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Modification of Thiol Functionalized Aptamers by Conjugation of Synthetic Polymers

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Chiara Da Pieve*^†, Paul Williams^‡, David M. Haddleton^§, Richard M. J. Palmer^‡ and Sotiris Missailidis*^†

Department of Chemistry and Analytical Sciences, The Open University, Milton Keynes, United Kingdom MK6 7AA, Warwick Effect Polymers Limited, Coventry, United Kingdom CV4 7EZ, and Department of Chemistry, University of Warwick, Coventry, United Kingdom CV4 7AL

Bioconjugate Chem., 2010, 21 (1), pp 169–174

DOI: 10.1021/bc900397s

Publication Date (Web): December 10, 2009

* To whom correspondences should be addressed at the Department of Chemistry and Analytical Sciences, The Open University, Walton Hall, Milton Keynes, UK MK6 7AA. Phone: +44 1908653366 (Chiara Da Pieve), +44 1908658382 (Sotiris Missailidis); Fax: +44 1908858327. E-mail: c.dapieve@open.ac.uk; s.missailidis@open.ac.uk., †

The Open University.

, ‡

Warwick Effect Polymers Limited.

, §

University of Warwick.

Section:

Pharmaceuticals

Abstract

Aptamers are known for their short in vivo circulating half-life and rapid renal clearance. Their conjugation to poly(ethylene glycol) (PEG) is a way to improve their residence in the body. Two aptamers (AptD and AptF), having a disulfide protected thiol modification on the 3′ end, have been conjugated to maleimide activated PEGs of various molecular weights and structures (linear PEG20; branched PEG20 and 40; PolyPEG17, 40, and 60 kDa). The high yield coupling (70−80% in most of the cases) could be achieved using immobilized tris[2-carboxyethyl]phosphine hydrochloride (TCEP) as reducing agent at pH 4. The affinity of PEGylated AptD for its target was reduced by conjugation to linear PEG20 and branched PEG40, but not to branched PEG20 and PolyPEGs. This work demonstrates an alternative approach to PEGylation of aptamers, and that the effect of PEG on the affinity for the target varies according to the structure and conformation of the synthetic polymer.

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