pH and H2O2 dual-sensitive nanoparticles enable enhanced and safe glucose-responsive oral insulin delivery for diabetes mellitus treatment

Background: Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injection. However, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Methods: To promote penetration across the intestinal epithelium and achieve enhanced and safe glucose-responsive oral insulin delivery, pH and H 2 O 2 dual-sensitive nanoparticles (NPs) were constructed. The NPs were loaded of glucose oxidase (GOx) and insulin by pH and H 2 O 2 dual-sensitive amphiphilic polymer incorporated with phenylboronic ester-conjugated poly(2-hydroxyethyl methacrylate) and poly(carboxybetaine) (PCB). The dual-sensitive NPs were utilized for the treatment of type 1 diabetes mellitus (T1DM) after oral administration. Results: The dual-sensitive NPs could enhance the transport of insulin across the intestinal epithelium into blood facilitated by zwitterionic PCB. By virtue of the generated low pH and high H 2 O 2 with GOx in hyperglycemic environment, the pH and H 2 O 2 dual-sensitive NPs were disassembled to achieve rapid and sustained release of insulin. After oral administration of the dual-sensitive NPs in enteric capsules into T1DM mouse model, the oral bioavailability of insulin reached 20.24%, and the NPs achieved hypoglycemic effect for a few hours longer than subcutaneously injected insulin. Importantly, the pH and H 2 O 2 dual-sensitive NPs could ameliorate the local decline of pH and rise of H 2 O 2 to avoid the toxic side effect. Conclusion: Therefore, this work would provide a promising platform for the enhanced and safe treatment of diabetes mellitus.

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