Fmoc-Conjugated PEG-Vitamin E2 Micelles for Tumor-Targeted Delivery of Paclitaxel: Enhanced Drug-Carrier Interaction and Loading Capacity

The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG_5K-(vitamin E)₂ (PEG_5K-VE₂) system. PEG_5K-(fluorenylmethoxycarbonyl)-(vitamin E)₂ (PEG_5K-FVE₂) was synthesized using lysine as the scaffold. PTX-loaded PEG_5K-FVE₂ micelles were prepared and characterized. Fluorescence intensity of Fmoc in the micelles was measured as an indicator of drug-carrier interaction. Cytotoxicity of the micelle formulations was tested on various tumor cell lines. The therapeutic efficacy and toxicity of PTX-loaded micelles were investigated using a syngeneic mouse model of breast cancer (4T1.2). Our data suggest that the PEG_5K-FVE₂ micelles have a low CMC value of 4 μg/mL and small sizes (~60 nm). The PTX loading capacity of PEG_5K-FVE₂ micelles was much higher than that of PEG_5K-VE₂ micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG_5K-FVE₂ micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG_5K-FVE₂ micelles showed superior anticancer activity compared with PEG_5K-VE₂ formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG_5K-VE₂ micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9651-2) contains supplementary material, which is available to authorized users.KEY WORDS: drug delivery, drug-interactive motif, micelles, paclitaxel, vitamin E derivative