title: In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.
abstract: The challenge in the synthesis of protein-polymer conjugates for biological applications is to synthesize a stoichiometric (typically 1:1) conjugate of the protein with a monodisperse polymer, with good retention of protein activity, significantly improved pharmacokinetics and increased bioavailability, and hence improved in vivo efficacy. Here we demonstrate, using myoglobin as an example, a general route to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], with low polydispersity and high yield, solely from the N-terminus of the protein by in situ atom transfer radical polymerization (ATRP) under aqueous conditions, to yield a site-specific (N-terminal) and stoichiometric conjugate (1:1). Notably, the myoglobin-poly(OEGMA) conjugate [hydrodynamic radius (R(h)): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (R(h): 1.7 nm) after IV administration to mice, thereby demonstrating that comb polymers that present short oligo(ethylene glycol) side chains are a class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this approach to the synthesis of N-terminal protein conjugates of poly(OEGMA) may be applicable to a large subset of protein and peptide drugs, and thereby provide a general methodology for improvement of their pharmacological profiles.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708-0281, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Gao
authors.forename: Wenge
authors.initials: W
authors.lastname: Liu
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Mackay
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
mesh_terms: D000179:Acrylates / Q000737:chemistry*; D001682:Biological Availability; D001704:Biopolymers / Q000096:biosynthesis* / Q000493:pharmacokinetics*; D055808:Drug Discovery / Q000379:methods*; D015394:Molecular Structure; D009211:Myoglobin / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000179:Acrylates; D001704:Biopolymers; D009211:Myoglobin; C530664:poly(oligoethylene glycol methyl ether acrylate); D011092:Polyethylene Glycols
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