Success in Navigating Hurdles to Oral Delivery of a Bioactive Peptide Complement Antagonist through Use of Nanoparticles to Increase Bioavailability and In Vivo Efficacy

Abstract Substantial preclinical data have validated cyclic hexapeptide complement C5a receptor 1 antagonists (C5aRAs) that target immune cells, as novel therapies for a range of inflammatory diseases that currently have limited effective treatment options. However, like most small‐molecule peptides, their poor oral bioavailability and short circulation half‐life are major hurdles that have limited their clinical translation. Here, a single emulsion technique is employed to produce poly(lactic‐ co ‐glycolic) acid nanoparticles (NPs) with exceptionally high peptide C5aRA (PMX205) loading efficiency (over 50%). Strikingly, the PMX205‐NPs not only facilitate prolonged release of the encapsulated PMX205 but also dramatically increase its oral bioavailability (from ≈25% to ≈50%), and therapeutic potential (≈95% inhibition of C5a induces neutrophilia in mice and maintenance of neuroprotective barrier integrity). The enhanced in vivo pharmacological activity of PMX205 in the form of NPs opens an exciting opportunity for the clinical application of peptide C5aRAs and possibly other therapeutic peptides.