Design and Characterization of PEG-Derivatized Vitamin E as a Nanomicellar Formulation for Delivery of Paclitaxel

Various PEG–Vitamin E conjugates including d-α-tocopheryl poly­(ethylene glycol) succinate 1000 (TPGS) have been extensively studied as a nonionic surfactant in various drug delivery systems. However, limited information is available about the structure–activity relationship of PEG–Vitamin E conjugates as a micellar formulation for paclitaxel (PTX). In this study, four PEG–Vitamin E conjugates were developed that vary in the molecular weight of PEG (PEG_2K vs PEG_5K) and the molar ratio of PEG/Vitamin E (1/1 vs 1/2) in the conjugates. These conjugates were systematically characterized with respect to CMC, PTX loading efficiency, stability, and their efficiency in delivery of PTX to tumor cells in vitro and in vivo. Our data show that PEG_5K-conjugates have lower CMC values and are more effective in PTX loading with respect to both loading capacity and stability. The conjugates with two Vitamin E molecules also worked better than the conjugates with one molecule of Vitamin E, particularly for PEG_2K-system. Furthermore, all of the PEG–Vitamin E conjugates can induce significant suppression of P-gp function. More importantly, PTX-loaded PEG_5K–VE₂ resulted in significantly improved tumor growth inhibitory effect in comparison to PTX formulated in PEG_2K–VE or PEG_2K–VE₂, as well as Cremophor EL (Taxol) in a syngeneic mouse model of breast cancer (4T1.2). Our study suggests that PEG_5K-Vitmin E₂ may hold promise as an improved micellar formulation for in vivo delivery of anticancer agents such as PTX.