Enhancement of Intestinal Permeability Utilizing Solid Lipid Nanoparticles Increases γ-Tocotrienol Oral Bioavailability

gamma-Tocotrienol (gamma-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. gamma-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that gamma-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing gamma-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance gamma-T3 permeability and bioavailability. gamma-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of gamma-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of gamma-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed gamma-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed gamma-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to gamma-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of gamma-T3, and passive diffusion enhancement of gamma-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced gamma-T3 oral bioavailability subsequent to enhanced passive permeability.