Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route

Solid lipid nanoparticles (SLN) could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport. Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment. They are mainly transported by oligopeptide transporter-1 (PepT-1) which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption. Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway. This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation. Herein, two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1 (GLP-1) analogue exenatide as model drugs. These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6 mice and type II diabetic KKAy mice. Compared with un-modified SLN, dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake. Interestingly, after internalization, more SLN could access the systemic circulation via lymphatic transport pathway, highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.