Effect of a Solid Lipid Nanoparticle Formulation on the Bioavailability of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine After Oral Administration

Previously, we developed a solid lipid nanoparticle (SLN) formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a compound with promising antitumor activity. Herein, we studied the feasibility of administering the DHA-dFdC by the oral route using the solid lipid nanoparticles (i.e., DHA-dFdC-SLNs). In simulated gastrointestinal fluids, the DHA-dFdC-SLNs did not aggregate. The release of the DHA-dFdC from the solid lipid nanoparticles in simulated gastrointestinal fluid was slow, but was slightly faster in simulated intestinal fluid than in simulated gastric fluid. In mice orally administered with DHA-dFdC-SLNs, plasma DHA-dFdC concentration vs. time curve has a Tmax of ~ 1.7 h and a Cmax of 17.01 μg/mL. The absolute oral bioavailability of DHA-dFdC when given as DHA-dFdC-SLNs was ~ 68% (based on AUC0–24 h values), while the relative oral bioavailability DHA-dFdC (compared with DHA-dFdC in a Tween 80/ethanol-in-water solution) was 126%. Finally, in mice with pre-establish B16-F10 murine melanoma, oral DHA-dFdC-SLNs increased their survival significantly, as compared with oral administration of the DHA-dFdC solution. It is concluded that the solid lipid nanoparticle formulation increased the bioavailability of the DHA-dFdC upon oral administration, as compared with the DHA-dFdC solution.