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

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Abstract

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.

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Abbreviations

PTX:

Paclitaxel

PEG5K-VE2 :

PEG5K-(vitamin E)2

PEG5K-FVE2 :

PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2

EPR:

Enhanced permeability and retention

TPGS:

d-alpha-tocopheryl polyethylene glycol (PEG)-1000 succinate

CMC:

Critical micelle concentration

DLS:

Dynamic light scattering

DLC:

Drug loading capacity

DLE:

Drug loading efficiency

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

PEI:

Polyethylenimine

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Acknowledgments

This work was supported in part by NIH grants (R01GM102989 and R21CA155983) and a DOD grant (BC09603).

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Authors and Affiliations

  1. Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA, 15261, USA

    Yifei Zhang, Yixian Huang, Jianqin Lu, Peng Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao & Song Li

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Yifei Zhang, Yixian Huang, Wenchen Zhao, Jianqin Lu, Peng Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao, Raman Venkataramanan & Song Li

  3. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Yifei Zhang, Yixian Huang, Jianqin Lu, Peng Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao, Raman Venkataramanan & Song Li

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  1. Yifei Zhang
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  2. Yixian Huang
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  3. Wenchen Zhao
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  5. Peng Zhang
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  7. Jiang Li
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  10. Song Li
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Correspondence to Song Li.

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Zhang, Y., Huang, Y., Zhao, W. et al. Fmoc-Conjugated PEG-Vitamin E2 Micelles for Tumor-Targeted Delivery of Paclitaxel: Enhanced Drug-Carrier Interaction and Loading Capacity. AAPS J 16, 1282–1291 (2014). https://doi.org/10.1208/s12248-014-9651-2

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  • DOI: https://doi.org/10.1208/s12248-014-9651-2

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