Propionate-functionalized chitosan hydrogel nanoparticles for effective oral delivery of insulin

• Published in: International journal of biological macromolecules 2025-02, Vol.291, p.139159, Article 139159
• Main Authors: Chen, Yaqiong, Song, Hongdong, Wang, Xinyue, Huang, Ruihan, Li, Sen, Guan, Xiao
• Format: Article
• Language: English
• Subjects: Chitosan; Hydrogel nanoparticles; Insulin; MCT1-targeting; Oral delivery
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.139159

Oral delivery of macromolecular drugs is often hampered by the harsh gastrointestinal environment, which makes the drugs have poor bioavailability. Insulin, the most used drug for diabetes, also faces the same challenge for oral administration. Hence, we decorated microbial metabolite propionate on chitosan (CS) to fabricate insulin-loaded propionate-modified CS hydrogel nanoparticles (IN-CS/PA HNPs). The prepared IN-CS/PA HNPs exhibited high encapsulation efficiency (> 95 %) and loading capacity (∼10 %) for insulin. The system provided better protection for insulin in gastrointestinal environment compared to unmodified IN-CS HNPs. Moreover, the active functional group of propionate can be recognized and transported by mono-carboxylate transporter protein 1 (MCT1) targeting. Thus, in both Caco-2 cells and the ligated intestinal loops of rats, IN-CS/PA HNPs significantly improved permeability and uptake of insulin on intestinal epithelium, which was attributed to MCT1-mediated endocytosis. In type 1 diabetic (T1D) rats, oral delivery of IN-CS/PA HNPs with 60 IU/kg insulin led to more stable and long-lasting hypoglycemic effect than a 5IU/kg dose of subcutaneously injected insulin. It also generated 2.29-fold and 11.88-fold higher relative oral bioavailability compared with empty IN-CS HNPs and free insulin, respectively. This study demonstrated that propanoic acid-functionalized chitosan hydrogel nanoparticles could improve the oral absorption of insulin by overcoming multiple barriers in gastrointestinal tract, providing a promising active targeting strategy for the oral delivery of macromolecules drugs. A novel bioinspired platform of IN-CS/PA HNPs was developed for oral delivery of insulin. Propanoic acid was used as a targeting ligand to modify CS to form CS/PA, which was used as a material to fabricate hydrogel nanoparticles IN-CS/PA HNPs by ionotropic gelation. This structural optimization of CS, on the one hand, improved the stability of CS under acidic conditions, allowing IN-CS/PA HNPs to provide better protection for insulin in the gastric acid environment. On the other hand, the grafting of propanoic acid endowed IN-CS/PA HNPs with the potential to increase intestinal permeability and uptake of insulin by MCT1-mediated endocytosis. Consequently, IN-CS/PA HNPs displayed superior and sustained hypoglycemic effects in T1D rats after oral administration. [Display omitted] •A novel bioinspired delivery platform was developed for oral delivery of insul