title: Disulfide-containing parenteral delivery systems and their redox-biological fate.
abstract: Exploiting the redox-sensitivity of disulfide bonds is an increasingly popular means to trigger drug release at a target location in the body. The bio-reducible linker (containing a disulfide) can be cleaved when the drug delivery system in which it is incorporated passes from the poorly reducing extra-cellular biological environments to the strongly reducing intra-cellular spaces. This phenomenon has been characterized for a variety of drug carriers (e.g. antibody-drug conjugates and nucleic acid carriers) and made use of not only for intra-cellular drug release, but also to provide a mechanism of biodegradation. However, successful therapeutic application of redox-sensitive drug delivery systems, which are mostly investigated in the treatment of cancer, depends on timely cleavage of the disulfide in the body. As a result, an accurate and detailed understanding of the biological redox stimulus and the properties of the redox-sensitive moiety is of importance. This review introduces a number of currently relevant reducing agents and redox enzymes, and provides an overview of the redox environments a disulfide-containing drug delivery system encounters upon parenteral administration. Furthermore, the current state of knowledge regarding the behavior and responsiveness of disulfides in these redox-biological compartments is discussed.
authors: Swiss Federal Institute of Technology Zurich (ETHZ), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors: Lorine
authors: L
authors: Brülisauer
authors: Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes J3X 1S2, Canada.
authors: Marc A
authors: MA
authors: Gauthier
authors: Swiss Federal Institute of Technology Zurich (ETHZ), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland. Electronic address: jleroux@ethz.ch.
authors: Jean-Christophe
authors: JC
authors: Leroux
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D004220:Disulfides
keywords: Cancer; Delivery system; Disulfide; Parenteral; Redox-potential; Thiol–disulfide exchange