Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities.
The first disulfide linkage-employing drug conjugate that exploits the reversible nature of this unique covalent bond was recently approved for human use. Increasing numbers of drug formulations that incorporate disulfide bonds have been reported, particularly in the next generation macromolecular pharmaceuticals. These are designed to exploit differences in the reduction potential at different locations within and upon cells. The recent characterization of a novel redox enzyme in endosomes and lysosomes adds more excitement to this approach. This review focuses on understanding where and how the disulfide bond in the bioconjugate is reduced upon contact with biological milieu, which affects delivery design and the interpretation of the delivery strategies.
Saito
Go
G
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.
Swanson
Joel A
JA
Lee
Kyung-Dall
KD
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000378:metabolism
D000906:Antibodies; D004220:Disulfides; D004798:Enzymes; D004364:Pharmaceutical Preparations; D013438:Sulfhydryl Compounds