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Cationic amphiphiles based on malonic acid amides as transfection mediators

https://doi.org/10.32362/2410-6593-2020-15-5-36-45

Abstract

Objectives. The aim of this work is to synthesize cationic amphiphiles based on malonic acid amides. The target compounds should contain saturated and unsaturated alkyl chains in the hydrophobic portion, and one or two positive charges in the polar head as created by ethylenediamine and amino acid L-ornithine. For such cationic amphiphiles, we determined physicochemical properties and transfection efficiency of liposomes based on them.

Methods. The initial compound in the synthesis is diethylmalonate. We used C-alkylation to add the first hydrophobic chain (with octylbromide, dodecylbromide, or octadecylbromide). N-oleylamine was used as the second hydrophobic chain, which was attached at the carboxyl group of the malonic acid via amide bond formation. The polar head was represented by ethylenediamine, which was then attached at the second carboxyl group of the malonic acid. Further, L-ornithine was attached to ethylenediamine to produce cationic lipids with two positive charges in the head group. The structures of the compounds were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis. Particle size distribution was evaluated by photon correlation spectroscopy. The luciferase test was used to determine transfection efficiency using HeLa cells.

Results. We have developed a synthesis scheme to produce new cationic amphiphiles with an asymmetric hydrophobic part. The obtained liposomal particles are approximately 120 nm in size and have a relatively high zeta potential of 29–30 mV.

Conclusions. The size of these liposomes allows them to penetrate into cells, which makes it possible to use these compositions for transfection. The high zeta potential shows that the particles are stable. Our results demonstrate that the transfection efficiency of our liposomes (mixed with cholesterol) is comparable to a commercial formulation. Cationic amphiphiles based on malonic acid amides have great potential for liposome development for transfection.

About the Authors

N. A. Romanova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Nadezhda A. Romanova, Master Student, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry

86, Vernadskogo pr., Moscow, 119571, Russia



U. A. Budanova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Ulyana A. Budanova, Cand. of Sci. (Chemistry), Assistant, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry. Scopus Author ID 14622352500, ResearcherID E-1659-2014

86, Vernadskogo pr., Moscow, 119571, Russia



Yu. L. Sebyakin
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Yury L. Sebyakin, Dr. of Sci. (Chemistry), Professor, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry. Scopus Author ID 6701455145, ResearcherID T-2835-2019

86, Vernadskogo pr., Moscow, 119571, Russia



References

1. O՚Connor T.P., Crystal R.G. Genetic medicines: treatment strategies for hereditary disorders. Nat. Rev. Genet. 2006;7(4):261-276. https://doi.org/10.1038/nrg1829

2. Maeder M.L., Gersbach C.A. Genome-editing Technologies for Gene and Cell Therapy. Mol. Ther. 2016;24(3):430-446. https://doi.org/10.1038/mt.2016.10

3. Tassler S., Pawlowska D., Janich C., Dobner B., Wölk C., Brezesinski G. Lysine-based amino-functionalized lipids for gene transfection: the influence of the chain composition on 2D properties. Phys. Chem. Chem. Phys. 2018;20(10):6936-6944. https://doi.org/10.1039/c8cp00047f

4. Sheridan C. Gene therapy finds its niche. Nat. Biotechnol. 2011;29(2):121-128. https://doi.org/10.1038/nbt.1769

5. Wagner E. Polymers for siRNA Delivery: Inspired by Viruses to be Targeted, Dynamic, and Precise. Acc. Chem. Res. 2012;45(7):1005-1013. https://doi.org/10.1021/ar2002232

6. Crystal R.G. Transfer of Genes to Humans: Early Lessons and Obstacles to Success. Science. 1995;270(5235):404-410. https://doi.org/10.1126/science.270.5235.404

7. Dittrich M., Brauer C., Funari S.S., Dobner B., Brezesinski G., Wölk C. Interactions of Cationic Lipids with DNA: A Structural Approach. Langmuir. 2018;34(49):14858-14868. https://doi.org/10.1021/acs.langmuir.8b01635

8. Sen J., Chaudhuri A. Design, Syntheses, and Transfection Biology of Novel Non-Cholesterol- Based Guanidinylated Cationic Lipids. J. Med. Chem. 2005;48(3):812-820. https://doi.org/10.1021/jm049417w

