title: Reduction-sensitive dual functional nanomicelles for improved delivery of paclitaxel.
abstract: We have developed a dual-functional nanocarrier composed of a hydrophilic polyethylene glycol (PEG) and a hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist), which is effective in delivery of hydrophobic anticancer drug, paclitaxel (PTX). To facilitate the retention of the therapeutic activity of the carrier, FTS was coupled to PEG via a reduction-sensitive disulfide linkage (PEG5k-S-S-FTS2). PEG5k-S-S-FTS2 conjugate formed uniform micelles with very small size (∼30 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG5k-FTS2 micellar system resulted in a 4-fold decrease in the critical micelle concentration (CMC). In addition, the PTX loading capacity and colloidal stability of PTX-loaded micelles were improved. HPLC-MS showed that parent FTS could be more effectively released from PEG5k-S-S-FTS2 conjugate in tumor cells/tissues compared to PEG5k-FTS2 conjugate in vitro and in vivo. PEG5k-S-S-FTS2 exhibited a higher level of cytotoxicity toward tumor cells than PEG5k-FTS2 without a disulfide linkage. Furthermore, PTX-loaded PEG5k-S-S-FTS2 micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG5k-FTS2 micelles. More importantly, PTX-loaded PEG5k-S-S-FTS2 micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG5k-FTS2 micelles in an aggressive murine breast cancer model (4T1.2).
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy; §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.forename: Jieni
authors.initials: J
authors.lastname: Xu
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005204:Farnesol / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008823:Micelles; D049329:Nanostructures / Q000737:chemistry*; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D012459:Salicylates / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D011092:Polyethylene Glycols; D005204:Farnesol; D017239:Paclitaxel