Abstract
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 239 nm, 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 24 h 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.
Highlights
Diabetes mellitus is a worldwide chronic disease and an estimated 415 million people had diabetes worldwide as of 2015 (IDF Diabetes Atalas, 2017)
Cyanine5 NHS ester (Cy5)-INS/HTCC-CA, Cy5-labeled insulin (Cy5-INS)/HTCC/hydroxypropyl methylcellulose phthalate (HPMCP), and Cy5-INS/HTCCCA/HPMCP nanoparticles were orally administrated at insulin dose of 30 IU/kg
We developed innovative INS/HTCC-CA/HPMCP nanoparticles for oral and liver-targeted delivery of insulin
Summary
Diabetes mellitus is a worldwide chronic disease and an estimated 415 million people had diabetes worldwide as of 2015 (IDF Diabetes Atalas, 2017). Insulin, secreted by pancreas, is the only hormone in human body that can reduce BGL (blood glucose level) directly (Saltiel & Kahn, 2001, Edgerton et al, 2006). As the primary acting site of insulin, liver plays a major role in carbohydrate metabolism and takes the responsibility for the balance of BGL by means of glycogenogenesis and glycogenolysis (Pessin & Saltiel, 2000; Arbit, 2004; Edgerton et al, 2006). Subcutaneously injected insulin enters into the general circulation directly, which exposes all tissues to the same insulin concentration and the liver only receives a small fraction of the injected dose; muscles and adipocytes can react to the insulin without hepatic monitoring, and side effects such as atherosclerosis, hypoglycemia and weight gain may occur (Arbit, 2004; Geho et al, 2009)
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