9. Antipina M.N., Schulze I., Heinze M., Dobner B., Langner A., Brezesinski G. Physical-Chemical Properties and Transfection Activity of Cationic Lipid/DNA Complexes. ChemPhysChem. 2009;10(14):2471-2479. https://doi.org/10.1002/cphc.200900069

10. Wölk C., Heinze M., Kreideweiss P., Dittrich M., Brezesinski G., Langner A., Dobner B. Synthesis and DNA transfection properties of new head group modified malonic acid diamides. Int. J. Pharm. 2011;409(1-2):46-56. http://doi.org/10.1016/j.ijpharm.2011.02.022

11. Wölk C., Janich C., Bakowsky U., Langner A., Brezesinski G. Malonic acid based cationic lipids – The way to highly efficient DNA-carriers. Adv. Colloid Interface Sci. 2017;248:20-34. https://doi.org/10.1016/j.cis.2017.08.003

12. Jones C.H., Chen C.K., Ravikrishnan A., Rane S., Pfeifer B.A. Overcoming Nonviral Gene Delivery Barriers: Perspective and Future. Mol. Pharm. 2013;10(11):4082-4098. https://doi.org/10.1021/mp400467x

13. Janich C., Taßler S., Meister A., Hause G., Schäfer J., Bakowsky U., Brezesinski G., Wölk C. Structures of malonic acid diamide/phospholipid composites and their lipoplexes. Soft Matter. 2016;12(27):5854-5866. https://doi.org/10.1039/C6SM00807K

14. Ahmad A., Evans H.M., Ewert K., George C.X., Samuel C.E., Safinya C.R. New multivalent cationic lipids reveal bell curve for transfection efficiency versus membrane charge density: lipid-DNA complexes for gene delivery. J. Gene Med. 2005;7(6):739-748. https://doi.org/10.1002/jgm.717

15. Serebrennikova G.A., Maslov M.A., Morozova N.G. Modular transport systems based on cationic and neutral amphiphiles for gene therapy. Tonk. Khim. Tekhnol. = Fine Chem. Technol. 2011;6(5):72-86 (in Russ.)

16. Denieva Z.G., Budanova U.A., Sebyakin Y.L. Synthesis of Cationic and Ionizable Amphiphiles Based on Heminal Aminodiol as Potential siRNA Delivery Systems. Tonk. Khim. Tekhnol. = Fine Chem. Technol. 2019;14(3):42-49 (in Russ.). https://doi.org/10.32362/2410-6593-2019-14-3-42-49

17. Heinze M., Brezesinski G., Dobner B., Langner A. Novel Cationic Lipids Based on Malonic Acid Amides Backbone: Transfection Efficacy and Cell Toxicity Properties. Bioconjug. Chem. 2010;21(4):696-708. https://doi.org/10.1021/bc9004624

18. Buck J., Grossen P., Cullis P.R., Huwyler J., Witzigmann D. Lipid-Based DNA Therapeutics: Hallmarks of Non-Viral Gene Delivery. ACS Nano. 2019;13(4):3754-3782. https://doi.org/10.1021/acsnano.8b07858


Supplementary files

1. Fig. 2. Transfection efficiency for obtained liposomes.
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Type Исследовательские инструменты
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2. This is to certify that the paper titled Cationic amphiphiles based on malonic acid amides as transfection mediators commissioned to us by Nadezhda A. Romanova, Ulyana A. Budanova, Yury L. Sebyakin has been edited for English language and spelling by Enago, an editing brand of Crimson Interactive Inc.
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  • A synthesis scheme was developed and new cationic amphiphiles with an asymmetric hydrophobic block were generated.
  • Liposomal dispersions were formed, and their physical and chemical properties and transfection activity were studied.
  • The obtained results indicate good potential of malonic acid amides for creating a new class of cationic amphiphiles used as transfection agents.

Review

For citations:


Romanova N.A., Budanova U.A., Sebyakin Yu.L. Cationic amphiphiles based on malonic acid amides as transfection mediators. Fine Chemical Technologies. 2020;15(5):36-45. https://doi.org/10.32362/2410-6593-2020-15-5-36-45

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ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)