Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein

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...

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Bibliographic Details
Published in:Bioconjugate chemistry 2017-03, Vol.28 (3), p.836-845
Main Authors: Liu, Yang, Lee, Juneyoung, Mansfield, Kathryn M, Ko, Jeong Hoon, Sallam, Sahar, Wesdemiotis, Chrys, Maynard, Heather D
Format: Article
Language:English
Subjects:
Animals
Chromatography
Female
Half-Life
High temperature
Humans
Hypoglycemic Agents - blood
Hypoglycemic Agents - chemistry
Inactivation
Insulin
Insulin - analogs & derivatives
Insulin - blood
Insulin - chemistry
Light scattering
Liquid chromatography
Mice
Models, Molecular
Pharmacokinetics
Polyethylene glycol
Polyethylene Glycols - chemistry
Polymers
Protein Stability
Proteins
Rodents
Swine
Trehalose - analogs & derivatives
Trehalose - blood
Trehalose - chemistry
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Summary: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.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.6b00659