title: 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.
authors.affiliation: Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA, 15261, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenchen
authors.initials: W
authors.lastname: Zhao
authors.forename: Jianqin
authors.initials: J
authors.lastname: Lu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D014810:Vitamin E; D011092:Polyethylene Glycols; D017239:Paclitaxel