Solubilization of α-galactosylceramide in aqueous medium: impact on Natural Killer T cell activation and antitumor responses.
Fiche publication
Date publication
juillet 2017
Journal
International journal of pharmaceutics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FOURNEL Sylvie, Dr FRISCH Benoit, Dr HEURTAULT Béatrice
Tous les auteurs :
Macho-Fernandez E, Chekkat N, Ehret C, Thomann JS, De Giorgi M, Spanedda MV, Bourel-Bonnet L, Betbeder D, Heurtault B, Faveeuw C, Fournel S, Frisch B, Trottein F
Lien Pubmed
Résumé
The potent antitumor effect of α-galactosylceramide (α-GalCer) is based on its recognition by invariant Natural Killer T cells (iNKT) after its capture and presentation by antigen presenting cells including dendritic cells (DCs). Synthetic α-GalCer has already been tested in advanced cancer patients but no or only moderate clinical responses were obtained. To optimize α-GalCer efficacy, we have postulated that alternative formulations impacting its molecular organization in aqueous medium could modify DC uptake and iNKT-based immune responses. To this end, we have developed two strategies: (1) the formulation of α-GalCer in non-cationic liposomes and (2) the synthesis of a water-soluble α-GalCer analogue by anchoring a polyethyleneglycol moiety on its sugar head. The biological activities of these new preparations were compared to that induced by the classically used Polysorbate 20 α-GalCer micelles. Both formulations retained their uptake by DCs and activated iNKT cells both in vitro and in vivo. Despite a lower cytokine production, the formulations induced a potent immune response able to control lung murine carcinoma. In conclusion, it is possible to increase α-GalCer solubility in aqueous solution without limiting its antitumor properties.
Mots clés
Cancer, Liposomes, Micelles, Water-soluble α-GalCer, iNKT, α-GalCer formulations
Référence
Int J Pharm. 2017 Jul;: