Solubilization of alpha-galactosylceramide in aqueous medium: Impact on Natural Killer T cell activation and antitumor responses. International Journal of Pharmaceutics 2017, 530 (1-2), 354-363.

The potent antitumor effect of alpha-galactosylceramide (alpha-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 alpha-GalCer has already been tested in advanced cancer patients but no or only moderate clinical responses were obtained. To optimize alpha-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 alpha-GalCer in non-cationic liposomes and (2) the synthesis of a water-soluble alpha-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 alpha-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 alpha-GalCer solubility in aqueous solution without limiting its antitumor properties.