Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
College of Pharmacy, Heze University, Heze 274015, China.
Theranostics. 2024 Sep 3;14(14):5596-5607. doi: 10.7150/thno.98177. eCollection 2024.
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. To promote penetration across the intestinal epithelium and achieve enhanced and safe glucose-responsive oral insulin delivery, pH and HO dual-sensitive nanoparticles (NPs) were constructed. The NPs were loaded of glucose oxidase (GOx) and insulin by pH and HO 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. 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 HO with GOx in hyperglycemic environment, the pH and HO 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 HO dual-sensitive NPs could ameliorate the local decline of pH and rise of HO to avoid the toxic side effect. Therefore, this work would provide a promising platform for the enhanced and safe treatment of diabetes mellitus.
口服胰岛素递药被认为是一种替代每日皮下注射的革命性方法。然而，由于胰岛素在血液循环中的口服吸收较差，其口服生物利用度非常低。为了促进穿过肠上皮的渗透，并实现增强和安全的葡萄糖响应性口服胰岛素递药，构建了 pH 和 HO 双重敏感纳米颗粒 (NPs)。NPs 通过 pH 和 HO 双重敏感的两亲聚合物负载葡萄糖氧化酶 (GOx) 和胰岛素，该聚合物与苯硼酸酯偶联的聚 (2-羟乙基甲基丙烯酸酯) 和聚 (羧酸甜菜碱) (PCB) 结合。在口服给药后，双重敏感的 NPs 用于治疗 1 型糖尿病 (T1DM)。双重敏感的 NPs 可以通过两性离子 PCB 促进胰岛素穿过肠上皮进入血液的转运。由于在高血糖环境中具有 GOx，因此会产生低 pH 和高 HO，使 pH 和 HO 双重敏感的 NPs 解体，以实现胰岛素的快速和持续释放。在 T1DM 小鼠模型中，口服肠溶胶囊中的双重敏感 NPs 后，胰岛素的口服生物利用度达到 20.24%，并且 NPs 的降血糖作用比皮下注射胰岛素持续时间长几个小时。重要的是，pH 和 HO 双重敏感 NPs 可以改善局部 pH 值下降和 HO 值升高，以避免毒性副作用。因此，这项工作为增强和安全的糖尿病治疗提供了一个有前途的平台。
