PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights
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 01683659Full text not available from this repository.
Official URL: http://dx.doi.org/10.1016/j.jconrel.2010.10.004
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|
|Official Date:||January 2011|
|Page Range:||pp. 126-132|
|Access rights to Published version:||Restricted or Subscription Access|
|Funder:||Science Foundation Ireland (SFI)|
|Grant number:||07/SRC/B1154 (SFI)|
Actions (login required)