Rubusoside-assisted solubilization of poorly soluble C₆-Ceramide for a pilot pharmacokinetic study

Although C₆-Ceramide has attracted much attention as a possible tumor suppressor, the delivery of C₆-Ceramide is still challenging due to its inherent hydrophobicity and insolubility. In this study we explored the use of a natural compound rubusoside (RUB) as a solubilizer to enhance the solubility of a fluorescence-labeled C₆-Ceramide (NBD C₆-Ceramide) and to characterize its pharmacokinetics and tissue distribution in an animal model. RUB significantly enhanced the solubility of NBD C₆-Ceramide by forming nanomicelles, and efficiently delivered NBD C₆-Ceramide in rats by oral and intravenous administration. RUB loaded 1.96 % of NBD C₆-Ceramide in the nanomicelles and solubilized it to a concentration of 3.6 mg/mL in water. NBD C₆-Ceramide in nanomicelles remained stable in aqueous solutions, allowing intravenous administration without the use of any organic solvents or surfactants. After oral administration, NBD C₆-Ceramide rapidly rose to peak plasma concentrations within the first 90 min, distributed to tissues, and remained in vivo for more than 24 h. Tissular levels of NBD C₆-Ceramide from high to low were associated with heart, lung, cerebellum, testicle, spleen, liver, kidney, and brain. Altogether, our study demonstrated that RUB-assisted nanomicelles can serve as an efficient and convenient delivery system for short-chain C₆-Ceramide and enable in vivo evaluation of potential new cancer treatments.