title: Reduction-responsive crosslinked micellar nanoassemblies for tumor-targeted drug delivery.
abstract: OBJECTIVE
  The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors.
  
  
  METHODS
  A novel copolymer comprised of polyethylene glycol 5000 (PEG114), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG114-VE4-TA4 copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG114-VE4-TA4 micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles were assessed in a human ovarian cancer xenograft murine model.
  
  
  RESULTS
  The crosslinked PEG114-VE4-TA4 micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol®, respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non-crosslinked counterparts and Taxol®.
  
  
  CONCLUSIONS
  These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.
authors.affiliation: Cancer Nanomedicine Laboratory Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, 3001 Mercer University Drive, Atlanta, Georgia, 30341, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: DeAngelo
authors.initials: D
authors.lastname: Mckinley
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D065546:Drug Liberation; D004355:Drug Stability; D005260:Female; D006801:Humans; D008819:Mice, Nude; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D013499:Surface Properties; D008063:Thioctic Acid / Q000737:chemistry*; D014018:Tissue Distribution; D014810:Vitamin E / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D008823:Micelles; D014810:Vitamin E; D011092:Polyethylene Glycols; D008063:Thioctic Acid; D017239:Paclitaxel