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

0554468 - BFÚ 2022 RIV NL eng J - Journal Article
Zatloukalová, M. - Jedinák, L. - Riman, D. - Franková, J. - Novák, D. - Cytryniak, A. - Nazaruk, E. - Bilewicz, R. - Vrba, J. - Papoušková, B. - Kabeláč, M. - Vacek, Jan
Cubosomal lipid formulation of nitroalkene fatty acids: Preparation, stability and biological effects.
Redox Biology. Roč. 46, OCT 2021 (2021), č. článku 102097. ISSN 2213-2317. E-ISSN 2213-2317
R&D Projects: GA ČR(CZ) GA19-09212S
Institutional support: RVO:68081707
Keywords : conjugated linoleic-acid * nitro-oleic acid * drug-delivery * cubic-phase * oxide * transduction
OECD category: Biochemistry and molecular biology
Impact factor: 10.787, year: 2021
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S2213231721002561?via%3Dihub

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 mu M 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.
Permanent Link: http://hdl.handle.net/11104/0329178