Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles enhance the oral absorption and hypoglycemic effect of insulin

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2021-08, Vol.9 (31), p.6234-6245
• Main Authors: Bao, Xiaoyan, Qian, Kang, Yao, Ping
• Format: Article
• Language: English
• Subjects: Absorption; Acids; Administration, Oral; Alloxan; Animals; Bioavailability; Biological Availability; Casein; Caseins - administration & dosage; Caseins - pharmacology; Cholic acid; Cholic Acid - administration & dosage; Cholic Acid - pharmacology; Cycloheximide; Dextran; Dextrans; Dextrans - administration & dosage; Dextrans - pharmacology; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - drug therapy; Gastric juice; Hydrophobicity; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Ileum; Insulin; Insulin - administration & dosage; Insulin - metabolism; Insulin - pharmacology; Intestine; Liver; Maillard reaction; Male; Materials Testing; Metabolic disorders; Mice; Mice, Inbred ICR; Nanoparticles; Nanoparticles - chemistry; Optical Imaging; Permeability; Surface chemistry; Zein; Zein - administration & dosage; Zein - pharmacology
• ISSN: 2050-750X; 2050-7518
• DOI: 10.1039/d1tb00806d

Diabetes mellitus is the most common metabolic disease in the world. Herein, insulin- and cholic acid-loaded zein nanoparticles with dextran surfaces were fabricated to enhance the oral absorptions of insulin in the intestine and in the liver which is the primary action organ of endogenous insulin. In the nanoparticles, zein acted as cement to embed insulin, cholic acid and casein by hydrophobic interactions. The hydrophilic dextran conjugated to casein by the Maillard reaction was located on the nanoparticle surface. The nanoparticles had an insulin loading efficiency of 74.6%, a cholic acid loading efficiency of 55.1% and a hydrodynamic diameter of 267 nm. The dextran significantly increased the disperse stability of the nanoparticles, protected the loaded insulin from hydrolysis in digestive juices, and increased the trans-mucus permeability of the insulin. The embedded cholic acid molecules were consecutively exposed to the surface when the nanoparticles were gradually eroded by proteases. The exposed cholic acid promoted the absorptions of the nanoparticles in the ileum and liver via bile acid transporters. The effect of pretreated lymphatic transport inhibitor cycloheximide revealed that about half of the nanoparticles were transported via the intestinal lymphatic transport pathway and the other half of the nanoparticles were transported via portal blood absorption. The oral pharmacological bioavailability of the nanoparticles in type I diabetic mice was 12.5-20.5%. This study demonstrates that nanoparticles are a promising oral delivery system for insulin. Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles increase the trans-mucus permeability, intestinal and hepatic absorptions, and lymphatic transport of the loaded insulin via bile acid transporters.