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Fmoc-conjugated PEG-vitamin E2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity.

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.
AuthorsYifei Zhang, Yixian Huang, Wenchen Zhao, Jianqin Lu, Peng Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao, Raman Venkataramanan, Song Li
JournalThe AAPS journal (AAPS J) Vol. 16 Issue 6 Pg. 1282-91 (Nov 2014) ISSN: 1550-7416 [Electronic] United States
PMID25193267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • Micelles
  • Vitamin E
  • Polyethylene Glycols
  • Paclitaxel
Topics
  • Animals
  • Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Drug Carriers (chemical synthesis, chemistry)
  • Drug Compounding
  • Drug Stability
  • Female
  • Humans
  • Mammary Neoplasms, Experimental (drug therapy, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Molecular Targeted Therapy
  • Neoplasm Transplantation
  • Paclitaxel (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
  • Particle Size
  • Polyethylene Glycols (chemical synthesis, chemistry)
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Vitamin E (analogs & derivatives, chemical synthesis, chemistry)

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