Ryan, Sinead M., Wang, Xuexuan, Mantovani, Giuseppe, Sayers, Claire, Haddleton, David M. and Brayden, David J.. (2009) Conjugation of salmon calcitonin to a combed-shaped end functionalized poly(poly(ethylene glycol) methyl ether methacrylate) yields a bioactive stable conjugate. Journal of Controlled Release, Vol.135 (No.1). pp. 51-59. ISSN 01683659

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Abstract

Salmon calcitonin (sCT) was conjugated via its N-terminal cysteine to a comb-shaped end-functionalized poly(poly(ethylene glycol) methyl ether methacrylate) (PolyPEG (R), 6.5 kDa). and to linear PEG (5 kDa). Conjugate molecular weight and purity was assessed by SEC-HPLC and MALDI-TOF MS. Bioactivity of conjugates was measured by cyclic AMP assay in T47D cells. Calcium and calcitonin levels were measured in rats following intravenous injections. Stability of conjugates was tested against serine proteases, intestinal and liver homogenates and serum. Cytotoxicity of conjugates was assessed by lactate dehydrogenase (LDH) assay and by haemolytic assay of rat red blood cells. Results showed that the two conjugates were of high purity with molecular weights similar to predictions. Both conjugates retained more than 85% bioactivity in vitro and had nanomolar EC50 values similar to sCT. While both sCT-PoIyPEG (R)(6.5) (K) and sCT-PEG(5) (K) were resistant to metabolism by serine proteases, homogenates and serum, PolyPEG (R)(6.5 K) was more so. Although both conjugates reduced serum calcium to levels similar to those achieved with sCT, PolyPEG (R)(6.5 K) extended the T-1/2 and AUC of serum sCT over values achieved with sCT-PEG and sCT itself. None of PolyPEG (R), PEG or methacrylic acid displayed significant cytotoxicity. PolyPEG (R) may therefore have potential to improve pharmacokinetic profiles of injected peptides. (C) 2008 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry R Medicine > RS Pharmacy and materia medica
Divisions:	Faculty of Science > Chemistry
Journal or Publication Title:	Journal of Controlled Release
Publisher:	Elsevier BV
ISSN:	01683659
Date:	2 April 2009
Volume:	Vol.135
Number:	No.1
Number of Pages:	9
Page Range:	pp. 51-59
Identification Number:	10.1016/j.jconrel.2008.12.014
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Science Foundation Ireland, UK's EPSRC
Grant number:	04 IN3 B575, 07/SRC/ B115
URI:	http://wrap.warwick.ac.uk/id/eprint/28167

Data sourced from Thomson Reuters' Web of Knowledge

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