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• W3137703170 abstract "Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery." @default.
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• W3137703170 date "2021-01-01" @default.
• W3137703170 modified "2023-09-27" @default.
• W3137703170 title "Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery" @default.
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• W3137703170 doi "https://doi.org/10.7150/thno.54176" @default.
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