A Metal-organic Framework Based Nanoplatform For Glucose-responsive Insulin Delivery

Diabetes mellitus,as a common disease which seriously affects the healthy life of many people,has been paid much attention.The miserable fact is that more and more people are suffering from diabetes.Insulin,as the most important drug to decrease blood glucose levels,is widely used in the treatment of diabetes.However,the insufficient content of insulin in the mammals with diabetes will lead to the high blood glucose levels,and the overdose of insulin in lives is easy to result in hypoglycemia and a series of adverse effects.Therefore,it is very important to develop a“closed-loop”insulin delivery system that mimics islet beta cells(which dynamically secret insulin in response to glucose)for the treatment of type 1 diabetes and advanced type 2 diabetes.In order to achieve intelligent insulin delivery,we developed a glucoseresponsive nanoplatform based on MOF.GR@ZIF-8 nanoparticles,coated with GOD,CAT and Ins,were successfully synthesized by a pot of biomineralization.The synthesis condition is mild,the experimental procedure is simple and the experimental operation is easy.ZIF-8 nanoparticles can protect the activities of GOD,CAT and Ins,and it can be dissolved in weak acid environment.GOD and CAT consist of glucose-response module.In particular,when GOD is in aerobic condition,it can catalyze glucose convert into glucose acid and hydrogen peroxide.The glucose acid can increase the acidity of solution.When the concentration of glucose acid accumulated to a certain degree,the pH of the solution will change inducing the decomposition of GR@ZIF-8 nanoparticles.As a result,GR@ZIF-8 nanoparticles will release insulin.The hydrogen peroxide can respond with the CAT,generating oxygen which can be used as a GOD catalytic glucose supply.Ins is a hypoglycemic drug for the treatment of diabetes.First of all,the synthesized GR@ZIF-8 nanoparticles were characterized for the confirm of the morphology and surface charge.And we also prove that the GR@ZIF-8 nanoparticles successfully encapsulate GOD,CAT and Ins.It means that the GR@ZIF-8 nanoparticles are suitable for further study.We test the activities of GOD and CAT in GR@ZIF-8 nanoparticles via mimicking the environment of the internal body in vitro.We also prove that the GR@ZIF-8 nanoparticles will be dissolved in weak acid solution and it can response with glucose.Second,we investigated the therapeutic effect of GR@ZIF-8 nanoparticles on mice with type 1 diabetes.Specifically,by investigating the change of blood glucose levels at 12 h and 60 h in mice with type 1 diabetes treated with GR@ZIF-8 nanoparticles and studying the anti-hypoglycemic risk ability in healthy mice treated with GR@ZIF-8 nanoparticles,we preliminarily prove the therapeutic effect of GR@ZIF-8 nanoparticles.The cytotoxicity of GR@ZIF-8 nanoparticles and the pathological analysis of the main organs of mice who were injected GR@ZIF-8 nanoparticles for two weeks confirmed that the GR@ZIF-8 nanoparticles had no obvious toxic and side effects on the main organs of mice.In conclusion,the comprehensive analysis in vitro and in vivo shows that we successfully built the intelligence of glucose-responsive platform for insulin delivery,which can be used in the treatment of mice with type 1 diabetes.It can maintain the normal blood glucose levels in mice with type 1 diabetes,at the same time,it can reduce the risk of hypoglycemia caused by too much insulin supplies.