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

Yaqiong Chen; Hongdong Song; Xinyue Wang; Ruihan Huang; Sen Li; Xiao Guan

doi:10.1016/j.ijbiomac.2024.139159

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

Int J Biol Macromol. 2024 Dec 24:139159. doi: 10.1016/j.ijbiomac.2024.139159. Online ahead of print.

Authors

Yaqiong Chen¹, Hongdong Song², Xinyue Wang³, Ruihan Huang³, Sen Li², Xiao Guan⁴

Affiliations

¹ School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
² School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China.
³ School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
⁴ School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China. Electronic address: gnxo@163.com.

PMID: 39725095
DOI: 10.1016/j.ijbiomac.2024.139159

Abstract

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.

Keywords: Chitosan; Hydrogel nanoparticles; Insulin; MCT1-targeting; Oral delivery.