title: Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein.
abstract: Biocompatible polymers such as poly(ethylene glycol) (PEG) have been successfully conjugated to therapeutic proteins to enhance their pharmacokinetics. However, many of these polymers, including PEG, only improve the in vivo lifetimes and do not protect proteins against inactivation during storage and transportation. Herein, we report a polymer with trehalose side chains (PolyProtek) that is capable of improving both the external stability and the in vivo plasma half-life of a therapeutic protein. Insulin was employed as a model biologic, and high performance liquid chromatography and dynamic light scattering confirmed that addition of trehalose glycopolymer as an excipient or covalent conjugation prevented thermal or agitation-induced aggregation of insulin. The insulin-trehalose glycopolymer conjugate also showed significantly prolonged plasma circulation time in mice, similar to the analogous insulin-PEG conjugate. The insulin-trehalose glycopolymer conjugate was active as tested by insulin tolerance tests in mice and retained bioactivity even after exposure to high temperatures. The trehalose glycopolymer was shown to be nontoxic to mice up to at least 1.6 mg/kg dosage. These results together suggest that the trehalose glycopolymer should be further explored as an alternative to PEG for long circulating protein therapeutics.
authors.affiliation: Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California, Los Angeles , 607 Charles E. Young Drive, East, Los Angeles, California 90095, United States.|Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University , Irvine, California 92618, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California, Los Angeles , 607 Charles E. Young Drive, East, Los Angeles, California 90095, United States.
authors.forename: Juneyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California, Los Angeles , 607 Charles E. Young Drive, East, Los Angeles, California 90095, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Mansfield
authors.affiliation: Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California, Los Angeles , 607 Charles E. Young Drive, East, Los Angeles, California 90095, United States.
authors.forename: Jeong Hoon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Department of Chemistry, The University of Akron , 190 East Buchtel Common, Akron, Ohio 44325, United States.
authors.forename: Sahar
authors.initials: S
authors.lastname: Sallam
authors.affiliation: Department of Chemistry, The University of Akron , 190 East Buchtel Common, Akron, Ohio 44325, United States.
authors.forename: Chrys
authors.initials: C
authors.lastname: Wesdemiotis
authors.affiliation: Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California, Los Angeles , 607 Charles E. Young Drive, East, Los Angeles, California 90095, United States.
authors.forename: Heather D
authors.identifier: 0000-0003-3692-6289
authors.initials: HD
authors.lastname: Maynard
mesh_terms: D000818:Animals; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000737:chemistry*; D007328:Insulin / Q000031:analogs & derivatives* / Q000097:blood* / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000737:chemistry; D055550:Protein Stability; D013552:Swine; D014199:Trehalose / Q000031:analogs & derivatives* / Q000097:blood* / Q000737:chemistry
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; C039441:insulin, polyethylene glycol(B1)-; D011092:Polyethylene Glycols; D014199:Trehalose