Oral insulin delivery by epithelium microenvironment-adaptive nanoparticles
Oral protein drug delivery using nano-based systems remains challenging, as contradictory surface properties are required for efficient navigation through the intestinal mucus and epithelium barriers. Therefore, new nanoplatforms with tunable surface properties in vivo are urgently needed. Inspired by the slightly acidic microclimate of the jejunal epithelial surface, we report a novel epithelium microenvironment-adaptive nanoplatform that undergoes a hydrophilicity-hydrophobicity transition at the epithelial surface.
Highlights
Biodegradable pH-sensitive nanoparticles-loaded capsules were prepared for effective oral insulin delivery.
The hydrophilicity/hydrophobicity balance of PLGA-Hyd-PEG NPs was reversed in the acidic microenvironment of jejunal epithelial surface.
PLGA-Hyd-PEG NPs promoted oral insulin delivery due to their excellent mucus penetration and cell internalization.
First, we synthesized and characterized a biodegradable copolymer consisting of PEG and PLGA building blocks linked by a hydrazone bond (PLGA-Hyd-PEG) to fabricate the pH-sensitive core-shell architecture of an oral insulin system. Then we loaded the system as a freeze-dried powder into enteric-coated capsules. PLGA-Hyd-PEG nanoparticles showed excellent drug protection and rapid mucus penetration owing to the high stability of the PEG coating in jejunal fluid. In the acidic microenvironment of the jejunal epithelial surface (pH ~5.5), PEG was rapidly cleaved and the hydrazone bond was hydrolyzed, converting the nanoparticle surface from hydrophilic to hydrophobic, thereby facilitating internalization into cells.
Pharmacodynamic studies showed that PLGA-Hyd-PEG nanoparticles resulted in significant decrease in blood glucose level after intrajejunal administration in both normal and diabetic rats relative to control nanoparticles. In addition, enteric-coated capsules containing PLGA-Hyd-PEG nanoparticles reduced blood glucose by 35% for up to 10 h after oral administration to diabetic rats. Our findings provide a new strategy for regulating the surface properties of nanoparticles for efficient oral drug delivery.
Article information: Jianbo Li, Hong Qiang, Weijing Yang, Yaru Xu, Tiange Feng, Huijie Cai, Shuaishuai Wang, Zhilei Liu, Zhenzhong Zhang, Jinjie Zhang, Oral insulin delivery by epithelium microenvironment-adaptive nanoparticles, Journal of Controlled Release, 2021. https://doi.org/10.1016/j.jconrel.2021.11.020.