An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs,Nature Nanotechnology

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An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs
Nature Nanotechnology ( IF 38.1 ) Pub Date : 2024-09-02 , DOI: 10.1038/s41565-024-01764-5
Kangfan Ji _{1,

2} , Xiangqian Wei _{1,

2} , Anna R Kahkoska ₃ , Juan Zhang _{1,

2} , Yang Zhang _{1,

2} , Jianchang Xu _{1,

2} , Xinwei Wei _{1,

2} , Wei Liu _{1,

2} , Yanfang Wang _{1,

2} , Yuejun Yao _{1,

2} , Xuehui Huang _{1,

2} , Shaoqian Mei _{1,

2} , Yun Liu _{1,

2} , Shiqi Wang _{1,

2} , Zhengjie Zhao _{1,

2} , Ziyi Lu _{1,

2} , Jiahuan You _{1,

2} , Guangzheng Xu _{1,

2} , Youqing Shen ₄ , John B Buse ₅ , Jinqiang Wang _{1,

2,

6,

7} , Zhen Gu _{1,

2,

6,

8,

9,

10,

11}

Affiliation

State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Jinhua Institute of Zhejiang University, Jinhua, China.
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Liangzhu Laboratory, Hangzhou, China.
Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, China.
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.

Contrary to current insulin formulations, endogenous insulin has direct access to the portal vein, regulating glucose metabolism in the liver with minimal hypoglycaemia. Here we report the synthesis of an amphiphilic diblock copolymer comprising a glucose-responsive positively charged segment and polycarboxybetaine. The mixing of this polymer with insulin facilitates the formation of worm-like micelles, achieving highly efficient absorption by the gastrointestinal tract and the creation of a glucose-responsive reservoir in the liver. Under hyperglycaemic conditions, the polymer triggers a rapid release of insulin, establishing a portal-to-peripheral insulin gradient—similarly to endogenous insulin—for the safe regulation of blood glucose. This insulin formulation exhibits a dose-dependent blood-glucose-regulating effect in a streptozotocin-induced mouse model of type 1 diabetes and controls the blood glucose at normoglycaemia for one day in non-obese diabetic mice. In addition, the formulation demonstrates a blood-glucose-lowering effect for one day in a pig model of type 1 diabetes without observable hypoglycaemia, showing promise for the safe and effective management of type 1 diabetes.

中文翻译：

一种口服葡萄糖反应性聚合物复合物，可在小鼠和猪中高效、安全地输送胰岛素

与目前的胰岛素制剂相反，内源性胰岛素可以直接进入门静脉，调节肝脏中的葡萄糖代谢，低血糖最低。在这里，我们报道了一种两亲性二嵌段共聚物的合成，该共聚物包含葡萄糖响应性带正电荷的链段和聚羧基甜菜碱。这种聚合物与胰岛素的混合促进了蠕虫状胶束的形成，实现了胃肠道的高效吸收，并在肝脏中建立了葡萄糖反应性储存库。在高血糖条件下，聚合物触发胰岛素的快速释放，建立门户到外周胰岛素的梯度（类似于内源性胰岛素），以安全调节血糖。这种胰岛素制剂在链脲佐菌素诱导的 1 型糖尿病小鼠模型中表现出剂量依赖性血液葡萄糖调节作用，并在非肥胖糖尿病小鼠中控制正常血糖一天的血糖。此外，该制剂在 1 型糖尿病猪模型中显示出一天的降血糖作用，没有观察到的低血糖，显示出安全有效管理 1 型糖尿病的前景。

更新日期：2024-09-02

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