Improved Micellar Formulation for Enhanced Delivery for Paclitaxel.

We have previously improved the bioactivity of PEG-FTS system by incorporating disulfide bond (PEG-S-S-FTS) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG-FTS system (PEG-Fmoc-FTS) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG-FTS to form a simple PEG-Fmoc-S-S-FTS micellar system. PEG-Fmoc-S-S-FTS conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC). Compared with PEG-Fmoc-FTS, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG-Fmoc-S-S-FTS in treated tumor cells compared to PEG-Fmoc-FTS, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG-Fmoc-S-S-FTS micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG-Fmoc-FTS. PTX release kinetics of PTX/PEG-Fmoc-S-S-FTS was much slower than that of Taxol and PTX/PEG-Fmoc-FTS in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG-Fmoc-S-S-FTS micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG-Fmoc-S-S-FTS system maintained PTX in circulation for a longer time and delivered more PTX to tumor sites with less accumulation in major organs. Finally, PTX-loaded PEG-Fmoc-S-S-FTS micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG-Fmoc-FTS micelles.