Combining dexamethasone and TNF-α siRNA within the same nanoparticles to enhance anti-inflammatory effect

Autor: Özgen Özer, Elias Fattal, Serra Gürcan, Juliette Vergnaud, Franceline Reynaud, Stéphanie Denis, Nicolas Tsapis
Přispěvatelé: Institut Galien Paris-Saclay (IGPS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Ege University - EGE (Izmir, Turkey), Universidade Federal do Rio de Janeiro (UFRJ), Ege Üniversitesi
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: International Journal of Pharmaceutics
International Journal of Pharmaceutics, Elsevier, 2021, 598, pp.120381. ⟨10.1016/j.ijpharm.2021.120381⟩
ISSN: 0378-5173
DOI: 10.1016/j.ijpharm.2021.120381⟩
Popis: We propose to combine two therapeutic anti-inflammatory approaches with different mechanisms of action in a single drug delivery system consisting of cationic dexamethasone palmitate nanoparticles (CDXP-NP) associated with TNF-alpha siRNA. The CDXP-NPs are obtained by the solvent emulsion evaporation technique using dexamethasone palmitate, a prodrug of dexamethasone, associated with a cationic lipid, DOTAP. Their physicochemical properties as well as their ability to bind siRNA were evaluated through gel electrophoresis and siRNA binding quantification. SiRNA cellular uptake was assessed by flow cytometry and confocal microscopy on RAW264.7 macrophages. TNF-alpha inhibition was determined on LPS-activated RAW264.7 macrophages. Stable and monodisperse nanoparticles around 100 nm with a positive zeta potential (+59 mV) were obtained with an encapsulation efficiency of the prodrug of 95%. A nitrogen/phosphate (N/P) ratio of 10 was selected that conferred the total binding of siRNA to the nanoparticles. Using these CDXP-siRNA-NPs, the siRNA was strongly internalized by RAW264.7 macrophage cells and localized within the cytoplasm. on the LPS-induced RAW264.7 macrophages, a larger inhibition of TNF-alpha was observed with CDXP-siRNA-NPs compared to CDXP-NPs alone. in conclusion, from these data, it is clear that a combination of DXP and TNF-alpha siRNA therapy could be a novel strategy and optimized alternative approach to cure inflammatory diseases.
TUB.ITAK 2214/A International Research Fellowship Program for PhD students; ANRFrench National Research Agency (ANR) [ANR-10-LABX-33]; CNRSCentre National de la Recherche Scientifique (CNRS)European Commission; l'Agence Nationale de la RechercheFrench National Research Agency (ANR) [ANR-11-EQPX-0029, ANR-10-INBS-04, ANR-11-IDEX-0003-02]
S. Gurcan was supported by TUB.ITAK 2214/A International Research Fellowship Program for PhD students. This research received support from Laboratory of Excellence LERMIT thanks to an ANR grant (ANR-10-LABX-33) and from CNRS. The present work has benefited from Imagerie-Gif core facility supported by l'Agence Nationale de la Recherche (ANR-11-EQPX-0029/Morphoscope, ANR-10-INBS-04/FranceBioImaging; ANR-11-IDEX-0003-02/Saclay Plant Sciences) with the precious help of C. Boulogne and C. Gillet. The authors would like to thank V. Nicolas (MIPSIT, Universite Paris-Saclay) for help with confocal microscopy.
Databáze: OpenAIRE
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