Chitosan coating of zein-carboxymethylated short-chain amylose nanocomposites improves oral bioavailability of insulin in vitro and in vivo

摘要

Non-invasive means of insulin administration circumvent some of the inconveniences of injections. Oral administration in particular is convenient, pain-free, and allows favorable glucose homeostasis, but is subject to chemical instability, enzymatic degradation, and poor gastrointestinal absorption. Natural polymeric nanoparticles have emerged as a promising oral delivery system for peptide therapeutics due their safety, biocompatibility, and stability. In this study, self-assembled nanocomposites from chitosan (CS) and insulin-loaded, zein-carboxymethylated short-chain amylose (IN-Z-CSA) nanocomposites were synthesized to improve oral bioavailability of insulin. The optimized IN-Z-CSA/CS0.2% nanocomposites exhibited an average size of 311.32 +/- 6.98 nm, a low polydispersity index (0.227 +/- 0.01), a negative zeta potential (43.77 +/- 1.36 mV), an encapsulation efficiency of 89.6 +/- 0.9%, and a loading capacity of 6.8 +/- 0.4%. The IN-Z-CSA/CS0.2% nanocomposites were stable in storage conditions. The transepithelial permeability of the N-Z-CSA/CS0.2% nanocomposites was 12-fold higher than that of insulin. Cellular uptake studies revealed that the IN-Z-CSA/CS0.2% nanocomposites were internalized into Caco-2 cells by both endocytosis and a paracellular route. Additionally, in pharmacological studies, orally administered IN-Z-CSA/CS0.2% nanocomposites had a stronger hypoglycemic effect with a relative bioavailability of 15.19% compared with that of IN-Z-CSA(1.0%) nanocomposites. Furthermore, cell toxicity and in vivo tests revealed that the IN-Z-CSA/CS0.2% nanocomposites were biocompatible. Overall, these results indicate that the IN-Z-CSA/CS0.2% nanocomposites can improve oral bioavailability of insulin and are a promising delivery system for insulin or other peptide/protein drugs.