Effective oral delivery of Exenatide-Zn²⁺ complex through distal ileum-targeted double layers nanocarriers modified with deoxycholic acid and glycocholic acid in diabetes therapy.

The oral administration route is popular with T2DM patients because they need convenience in lifelong medication. At present, oral Exenatide is not available on the market and therefore the relevant studies are valuable. Herein, we constructed a novel dual cholic acid-functionalized nanoparticle for oral delivery of Exenatide, which was based on the functionalized materials of deoxycholic acid-low molecular weight protamine and glycocholic acid-poly (ethylene glycol)-b-polysialic acid. The hydrophobic deoxycholic acid strengthened the nanoparticles and the hydrophilic glycolic acid targeted to specific transporter. We first condensed Exenatide-Zn complex with deoxycholic acid-low molecular weight protamine to prepare nanocomplexes with ζ-potentials of +8 mV and sizes of 95 nm. Then, we used glycocholic acid-poly (ethylene glycol)-b-polysialic acid copolymers masking the positive charge of nanocomplexes to prepare nanoparticles with negative charges of -22 mV and homogeneous sizes of 140 nm. As a result, this dual cholic acid-functionalized nanoparticle demonstrated enhanced uptake and transport of Exenatide, and a special targeting to apical sodium-dependent cholic acid transporter in vitro. Moreover, in vivo studies showed that the nanoparticle effectively accumulated in distal ileum, raised the plasma concentration of Exenatide, prolonged hypoglycemic effect, reduced blood lipid levels, and lightened organ lesions.