title: An improved D-α-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance.
abstract: Nanocarriers have recently emerged as an attractive platform for the delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K-VE2/DOX in PC-3 and 4T1.2 cells. A cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have the potential to reverse multidrug resistance, which was supported by its inhibition of P-gp ATPase. Pharmacokinetic (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accuulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~30 mgDOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated by PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX.
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: Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; 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: Department of Molecular Biosciences, 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, Lawrence, KS 66045, USA.
authors.forename: Rebecca
authors.initials: R
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: Yixian
authors.initials: Y
authors.lastname: Huang
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: Yifei
authors.initials: Y
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: Jiang
authors.initials: J
authors.lastname: Li
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: Wen
authors.initials: W
authors.lastname: Xie
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, 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: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D049329:Nanostructures; D014018:Tissue Distribution; D024502:alpha-Tocopherol / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D024502:alpha-Tocopherol
keywords: Chemotherapeutics; Drug-interactive motif; Fluorenylmethyloxycarbonyl; Nanomedicine; Reversal of multidrug resistance