We have recently taken the surface-iniated polymerization concept to proteins. We have developed two new and general routes 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 or C-terminus of a protein by in situ atom-transfer radical polymerization (ATRP) under aqueous conditions, to yield site-specific (N- or C-terminal) and stoichiometric conjugates (1:1). Protein-POEGMA conjugates show a dramatic increase in their blood exposure compared to the unmodified protein after intravenous administration to mice, thereby demonstrating that comb polymers that present short oligo(ethylene glycol) side-chains are a new class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this new approach to the synthesis of N/C-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. Current work is focused on applying this technology to pharmacologically relevant peptides and proteins.
Stealth Protein-Polymer Conjugates
Publications
Self-Assembled Hybrid Elastin-like Polypeptide / Silica Nanoparticles Enable Triggered Drug Release. W. Han; A. Chilkoti; G.P. López. (2017).
A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity. Y. Qi; A. Simakova; N.J. Ganson; X. Li; K.M. Luginbuhl; I. Ozer; W. Liu; M.S. Hershfield; K. Matyjaszewski; A. Chilkoti. (2016).
Protein–polymer conjugation—moving beyond PEGylation. Y. Qi; A. Chilkoti. (2015).
Growing polymers from peptides and proteins: a biomedical perspective. Y. Qi; A. Chilkoti. (2013).
Sortase-Catalyzed Initiator Attachment Enables High Yield Growth of a Stealth Polymer from the C Terminus of a Protein. Y. Qi; M. Amiram; W. Gao; D.G. McCafferty; A. Chilkoti. (2013).
In situ growth of a thermoresponsive polymer from a genetically engineered elastin-like polypeptide. W. Gao; D. Xu; D.W. Lim; S.L. Craig; A. Chilkoti. (2011).
In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation. W. Gao; W. Liu; T. Christensen; M.R. Zalutsky; A. Chilkoti. (2010).
In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics. W. Gao; W. Liu; J.A. MacKay; M.R. Zalutsky; E.J. Toone; A. Chilkoti. (2009).