Document Type

Article

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

Polymer science, Pharmacology and pharmacy

Publication Details

Ryan S. M., Frías J.M., Haddleton, DH & Brayden, DJ (2010) PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights. Journal of Controlled Release. 149(2) 126-132

doi:10.1016/j.jconrel.2010.10.004

Abstract

Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped end-functionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped 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 and an EC50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 20-30 % in 240 min, the half life (T½) was increased and 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 T½ of 8 hr, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

DOI

10.1016/j.jconrel.2010.10.004

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