Effective Enhancement of Hypoglycemic Effect of Insulin by Liver Targeted Nanoparticles Containing Cholic Acid-Modified Chitosan Derivative

Liver is responsible for the balance of blood glucose level. In this study, cholic acid and N-(2-hydroxy)-propyl-3-trimethylammonium chloride modified chitosan (HTCC-CA) was used as a liver-targeted vehicle for insulin delivery. A novel approach was developed to effectively load insulin by mixing insulin and HTCC-CA in 50% ethanol and water mixed solvent at pH 2 and then dialysis against pH 7.4 phosphate buffer subsequently against water. The insulin-loaded HTCC-CA nanoparticles have an average diameter of 86 nm and insulin loading efficiency of 98.7%. Due to random distribution of the hydrophobic cholic acid groups in HTCC-CA, some of the cholic acid groups located on the nanoparticle surface. Compared with free insulin, the nanoparticles increased in vitro cellular uptake of insulin to 466%, and the nanoparticles accumulated in liver for more time after subcutaneous injection into mice. The therapy for diabetic rats displayed that the nanoparticles increased the pharmacological bioavailability of insulin to 475% relative to free insulin, and the nanoparticles could maintain the hypoglycemic effect for more than 24 h. This study demonstrates that the nanoparticles with cholic acid groups on their surface possess liver-targeted property and biocompatible insulin-loaded HTCC-CA nanoparticles can effectively enhance the hypoglycemic effect of insulin.