PHEA-graft-polymethacrylate supramolecular aggregates for protein oral delivery

Salmon calcitonin (sCT) is characterized by a poor oral availability. A new copolymer, β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide (PHEA-IB-p(MANa+)), was designed for the oral administration of sCT through the formation of supramolecular aggregates (SAs) based on electrostatic interactions. Several sCT/PHEA-IB-p(MANa+) weight ratios were characterized by turbidimetry, DLS, zeta potential, and microscopy analysis. After the incubation of sCT/PHEA-IB-p(MANa+) complex with digestive enzymes, 10% (w/w) of loaded sCT was released in the native form. In vitro investigation was carried out to determine the copolymer effect on the permeability of sCT in Caco-2 cell monolayers. sCT pharmacokinetic profile and the pharmacodynamic effect on calcium plasma level were determined following an oral administration of the lead sCT/PHEA-IB-p(MANa+) SA (1/5 ratio) in rats. The SA yielded a marked prolongation of the sCT lowering calcium effect. The maximum decrease, 35% with respect the basal calcium plasma level at time 0 h, was achieved after 4 h post-administration, and after 7 h, a decrease of 20% was still present. Differently, sCT yielded a transient calcium decrease that was completely restored after 5 h. The higher bioavailability of sCT administered as SA was confirmed by the pharmacokinetic studies. In fact, the AUC and the Cmax were about 15 times higher for the sCT formulated as SA than the free sCT. This study indicates the potentials of PHEA-IB-p(MANa+) as carrier of sCT for oral delivery.

Graphical abstractThe anionic copolymer PHEA-IB-p(MANa+) resulted a promising material for the oral delivery of positively charged polypeptides such as sCT as delivery system based on electrostatic interactions. This drug delivery system can be easily and effectively applied to others positively charged peptides.Figure optionsDownload full-size imageDownload high-quality image (99 K)Download as PowerPoint slide