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Cubosomal lipid formulation of nitroalkene fatty acids: Preparation, stability and biological effects

M. Zatloukalová, L. Jedinák, D. Riman, J. Franková, D. Novák, A. Cytryniak, E. Nazaruk, R. Bilewicz, J. Vrba, B. Papoušková, M. Kabeláč, J. Vacek

. 2021 ; 46 (-) : 102097. [pub] 20210808

Language English Country Netherlands

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003638

Lipid nitroalkenes - nitro-fatty acids (NO2-FAs) are formed in vivo via the interaction of reactive nitrogen species with unsaturated fatty acids. The resulting electrophilic NO2-FAs play an important role in redox homeostasis and cellular stress response. This study investigated the physicochemical properties and reactivity of two NO2-FAs: 9/10-nitrooleic acid (1) and its newly prepared 1-monoacyl ester, (E)-2,3-hydroxypropyl 9/10-nitrooctadec-9-enoate (2), both synthesized by a direct radical nitration approach. Compounds 1 and 2 were investigated in an aqueous medium and after incorporation into lipid nanoparticles prepared from 1-monoolein, cubosomes 1@CUB and 2@CUB. Using an electrochemical analysis and LC-MS, free 1 and 2 were found to be unstable under acidic conditions, and their degradation occurred in an aqueous environment within a few minutes or hours. This degradation was associated with the production of the NO radical, as confirmed by fluorescence assay. In contrast, preparations 1@CUB and 2@CUB exhibited a significant increase in the stability of the loaded 1 and 2 up to several days to weeks. In addition to experimental data, density functional theory-based calculation results on the electronic structure and structural variability (open and closed configuration) of 1 and 2 were obtained. Finally, experiments with a human HaCaT keratinocyte cell line demonstrated the ability of 1@CUB and 2@CUB to penetrate through the cytoplasmic membrane and modulate cellular pathways, which was exemplified by the Keap1 protein level monitoring. Free 1 and 2 and the cubosomes prepared from them showed cytotoxic effect on HaCaT cells with IC50 values ranging from 1 to 8 μM after 24 h. The further development of cubosomal preparations with embedded electrophilic NO2-FAs may not only contribute to the field of fundamental research, but also to their application using an optimized lipid delivery vehicle.

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$a Lipid nitroalkenes - nitro-fatty acids (NO2-FAs) are formed in vivo via the interaction of reactive nitrogen species with unsaturated fatty acids. The resulting electrophilic NO2-FAs play an important role in redox homeostasis and cellular stress response. This study investigated the physicochemical properties and reactivity of two NO2-FAs: 9/10-nitrooleic acid (1) and its newly prepared 1-monoacyl ester, (E)-2,3-hydroxypropyl 9/10-nitrooctadec-9-enoate (2), both synthesized by a direct radical nitration approach. Compounds 1 and 2 were investigated in an aqueous medium and after incorporation into lipid nanoparticles prepared from 1-monoolein, cubosomes 1@CUB and 2@CUB. Using an electrochemical analysis and LC-MS, free 1 and 2 were found to be unstable under acidic conditions, and their degradation occurred in an aqueous environment within a few minutes or hours. This degradation was associated with the production of the NO radical, as confirmed by fluorescence assay. In contrast, preparations 1@CUB and 2@CUB exhibited a significant increase in the stability of the loaded 1 and 2 up to several days to weeks. In addition to experimental data, density functional theory-based calculation results on the electronic structure and structural variability (open and closed configuration) of 1 and 2 were obtained. Finally, experiments with a human HaCaT keratinocyte cell line demonstrated the ability of 1@CUB and 2@CUB to penetrate through the cytoplasmic membrane and modulate cellular pathways, which was exemplified by the Keap1 protein level monitoring. Free 1 and 2 and the cubosomes prepared from them showed cytotoxic effect on HaCaT cells with IC50 values ranging from 1 to 8 μM after 24 h. The further development of cubosomal preparations with embedded electrophilic NO2-FAs may not only contribute to the field of fundamental research, but also to their application using an optimized lipid delivery vehicle.
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$a Jedinák, Lukáš $u Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46, Olomouc, Czech Republic
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$a Riman, Daniel $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15, Olomouc, Czech Republic
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$a Franková, Jana $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15, Olomouc, Czech Republic
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$a Novák, David $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15, Olomouc, Czech Republic
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$a Cytryniak, Adrianna $u Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland
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$a Nazaruk, Ewa $u Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland
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$a Bilewicz, Renata $u Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland
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$a Vrba, Jiří $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15, Olomouc, Czech Republic
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$a Papoušková, Barbora $u Department of Analytical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 77146, Olomouc, Czech Republic
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$a Kabeláč, Martin $u Department of Chemistry, Faculty of Science, University of South Bohemia, Branišovská 31, České Budějovice, 370 05, Czech Republic
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$a Vacek, Jan $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15, Olomouc, Czech Republic; The Czech Academy of Sciences, Institute of Biophysics, Kralovopolská 135, Brno, 612 65, Czech Republic. Electronic address: jan.vacek@upol.cz
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