Title | In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Gao, W, Liu, W, MacKay, JA, Zalutsky, MR, Toone, EJ, Chilkoti, A |
Journal | Proceedings of the National Academy of Sciences |
Volume | 106 |
Issue | 36 |
Pagination | 15231 - 15236 |
Date Published | 09/2009 |
ISSN | 1091-6490 |
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 (Rh): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (Rh: 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. |
DOI | 10.1073/pnas.0904378106 |
Short Title | Proceedings of the National Academy of Sciences |