A PEG-Fmoc conjugate as a nanocarrier for paclitaxel

  • Biomaterials. 2014 Aug;35(25):7146-56. doi: 10.1016/j.biomaterials.2014.04.108.
Peng Zhang  1 ,  Yixian Huang  1 ,  Hao Liu  2 ,  Rebecca T Marquez  2 ,  Jianqin Lu  1 ,  Wenchen Zhao  3 ,  Xiaolan Zhang  1 ,  Xiang Gao  1 ,  Jiang Li  1 ,  Raman Venkataramanan  3 ,  Liang Xu  2 ,  Song Li  4
Affiliations
  • 1. Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 2. Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, KS 66045, USA; Department of Radiation Oncology, University of Kansas Cancer Center, University of Kansas, Lawrence, KS 66045, USA.
  • 3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 4. Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: [email protected].
PMID: 24856103 DOI: 10.1016/j.biomaterials.2014.04.108
Abstract

We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25-30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and (13)C NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study.

Keywords
9-Fluorenylmethoxycarbonyl; Cancer therapy; Drug delivery; Drug–carrier interaction; Micelle; Paclitaxel.
Products