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Facile fabrication of redox-responsive thiol-containing drug delivery system via RAFT polymerization.

Abstract
A novel kind of redox-responsive polymeric drug delivery system has been designed and prepared successfully through the coupling of the multithiol branched polymers and thiol-containing drugs. The branched poly((S-(4-vinyl) benzyl S'-propyltrithiocarbonate)-co-(poly(ethylene glycol) methacrylate)) (poly(VBPT-co-PEGMA)) was synthesized by one-pot reaction via reversible addition-fragmentation chain transfer (RAFT) copolymerization. Subsequently, the hydrophobic thiol-containing anticancer drug 6-mercaptopurine (MP) was conjugated to poly(VBPT-co-PEGMA) by thiol-disulfide exchange reaction, resulting in the formation of poly(VBPT-co-PEGMA)-S-S-MP conjugate. Due to its amphiphilicity, poly(VBPT-co-PEGMA)-S-S-MP conjugate self-assembled into amphiphilic micelles in aqueous solution. Under a reductive environment, the disassembly of polymeric micelles resulted in the MP release. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements demonstrated that the poly(VBPT-co-PEGMA)-S-S-MP micelles could be taken up by Raji cells (a Burkitt lymphoma cell line). The viability of the Raji cells incubated with the glutathione (GSH) mediated poly(VBPT-co-PEGMA)-S-S-MP micelles was investigated by Cell Counting Kit-8 (CCK-8) assay. The experimental results showed that the viability of the glutathione monoester (GSH-OEt) pretreated cells was lower than that without pretreatment, while the viability of the buthionine sulfoximine (BSO) pretreated cells was higher than that without pretreatment. The poly(VBPT-co-PEGMA)-S-S-MP micelles could induce the apoptosis of Raji cells, and the apoptosis behavior was dose-dependent. This redox-responsive polymer-drug conjugate provides a promising platform for the delivery of thiol-containing biological molecules.
AuthorsYuanyuan Zhuang, Yue Su, Yu Peng, Dali Wang, Hongping Deng, Xiaodong Xi, Xinyuan Zhu, Yunfeng Lu
JournalBiomacromolecules (Biomacromolecules) Vol. 15 Issue 4 Pg. 1408-18 (Apr 14 2014) ISSN: 1526-4602 [Electronic] United States
PMID24598057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drug Carriers
  • Methacrylates
  • Micelles
  • Solutions
  • Sulfhydryl Compounds
  • polyethylene glycol methacrylate
  • Polyethylene Glycols
  • Buthionine Sulfoximine
  • Mercaptopurine
  • Glutathione
Topics
  • Animals
  • Apoptosis (drug effects)
  • Buthionine Sulfoximine (pharmacology)
  • Drug Carriers (chemical synthesis, chemistry, pharmacology)
  • Drug Delivery Systems (methods)
  • Drug Liberation
  • Flow Cytometry
  • Glutathione
  • Hydrophobic and Hydrophilic Interactions
  • Mercaptopurine (chemistry, pharmacokinetics, pharmacology)
  • Methacrylates (chemistry)
  • Mice
  • Micelles
  • Microscopy, Confocal
  • Molecular Structure
  • NIH 3T3 Cells (drug effects)
  • Oxidation-Reduction
  • Polyethylene Glycols (chemistry)
  • Polymerization
  • Solutions
  • Sulfhydryl Compounds (chemistry)

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