Amphiphilic cationic dendrons for the delivery of small interfering RNA in the treatment of rheumatoid arthritis ; Nanoparticules à base de dendrons cationiques amphiphiles pour l’administration de petits ARN interférents dans le traitement de la polyarthrite rhumatoïde

We have screened out two amphiphilic phosphorus dendrons (C17P10 and C11P10) for their potential as delivery system for siRNA alone or in combination with dexamethasone (DXM) for the treatment of rheumatoid arthritis. C17P10 dendron can form micelles and bind TNF-α siRNA forming dendriplexes. Dendriplexes at the N/P (nitrogen/phosphorus) ratio of 5 were considered as a good compromise between size and good binding affinity for high siRNA concentration. They presented a good inhibition of TNF-α in vitro and significant anti-inflammatory effect in CIA mice model. The dose and sequence-dependent effect of siRNA in dendriplexes were demonstrated both in vitro and in vivo. Dendriplexes were able to induce siRNA accumulation in the inflamed paw by Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS). Amphiphilic dendrons (C11P10) bearing C11 aliphatic chain possess the capacity of loading dexamethasone and bind TNF-α siRNA through electrostatic interaction forming nanostructured DXM-loaded dendriplexes. DXM-loaded dendriplexes at the dendron/DXM molar ratio of 5 and the N/P ratio of 5 were a good compromise between good binding, high DXM dose, and high siRNA concentration. A synergistic anti-inflammatory activity between dexamethasone and siRNA was confirmed in LPS-activated Raw 264.7 cells. We believe that dendrons are potent and flexible carriers for siRNA delivery. Even if more need to be discovered about their innocuity, there are at least as much efficient as many cationic lipid or polymers in the inhibition of TNF-α. ; Dans ce travail de thèse, nous avons sélectionné deux dendrons amphiphiles phosphorés (C17P10 et C11P10) pour leur potentiel en tant que système de délivrance de siRNA seul ou en combinaison avec la dexaméthasone (DXM) pour le traitement de la polyarthrite rhumatoïde. Le dendron C17P10 est capable de former des micelles et de complexer des siRNA, formant des dendriplexes qui ciblent TNF-α. Les dendriplexes de rapport N/P (azote/phosphore) de 5 ont ...