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

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Title: PK/PD modelling of combed-shaped PEGylated salmon calcitonin conjugates of differing molecular weights
Authors: Ryan, Sinéad M.
Frías, Jesús M.
Wang, Xuexuan
Sayers, Claire T.
Haddleton, David M.
Brayden, David James
Permanent link: http://hdl.handle.net/10197/3020
Date: 20-Jan-2011
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.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier
Copyright (published version): 2010 Elsevier B.V.
Keywords: Salmon calcitonin;PEGylation;Comb-shaped polymers;Conjugated peptides;;Osteoporosis;Pharmacokinetic modelling;
Subject LCSH: Calcitonin
Peptides
Pharmacokinetics
Polymers
Bioconjugates
Osteoporosis
DOI: 10.1016/j.jconrel.2010.10.004
Language: en
Status of Item: Peer reviewed
Appears in Collections:Irish Drug Delivery Network Research Collection

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