Oral delivery of insulin with intelligent glucose-responsive switch for blood glucose regulation

Xia Zhou,Yanhua Xia,Pei Wang,Yuanyuan Cai,Yuangang Liu,Hongwei Wu,Ruimin Long,Duanhua Cai,Yifeng Lei,Shibin Wang,Haiwang Huang

doi:10.1186/s12951-020-00652-z

Abstract

BackgroundThe traditional treatment for diabetes usually requires frequent insulin injections to maintain normoglycemia, which is painful and difficult to achieve blood glucose control.ResultsTo solve these problems, a non-invasive and painless oral delivery nanoparticle system with bioadhesive ability was developed by amphipathic 2-nitroimidazole–l-cysteine–alginate (NI–CYS–ALG) conjugates. Moreover, in order to enhance blood glucose regulation, an intelligent glucose-responsive switch in this nanoparticle system was achieved by loading with insulin and glucose oxidase (GOx) which could supply a stimulus-sensitive turnover strategy. In vitro tests illustrated that the insulin release behavior was switched “ON” in response to hyperglycemic state by GOx catalysis and “OFF” by normal glucose levels. Moreover, in vivo tests on type I diabetic rats, this system displayed a significant hypoglycemic effect, avoiding hyperglycemia and maintaining a normal range for up to 14 h after oral administration.ConclusionThe stimulus-sensitive turnover strategy with bioadhesive oral delivery mode indicates a potential for the development of synthetic GR-NPs for diabetes therapy, which may provide a rational design of proteins, low molecular drugs, as well as nucleic acids, for intelligent releasing via the oral route.

Highlights

More than 425 million people suffered from diabetes mellitus (DM) in the world in 2017 according to a report from the 8th edition of the International Diabetes Federation (IDF) Diabetes Atlas, making the management of diabetes one of the largest worldwide health challenges [1]
L-cysteine was first conjugated to the backbone of protonated alginate to obtain CYS–ALG conjugate, including multiple thiol groups that can enhance bioadhesive ability of the glucose-responsive nanoparticles (GR-NPs), which have a capability to prolong the resistant time of drug in the epithelia
CYS–ALG was covalently modified by the NI derivative, which could be bio-reduced from hydrophobic to hydrophilic under hypoxic conditions, to provide hypoxia-sensitive ability

Summary

Introduction

More than 425 million people suffered from diabetes mellitus (DM) in the world in 2017 according to a report from the 8th edition of the International Diabetes Federation (IDF) Diabetes Atlas, making the management of diabetes one of the largest worldwide health challenges [1]. Significant developments have been made in insulin therapy over the past few decades through traditional care, i.e. subcutaneous injection for people with diabetes, which often is lacking adequate control of blood glucose and includes painful injections to maintain normoglycemia [6], there is need to explore a non-invasive insulin delivery system for diabetes therapy. Various strategies have emerged to be studied, such as a nasal management route, lung drug delivery, micro-array patch and so on. Those strategies are currently lacking due to low drug penetration, cilia scavenging effect, indeterminate biological safety and inconvenient management, which means they are not optimal for drug delivery of insulin. The traditional treatment for diabetes usually requires frequent insulin injections to maintain normoglycemia, which is painful and difficult to achieve blood glucose control

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Results

Conclusion