocins. Applied and Environmental Microbiology, 21, 943-947.
Yao, C., Tai, Z., Wang, X., Liu, J., Zhu, Q., Wu, X., Zhang, L., Zhang, W., Tian, J., Gao, Y. and Gao, S. (2015) Reduction-Responsive Cross-Linked Stearyl Peptide for Effective Delivery of Plasmid DNA. International Journal of Nanomedicine, 10, 3403-3416.
Kumar, V., Chatterjee, A., Kumar, N., Ganguly, A., Chakraborty, I. and Banerjee, M. (2014) D-Glucose Derived Novel Gemini Surfactants: Synthesis and Study of Their Surface Properties, Interaction with DNA, and Cytotoxicity. Carbohydrate Research, 397, 37-45.
Mahato, R.I., Anwer, K., Tagliaferri, F., Meaney, C., Leonard, P., Wadhwa, M., Logan, S., French, M. and Rolland, A. (2008) Biodistribution and Gene Expression of Lipid/Plasmid Complexes after Systemic Administration. Human Gene Therapy, 9, 2083-2099. https://doi.org/10.1089/hum.1998.9.14-2083
Lobo, B.A., Rogers, S.A., Wiethoff, C.M., Choosakoonkriang, S., Bogdanowich-Knipp, S. and Middaugh, C.R. (2001) Characterization of Cationic Vector-Based Gene Delivery Vehicles Using Isothermal Titration and Differential Scanning Calorimetry. Meth. Mol. Med, 65, 319-348.
Marsh, D. and King, M.D. (1986) Prediction of the Critical Micelle Concentrations of Mono- and Di-Acyl Phospholipids. Chemistry and Physics of Lipids, 42, 271-277.
Yoshimura, T., Sakato, A. and Esumi, K. (2013) Solution Properties and Emulsification Properties of Amino Acid-Based Gemini Surfactants Derived from Cysteine. Journal of Oleo Science, 62, 579-586. https://doi.org/10.5650/jos.62.579
Koloskova, O.O., Nikonova, A.A., Budanova, U.A., Shilovskiy, I.P., Kofiadi, I.A., Ivanov, A.V., Smirnova, O.A., Zverev, V.V., Sebaykin, Yu.L., Andreev, S.M. and Khaitov, M.R. (2016) Synthesis and Evaluation of Novel Lipopeptide as a Vehicle for Efficient Gene Delivery and Gene Silencing. European Journal of Pharmaceutics and Biopharmaceutics, 102, 159-167.
Castro, M., Griffiths, D., Patel, A., Pattrick, N., Kitson, C. and Ladlow, M. (2004) Effect of Chain Length on Transfection Properties of Spermine-Based Gemini Surfactants. Organic & Biomolecular Chemistry, 2, 2814-2820. https://doi.org/10.1039/b410240a
Takayama, K., Nakase, I., Michiue, H., Takeuchi, T., Tomizawa, K., Matsui, H. and Futaki, S. (2009) Enhanced Intracellular Delivery Using Arginine-Rich Peptides by the Addition of Penetration Accelerating Sequences (Pas). Journal of Controlled Release, 138, 128-133.
Chan, D.I., Prenner, E.J. and Vogel, H.J. (2006) Tryptophan- and Arginine-Rich Antimicrobial Peptides: Structures and Mechanisms of Action. Biochimica et Biophysica Acta, 1758, 1184-1202.
Bechara, C., Pallerla, M., Zaltsman, Y., Burlina, F., Alves, D.I., Lequin, O. and Sagan, S. (2013) Tryptophan within Basic Peptide Sequences Triggers Glycosaminoglycan-Dependent Endocytosis The FASE Journal, 27, 738-749.
Bechara, C., Pallerla, M., Burlina, F., Illien, F., Cribier, S. and Sagan, S. (2015) Massive Glycosaminoglycan-Dependent Entry of Trp-Containing Cell-Penetrating Peptides Induced by Exogenous Sphingomyelinase or Cholesterol Depletion. Cellular and Molecular Life Sciences, 72, 809-820. https://doi.org/10.1007/s00018-014-1696-y
Fang, S.L., Fan, T.C., Fu, H.W., Chen, C.J., Hwang, C.S., Hung, T.J., Lin, L.Y. and Chang, M.D. (2013) A Novel Cell-Penetrating Peptide Derived from Human Eosi-nophil Cationic Protein. PLoS ONE, 8, e57318. https://doi.org/10.1371/journal.pone.0057318
Xu, R., Wang, X.L. and Lu, Z.R. (2010) New Amphiphilic Carriers Forming pH-Sensitive Nanoparticles for Nucleic Acid Delivery. Langmuir, 26, 13874-13882. https://doi.org/10.1021/la1024185