The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG5K-(vitamin E)2 (PEG5K-VE2) system. PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2 (PEG5K-FVE2) was synthesized using lysine as the scaffold. PTX-loaded PEG5K-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 PEG5K-FVE2 micelles have a low CMC value of 4 μg/mL and small sizes (~60 nm). The PTX loading capacity of PEG5K-FVE2 micelles was much higher than that of PEG5K-VE2 micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG5K-FVE2 micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG5K-FVE2 micelles showed superior anticancer activity compared with PEG5K-VE2 formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG5K-VE2 micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.