Development and in-vitro characterization of nanoemulsions loaded with paclitaxel/γ-tocotrienol lipid conjugates

Vitamin E TPGS is a tocopherol (alpha-T) based nonionic surfactant that was used in the formulation of the Tocosol (TM) paclitaxel nanoemulsion, which was withdrawn from phase III clinical trials. Unlike tocopherols, however, the tocotrienol (T-3) isomers of vitamin E were found to have innate anticancer activity and were shown to potentiate the antitumor activity of paclitaxel. The primary objective of the present study was therefore to develop a paclitaxel nanoemulsions by substituting alpha-T oil core of Tocosol (TM) with gamma-T-3 in, and vitamin E TPGS with PEGylated gamma-T-3 as the shell, and test the nanoemulsions against Bx-PC-3 and PANC-1 pancreatic tumor cells. A secondary objective was to test the activity of paclitaxel when directly conjugated with the gamma-T-3 isomer of vitamin E. The synthesis of the conjugates was confirmed by NMR and mass spectroscopy. Developed nanoemulsions were loaded with free or lipid conjugated paclitaxel. Nanoemulsions droplets were < 300 nm with fastest release observed with formulations loaded with free paclitaxel when gamma-T-3 was used as the core. Substituting alpha-T with gamma-T-3 was also found to potentiate the anticancer activity of the nanoemulsions. Although marginal increase in activity was observed when nanoemulsions were loaded with free paclitaxel, a significant increase in activity was observed when lipid conjugates were used. The results from this study suggest that the developed paclitaxel nanoemulsions with either alpha-T-3, PEGylated gamma-T-3, or paclitaxel lipid conjugates may represent a more promising option for paclitaxel delivery in cancer chemotherapy.