Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V
Sofie TrierThomas Lars Andresen

Abstract

Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate its influence on intestinal cell translocation and membrane interaction. We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain provides 6- or 9-fold increase in pept...Continue Reading

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Citations

Sep 10, 2019·Expert Opinion on Drug Delivery·Sadia SikderDhananjay Pal
Dec 24, 2018·Journal of Controlled Release : Official Journal of the Controlled Release Society·Romel Menacho-MelgarMichael D Lynch
Jul 24, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Ragna Guldsmed DiedrichsenHanne Mørck Nielsen

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