Lipid-based nanocarriers for oral delivery of peptides

Therapeutic peptides can treat a wide variety of diseases with selective and potent action. Their oral bioavailability is strongly limited by an important proteolytic activity in the intestinal lumen and poor permeation across the intestinal border. We have evaluated the capacity of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to overcome both oral bioavailability limiting aspects, using leuprolide (LEU) as model peptide. Lipidization of LEU by formation of a hydrophobic ion pair (HIP) with sodium docusate enables a significant increase of peptide encapsulation efficiency in both SLN and NLC. The nanocarriers, obtained by high-pressure homogenization, measured 120 nm and were platelet shaped. Regarding the protective effect towards proteolytic degradation, only NLC maintained LEU integrity in presence of trypsin. Intestinal transport, evaluated on Caco-2 (enterocyte-like model) and Caco-2/HT29-MTX (mucin-secreting model) monolayers, showed nanocarriers internalization by enterocytes but no improvement of LEU permeability. Indeed, the combination of nanoparticles platelet-shape with the poor stability of the HIP in the transport medium induces a high burst release of the peptide, limiting nanoparticles capacity to transport LEU across the intestinal border. Stability of peptide lipidization needs to be improved to withstand biorelevant medium to benefit from the advantages of encapsulation in solid lipid nanocarriers and consequently improve their oral bioavailability.