title: Reductive amination using poly(ethylene glycol) acetaldehyde hydrate generated in situ: applications to chitosan and lysozyme.
abstract: Covalent linkage of poly(ethylene glycol) (PEG) to drug molecules results in water-soluble conjugates with altered bioavailability, pharmacokinetics, immunogenic properties, and biological activities. For drugs bearing one or more amino groups, reductive amination is a potentially useful method for conjugation to PEG. PEG acetaldehyde has been used for this purpose, but its ease of polymerization under certain conditions and its susceptibility to air oxidation have caused some problems in its application. A simple and reliable method for preparation and use in reductive amination of PEG acetaldehyde hydrate generated in situ by hydrolysis of PEG acetaldehyde diethylacetal is demonstrated. PEG acetaldehyde diethylacetal is prepared in high yield and purity by reaction of PEG with chlorodiethylacetal in dioxane in the presence of finely powdered sodium hydroxide under heterogeneous conditions. PEG acetaldehyde hydrate is generated in solution by hydrolysis in aqueous acids. Solutions of the hydrate may be used directly, in conjunction with sodium cyanoborohydride, to effect reductive amination. We demonstrate application of these methods in PEGylation of lysozyme and chitosan to form water-soluble methoxy poly(ethylene glycol) (mPEG) derivatives and PEG-chitosan hydrogels.
authors.affiliation: Shearwater Polymers, Inc., 2307 Spring Branch Road, Huntsville, Alabama 35801, USA. mbentley@swpolymers.com
authors.forename: M D
authors.initials: MD
authors.lastname: Bentley
authors.forename: M J
authors.initials: MJ
authors.lastname: Roberts
authors.forename: J M
authors.initials: JM
authors.lastname: Harris
mesh_terms: D001565:Benzoates / Q000008:administration & dosage* / Q000378:metabolism; D001704:Biopolymers / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry; D048271:Chitosan; D020100:Hydrogels / Q000138:chemical synthesis*; D009113:Muramidase / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: C116058:1-(ethoxycarbonyl)pentyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate; D001565:Benzoates; D001704:Biopolymers; D020100:Hydrogels; C116057:poly(ethylene glycol)acetaldehyde diethylacetal; C116056:poly(ethylene glycol)acetaldehyde hydrate; D002686:Chitin; D011092:Polyethylene Glycols; D048271:Chitosan; D009113:Muramidase