PEGylated γ-tocotrienol isomer of Vitamin E: Synthesis, characterization, in vitro cytotoxicity, and oral bioavailability

Abstract

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T 3). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T 3 variants with mPEG molecular weights of 350 (γ-T 3 PGS 350) and 1000 (γ-T 3 PGS 1000) were synthesized by a two-step reaction procedure and characterized by 1 H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T 3 and vitamin E TPGS. PEGylated T 3 were also found to retain the in vitro cytotoxic activity of the free T 3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T 3 also increased the oral bioavailability of γ-T 3 by threefolds when compared to the bioavailability of γ-T 3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T 3 represents a viable platform for the oral and parenteral delivery of γ-T 3 for potential use in the prevention of breast cancer.