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

• Published in: Journal of controlled release Vol. 313; pp. 1 - 13
• Main Authors: Ji, Na, Hong, Yan, Gu, Zhengbiao, Cheng, Li, Li, Zhaofeng, Li, Caiming
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.11.2019
• Subjects: amylose; bioavailability; biocompatibility; Caco-2; chitosan; coatings; cytotoxicity; drugs; encapsulation; endocytosis; glucose; glycemic effect; homeostasis; human cell lines; Hypoglycemic effect; in vivo studies; insulin; intestinal absorption; nanocomposites; nanoparticles; oral administration; Oral delivery; Paracellular transport; peptides; permeability; polymers; storage conditions; Tight junctions; zeta potential; EE; Tight junctions; XRD; Hypoglycemic effect; CS; CSA; PDI; Caco-2; FTIR; Paracellular transport; LC; Oral delivery; IN-Z-CSA; TEER
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2019.10.006

[Display omitted] •The nanocomposites (NPs) coating chitosan (CS) enhanced oral insulin bioavailability.•The NPs coating CS transported insulin by endocytosis and paracellular route.•The NPs coating CS are a promising delivery system for peptide/protein drugs. 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-CSA1.0% 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.