title: Targeted gene delivery to hepatocytes with galactosylated amphiphilic cyclodextrins.
abstract: OBJECTIVE
  Achieving targeted delivery of gene medicines is desirable to maximise activity. Here, galactosylated amphiphilic cyclodextrins (CDs) are examined in terms of their ability to transfect asialoglycoprotein receptor-bearing HepG2 cells.
  
  
  METHODS
  Cationic amphiphilic CDs were synthesised as well as amphiphilic CDs bearing galactose-targeting ligands with different linker lengths. Binding of galactosylated CDs to a galactose-specific lectin was examined by surface plasmon resonance. CDs were formulated with and without the helper lipid DOPE and complexed with plasmid DNA. Transfection was evaluated by luciferase assay. Intracellular trafficking was assessed by confocal microscopy.
  
  
  RESULTS
  Binding of targeted CDs to a galactose-specific lectin was achieved. Binding decreased with linker length between the galactosyl group and the CD core. Contrary to the lectin binding results, transfection levels increased with an increase in linker length from 7 atoms to 15. Compared to non-targeted formulations, a significant increase in transfection was observed only in the presence of the helper lipid DOPE. Confocal microscopy revealed that DOPE caused a pronounced effect on cellular distribution.
  
  
  CONCLUSIONS
  The galactose-targeting ligand induced substantial increases in transfection over non-targeted formulations when DOPE was included, indicating the potential for targeted gene delivery using CD-based delivery systems.
authors: Azur Pharma Ltd, Dublin 2 Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors: Anthony
authors: A
authors: McMahon
authors: Martin J
authors: MJ
authors: O'Neill
authors: Eva
authors: E
authors: Gomez
authors: Ruth
authors: R
authors: Donohue
authors: Damien
authors: D
authors: Forde
authors: Raphael
authors: R
authors: Darcy
authors: Caitriona M
authors: CM
authors: O'Driscoll
mesh_terms: D037263:Asialoglycoprotein Receptor / Q000235:genetics*; D002412:Cations; D003505:Cyclodextrins / Q000378:metabolism*; D004247:DNA / Q000008:administration & dosage*; D005690:Galactose / Q000378:metabolism*; D018390:Gene Targeting; D015316:Genetic Therapy; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D037102:Lectins / Q000378:metabolism; D008055:Lipids; D008156:Luciferases / Q000378:metabolism; D018613:Microscopy, Confocal; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010957:Plasmids; D014162:Transfection
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D037263:Asialoglycoprotein Receptor; D002412:Cations; D003505:Cyclodextrins; D037102:Lectins; D008055:Lipids; D010714:Phosphatidylethanolamines; D004247:DNA; D008156:Luciferases; D005690:Galactose