Ryan, Sinéad M., Frías, Jesús M., Wang, Xuexuan, Sayers, Claire T., Haddleton, David M. and Brayden, David J.. (2011) PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights. Journal of Controlled Release, Vol.149 (No.2). pp. 126-132. ISSN 01683659

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Abstract

Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel comb-shaped end-functionalised (poly(PEG) methyl ether methacrylate) (sCT-P) polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of Emax and an EC50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15–30% over 240 min, the half-life (T1/2) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T1/2 for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Pharmacokinetics, Bioconjugates, Osteoporosis, Polymers
Journal or Publication Title:	Journal of Controlled Release
Publisher:	Elsevier BV
ISSN:	01683659
Date:	January 2011
Volume:	Vol.149
Number:	No.2
Page Range:	pp. 126-132
Identification Number:	10.1016/j.jconrel.2010.10.004
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Science Foundation Ireland (SFI)
Grant number:	07/SRC/B1154 (SFI)
URI:	http://wrap.warwick.ac.uk/id/eprint/36953

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