title: Improved Micellar Formulation for Enhanced Delivery for Paclitaxel.
abstract: We have previously improved the bioactivity of PEG5k-FTS2system by incorporating disulfide bond (PEG5k-S-S-FTS2) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG5k-FTS2system (PEG5k-Fmoc-FTS2) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG5k-FTS2to form a simple PEG5k-Fmoc-S-S-FTS2micellar system. PEG5k-Fmoc-S-S-FTS2conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC). Compared with PEG5k-Fmoc-FTS2, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG5k-Fmoc-S-S-FTS2in treated tumor cells compared to PEG5k-Fmoc-FTS2, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG5k-Fmoc-S-S-FTS2micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG5k-Fmoc-FTS2. PTX release kinetics of PTX/PEG5k-Fmoc-S-S-FTS2was much slower than that of Taxol and PTX/PEG5k-Fmoc-FTS2in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG5k-Fmoc-S-S-FTS2micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG5k-Fmoc-S-S-FTS2system maintained PTX in circulation for a longer time and delivered more PTX to tumor sites with less accumulation in major organs. Finally, PTX-loaded PEG5k-Fmoc-S-S-FTS2micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG5k-Fmoc-FTS2micelles.
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Jieni
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005204:Farnesol / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D005978:Glutathione / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D012459:Salicylates / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D011092:Polyethylene Glycols; D005204:Farnesol; D005978:Glutathione; D017239:Paclitaxel
keywords: drug delivery; drug-interactive motif; paclitaxel; polymeric micelle; reduction-sensitive