Improved Micellar Formulation for Enhanced Delivery for Paclitaxel

Abstract

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 ∼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.

Keywords: drug delivery; drug-interactive motif; paclitaxel; polymeric micelle; reduction-sensitive.