PK/PD modelling of combed-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

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Show simple item record Ryan, Sinéad M. Frías, Jesús M. Wang, Xuexuan Sayers, Claire T. Haddleton, David M. Brayden, David James 2011-07-19T13:41:40Z 2011-07-19T13:41:40Z 2010 Elsevier B.V. en 2011-01-20
dc.identifier.citation Journal of Controlled Release en
dc.identifier.issn 0168-3659
dc.description.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. en
dc.description.sponsorship Science Foundation Ireland en
dc.format.extent 1205289 bytes
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Elsevier en
dc.rights This is the author’s version of a work that was accepted for publication in Journal of Controlled Release. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Controlled Release, Volume 149, Issue 2, 20 January 2011, Pages 126-132, DOI: 10.1016/j.jconrel.2010.10.004 en
dc.subject Salmon calcitonin en
dc.subject PEGylation en
dc.subject Comb-shaped polymers en
dc.subject Conjugated peptides; en
dc.subject Osteoporosis en
dc.subject Pharmacokinetic modelling; en
dc.subject.lcsh Calcitonin en
dc.subject.lcsh Peptides en
dc.subject.lcsh Pharmacokinetics en
dc.subject.lcsh Polymers en
dc.subject.lcsh Bioconjugates en
dc.subject.lcsh Osteoporosis en
dc.subject.mesh Calcitonin en
dc.subject.mesh Polymers en
dc.subject.mesh Peptides en
dc.subject.mesh Pharmacokinetics en
dc.subject.mesh Polymers en
dc.subject.mesh Osteoporosis--drug therapy en
dc.title PK/PD modelling of combed-shaped PEGylated salmon calcitonin conjugates of differing molecular weights en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.status Peer reviewed en
dc.identifier.volume 149 en
dc.identifier.issue 2 en
dc.identifier.startpage 126 en
dc.identifier.endpage 132 en
dc.identifier.doi 10.1016/j.jconrel.2010.10.004
dc.neeo.contributor Ryan|Sinéad M.|aut|
dc.neeo.contributor Frías|Jesús M.|aut|
dc.neeo.contributor Wang|Xuexuan|aut|
dc.neeo.contributor Sayers|Claire T.|aut|
dc.neeo.contributor Haddleton|David M.|aut|
dc.neeo.contributor Brayden|David James|aut|

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