Oral insulin nanoparticles with glucose-responsive release and lysosomal escape for diabetes therapy

Abstract

Oral insulin application is limited to gastrointestinal degradation and poor intestinal absorption, moreover, its formulations design lacks glucose-triggered on-demand release and is prone to induce abnormal blood glucose fluctuation. Herein, chitosan (CS) and alginate (Alg) were selected to construct functional oral insulin nanoparticles (NPs) through electrostatic interaction cross-linking, in which CS was grafted by biguanide groups (BG-CS) to improve its positive charges and hydrophilic, and also increase the proton sponge effect of NPs. Moreover, to construct glucose-responsive NPs, BG-CS was further grafted with phenylboronic acid groups (PBA) to form BG-CS-PBA, which could reversibly binding with Alg and glucose for insulin release on-demand. This work explores the critical parameter law for nanoparticle formation, in which the effective crosslinking density and network structure depend on the Alg/BG-CS-PBA stoichiometry. The optimized particle size range of NPs and the loading capacity of insulin could reach 230.2±46.3 nm 71.2±0.1%, respectively. The drug release of NPs results displayed that insulin release efficiency increased from 40.71% to 71.08% with glucose concentration increasing from 0 to 4 mg/mL, and the released insulin from the NPs maintained conformational stability. Moreover, the NPs were observed to be efficient mucus penetration and lysosomal escape capacity through confocal laser scanning microscope, yielding apparent permeability coefficients approximately 29-fold greater than those of free insulin. To sum up, the glucose-responsive NPs hold great promise for oral insulin delivery. Schematic diagram of the preparation process, characterization, drug release and cell experiment of BG-CS-PBA/Tre/INS/Alg NPs. Download: Download high-res image (439KB) Download: Download full-size image