Oral delivery of berberine by liver-targeted zwitterionic nanoparticles to overcome multi-intestinal barriers and extend insulin treatment duration
CHEMICAL ENGINEERING JOURNAL(2024)
Abstract
Oral insulin is a promising strategy due to its favorable patient compliance and repeatable administration, while it faces with critical problem of multi-intestinal barriers. Moreover, the restricted oral bioavailability necessitates long-term administration of high-dose insulin and could increase the risk of hypoglycemia and insulin resistance. In this study, oral delivery of berberine by liver-targeted zwitterionic nanoparticles (ACU@BI) was designed to overcome multi-intestinal barriers and extend insulin treatment duration. Ursodeoxycholic acid (UDCA) and carboxy betaine (CB) modification endowed ACU@BI with the ability to penetrate mucus and target the apical and basolateral side of enterocytes, respectively, which jointly overcame multi-intestinal barriers. In vivo experiments indicated that the sustained release and prolonged circulation of insulin and berberine in the intestinal tract synergistically maintained the hypoglycemic effect (approximately 10 h) and avoided the risk of hypoglycemia after oral administration of ACU@BI with lowered dosage (insulin: 25 U/kg). Moreover, the oral codelivery of berberine by ACU@BI reversed insulin resistance mainly via not only the facilitation of the AMPK/ AKT/IRS-1 signaling pathway, but also the suppression of GSK3-8 activity that was found for the first time, thereby ultimately extended the duration of insulin therapy. Therefore, berberine-loaded liver-targeted zwitterionic nanoparticles may provide a prospective oral therapeutic diabetes strategy for clinical practice.
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Key words
Oral diabetes treatment,Low dosage,Berberine,Carboxy betaine,Ursodeoxycholic acid,Insulin resistance
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