PEGylation Enhances the Oral Bioavailability of γ-Tocotrienol Isomer of Vitamin E

Objective: To Synthesize and characterize PEGylated γ-T3 with m-PEG molecular weights of 350 (γ-T3PGS 350) and 1000 (γ-T3PGS 1000) and to Determine the oral bioavailability of the PEGylated γ-T3 in rats. Methods: γ-T3 was extracted from a 500 g batch of TocotrolTM L50P. γ-T3PGS 350 and γ-T3PGS 1000 were synthesized by a simple single ring-opening of half acid ester precursor, followed by controlled coupling to the terminally methylated PEG. Succination and subsequent PEGylation of γ -T3 were confirmed by HPLC, MS, and 1H-NMR studies. The effect of PEGylation on the oral bioavailability was tested in rats. Results: The succination of γ-T3 was confirmed by the appearance of the ethyl protons of the succinate at 2.75-2.86 ppm and the disappearance of the proton chemical shift from the hydroxyl group of γ-T3 at 4.7 ppm. Subsequent PEGylation was confirmed by the chemical shift at 4.23 ppm, which corresponds to the protons of the ethylene group of PEG that is directly linked to γ-T3S, and confirmed by MS and HPLC. Thee most interesting is that PEGylation significantly enhanced the oral bioavailability of γ-T3 as compared with regular formula and no significant difference was observed between the two molecular variants of mPEG 350 or mPEG 1000. Conclusion: Results from this study suggest that PEGylation of γ-T3 represents a viable platform for the oral and parenteral delivery of γ-T3 for potential use in the prevention of breast cancer.