title: Tunable pH-Sensitive Linker for Controlled Release.
abstract: We have developed a novel pH-sensitive linker based on a phosphoramidate scaffold that can be tuned to release amine-containing drug molecules at various pH values. The pH-triggered phosphoramidate-based linkers are responsive to pH alone and do not require intracellular enzymatic action to initiate drug release. Key to the pH-triggered amine release from these linkers is a proximal acidic group (e.g., pyridinium or carboxylic acid) to promote the hydrolysis of the phosphoramidate P-N bond, presumably through an intramolecular general-acid type mechanism. Phosphoramidate hydrolysis is largely governed by the pKa of the leaving amine (e.g., primary, secondary, aniline). However, the proximity of the neighboring pyridine group attenuates the stability of the P-N bond to hydrolysis, thus allowing for control over the release of an amine from the phosphoramidate center. Based on the model scaffolds examined, phosphoramidate-based linkers could be selected for particular properties for controlled-release applications such as amine type, stability under physiological conditions, or release rates at various pH values such as intracellular endosomal conditions. The tunability of the phosphoramidate scaffold is expected to find broad applicability in various controlled drug-release applications such as antibody or small-molecule drug conjugates, drug-eluting stents, prodrug activation, as well as intracellular trafficking studies in which pH changes can trigger the release of turn-on dyes.
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: Choy
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Geruntho
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Austen L
authors.initials: AL
authors.lastname: Davis
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations