Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Liver is the primary acting site of insulin. In this study, we developed innovative nanoparticles for oral and liver-targeted delivery of insulin by using enterohepatic circulation of bile acids. The nanoparticles were produced from cholic acid and quaternary ammonium modified chitosan derivative and hydroxypropyl methylcellulose phthalate (HPMCP). The nanoparticles had a diameter of 239nm, an insulin loading efficiency of 90.9%, and a loading capacity of 18.2%. Cell culture studies revealed that the cholic acid groups effectively enhanced the transport of the nanoparticles through Caco-2 cell monolayer and greatly increased the absorption of the nanoparticles in HepG-2 cells via bile acid transporter mechanism. Ex vivo fluorescence images of ileum section, gastrointestinal tract, and liver demonstrated that the HPMCP increased the mucoadhesion of the nanoparticles in ileum, and the cholic acid groups facilitated the absorptions of the nanoparticles in both ileum and liver by use of bile acid transporters via enterohepatic circulation of bile acids. The therapy for diabetic mice displayed that the oral nanoparticle group could maintain hypoglycemic effect for more than 24h and its pharmacological availability was about 30% compared with the insulin injection group. For the first time, this study demonstrates that using enterohepatic circulation of bile acids is an effective strategy for oral delivery of insulin.