title: Nanocarrier-based antioxidant therapy: promise or delusion?
abstract: BACKGROUND
  Oxidative stress has generally been recognized as an important factor in the pathogenesis of human diseases, making antioxidant therapy a plausible strategy to either prevent or treat human disorders. Yet so far, numerous antioxidant-based clinical trials aimed at developing clinically approved protocols have been disappointing and many reasons for their failure are being discussed, including the limited bioavailability of most antioxidants. To overcome the hurdles associated with the direct administration of antioxidant molecules, a variety of nanotechnology-based drug delivery systems are being developed. All the strategies currently being explored, however, appear in our opinion to underappreciate the crucial role reactive oxygen and nitrogen species (RO/NS) play in the regulation of the metabolome, as revealed by recent progress made in redox biology.
  
  
  METHODS
  We briefly review antioxidant-based clinical trials and discuss the functions of RO/NS as crucial intracellular messengers. We emphasize the probable existence of three distinct concentration levels of RO/NS: a physiological level reflecting their functions as messenger molecules, an elevated level crucial for activation of protective pathways and a toxic level causing oxidative damage to cellular components.
  
  
  CONCLUSIONS
  Site-specific, multifunctional nanodrug delivery systems able to sense the actual intracellular concentrations of RO/NS and release antioxidants accordingly in order to only neutralize the pathologic excess of RO/NS need to be developed.
authors.affiliation: a 1 Midwestern University College of Pharmacy Glendale , 19555 N. 59th Avenue, Glendale, AZ 85308, USA +1 623 572 3574 ; +1 623 572 3565 ; vweiss@midwestern.edu.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Weissig
authors.affiliation: b 2 Midwestern University College of Pharmacy Glendale , 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Guzman-Villanueva
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species
keywords: antioxidant delivery; antioxidant therapy; clinical trials; oxidative stress; reactive oxygen species