In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.
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.
Gao
Weiping
W
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708-0281, USA.
Liu
Wenge
W
Mackay
J Andrew
JA
Zalutsky
Michael R
MR
Toone
Eric J
EJ
Chilkoti
Ashutosh
A
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*
D000179:Acrylates; D001704:Biopolymers; D009211:Myoglobin; C530664:poly(oligoethylene glycol methyl ether acrylate); D011092:Polyethylene Glycols
Clin Pharmacokinet. 2006;45(10):965-88
16984211
Clin Pharmacokinet. 2001;40(7):539-51
11510630
Langmuir. 2006 Apr 11;22(8):3751-6
16584252
Adv Drug Deliv Rev. 2002 Jun 17;54(4):459-76
12052709
J Am Chem Soc. 2008 Aug 27;130(34):11288-9
18665597
Adv Drug Deliv Rev. 2002 Jun 17;54(4):477-85
12052710
Eur J Biochem. 1988 Jan 4;170(3):589-95
3338455
Adv Drug Deliv Rev. 2003 Sep 26;55(10):1261-77
14499706
J Am Chem Soc. 2007 Jun 6;129(22):7145-54
17500523
Bioconjug Chem. 2006 May-Jun;17(3):618-30
16704199
J Am Chem Soc. 2005 Dec 7;127(48):16955-60
16316241
Angew Chem Int Ed Engl. 2006 Aug 11;45(32):5307-11
16847857
Biopolymers. 1999;51(5):311-32
10685043
Angew Chem Int Ed Engl. 2008;47(33):6263-6
18618559
Chem Commun (Camb). 2006 Dec 7;(45):4697-9
17109040
J Am Chem Soc. 2005 May 11;127(18):6508-9
15869252
Int J Hematol. 1998 Jul;68(1):1-18
9713164
Biomaterials. 2001 Mar;22(5):405-17
11214751
Bioconjug Chem. 2006 Jan-Feb;17(1):179-88
16417267
Angew Chem Int Ed Engl. 2007;46(17):3099-103
17373024
Science. 1994 Nov 4;266(5186):776-9
7973629
Curr Opin Drug Discov Devel. 2008 Mar;11(2):242-50
18283612
Adv Mater. 2009 May 18;21(19):1968-1971
31097880
Pharm Res. 2003 May;20(5):818-25
12751640
Biomacromolecules. 2005 Nov-Dec;6(6):3380-7
16283769
Chem Commun (Camb). 2007 Apr 14;(14):1453-5
17389990