Improved Micellar Formulation for Enhanced Delivery for Paclitaxel

We have previously improved the bioactivity of PEG(5k)-FTS2 system by incorporating disulfide bond (PEG(5k)-S-S-FTS2) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG(5k)-FTS2 system (PEG(5k)-Fmoc-FTS2) 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(5k)-FTS2 to form a simple PEG(5k)-Fmoc-S-S-FTS2 micellar system. PEG(5k)-Fmoc-S-S-FTS2 conjugate formed filamentous micelles with a similar to 10-fold decrease in critical micellar concentration (CMC). Compared with PEG(5k)-Fmoc-FTS2, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG(5k)-Fmoc-S-S-FTS2 in treated tumor cells compared to PEG(5k)-Fmoc-FTS2, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG(5k)-Fmoc-S-S-FTS2 micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG(5k)-Fmoc-FTS2. PTX release kinetics of PTX/PEG(5k)-Fmoc-S-S-FTS2 was much slower than that of Taxol and PTX/PEG(5k)-Fmoc-FTS2 in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG(5k)-Fmoc-S-S-FTS2 micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG(5k)-Fmoc-S-S-FTS2 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(5k)-Fmoc-S-S-FTS2 micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG(5k)-Fmoc-FTS2 micelles.