title: A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.
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.
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Marquez
authors.affiliation: 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.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Wenchen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 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: sol4@pitt.edu.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D017239:Paclitaxel
keywords: 9-Fluorenylmethoxycarbonyl; Cancer therapy; Drug delivery; Drug–carrier interaction; Micelle; Paclitaxel