Oral delivery of therapeutic peptides and proteins is hampered by their poor enzymatic stability and large molecular size, thus limiting their permeation across the intestinal epithelium. A promising approach to overcome the latter is by co-administration with carrier-peptides, such as the cell-penetrating peptides (CPPs). Two approaches for the carrier peptide-mediated transepithelial permeation of biopharmaceuticals are generally explored: Co-administration1 or covalent conjugation2. Co-administration is often the method of choice due to e.g. ease in sample preparation and flexibility in adjustment of the molar mixing ratio between the carrier peptide and the therapeutic cargo, whereas the direct conjugation approach ensures an inherent proximity of the carrier peptide to its therapeutic cargo. So far studies addressing the choice of using the co-administration approach over the conjugation approach, or vice versa, are limited.
Thus, the objective of the present research was to investigate the effect of co-administration versus direct conjugation with respect to transepithelial permeation efficiency and cellular viability. The 34-residue pharmacologically active part of parathyroid hormone (PTH(1-34)) and the widely studied CPP penetratin were employed as therapeutic cargo and carrier peptide, respectively.