title: Lipoic acid-derived amphiphiles for redox-controlled DNA delivery.
abstract: BACKGROUND
  Intracellular release of free DNA from the vector complex is one of the critical steps limiting the efficiency of non-viral gene delivery. The complex should be stable enough to prevent DNA degradation but it should be destabilized inside the cell to allow DNA release and transcription. Destabilization and degradation of synthetic vectors is also required to reduce their cytotoxicity and augment the life-time of transfected cells.
  
  
  RESULTS
  Here we describe new cationic amphiphiles made from the natural pro-vitamin, lipoic acid, that reversibly binds and releases DNA, depending on the redox state of the lipoate moieties. In the oxidized state these amphiphiles condense DNA into homogeneous spherical particles, which, upon reduction, swell into DNA toroids with subsequent release of free DNA. Complex reduction and DNA release can be induced by various thiols as well as enzymatically, by thioredoxin reductase. Transfection with amphiphile-DNA complexes in vitro shows a several fold increase of transgene expression compared with DOTAP, and can be further augmented by attachment of the nucleus-targeting peptide to the amphiphile. The increase of transfection efficiency results from GSH- and NAD(P)H-dependent complex reduction and release of free DNA inside the cells.
  
  
  CONCLUSIONS
  The present work demonstrates the principle of a redox-controlled gene delivery system that uses the reversibility of thiol-disulfide exchange reaction. Our data suggest that the efficiency of synthetic vectors can be augmented by their controlled destabilization inside the cells. Being formed from the natural non-toxic compound lipoic acid, these cationic amphiphiles provide a new promising class of synthetic vectors for gene delivery.
authors.affiliation: Institute de Biologie Structurale, Grenoble, France. maxbala@ibs.fr
authors.forename: M
authors.initials: M
authors.lastname: Balakirev
authors.forename: G
authors.initials: G
authors.lastname: Schoehn
authors.forename: J
authors.initials: J
authors.lastname: Chroboczek
mesh_terms: D001583:Benzoxazoles / Q000378:metabolism; D001711:Biotransformation; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005453:Fluorescence; D015870:Gene Expression; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008854:Microscopy, Electron; D008968:Molecular Conformation; D009249:NADP / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D011419:Propidium / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism; D011806:Quinolinium Compounds / Q000378:metabolism; D013501:Surface-Active Agents / Q000737:chemistry / Q000378:metabolism*; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection / Q000379:methods*; D019076:Transgenes / Q000235:genetics
chemical_list: C417522:AP1 compound; C417523:AP2 compound; C417524:AP3 compound; D001583:Benzoxazoles; D004279:DNA, Viral; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D019913:Nuclear Localization Signals; D011108:Polymers; D000644:Quaternary Ammonium Compounds; D011806:Quinolinium Compounds; D013501:Surface-Active Agents; C075296:1,1'-((4,4,7,7-tetramethyl)-4,7-diazaundecamethylene)bis-4-(3-methyl-2,3-dihydro(benzo-1,3-oxazole)-2-methylidene)quinolinium; D011419:Propidium; D009249:NADP; D008063:Thioctic Acid; D004247:DNA; D005978:Glutathione; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane