A Nanocarrier Approach for Oral Peptide Delivery: Evaluation of Cell-Penetrating-Peptide-Modified Liposomal Formulations in Dogs

Abstract

Oral delivery of peptides is severely limited by their instability and poor absorption in the gastrointestinal tract. In contrast to coadministration strategies using medium-chain fatty acids, which have recently gained regulatory approval with low oral bioavailabilities ≤ 1% (Rybelsus and Mycapssa), efforts to clinically implement delivery systems based on nanocarriers have not been successful to date. The approved drug-delivery formulations show fairly accurate correlation between clinical results and nonrodent mammal bioavailability, including Beagle dogs for Rybelsus, indicating that Beagle dogs represent a translationally relevant model. Here, a nanocarrier formulation for the oral administration of peptide therapeutics is reported with systemic targets consisting of liposomes decorated with cyclic cell-penetrating peptides, which significantly increase oral bioavailability in translationally relevant Beagle dogs. This nanocarrier formulation is optimized using the glycopeptide vancomycin, and results in a considerable oral bioavailability of 3.9%. Further, this nanocarrier system increases the oral bioavailability of the large linear peptide therapeutic exenatide 20-fold, and consistently achieves effective plasma concentrations in Beagle dogs.