Introduction: Diabetes mellitus is a group of metabolic diseases characterized by accumulation of glucose in the body, which currently affects 387 million people in the world. The traditional care for diabetic patients often requires monitoring of blood glucose and several insulin injections to maintain normoglycemia daily. Nonetheless, such self-administration is often painful and associated with inadequate glucose control[1],[2].
Materials and Methods: Here we design a novel glucose-responsive insulin delivery system based on the microneedle-array patches integrated with hypoxia-sensitive polymeric vesicles containing insulin and glucose oxidase (GOx)[3]. The dissolved oxygen was rapidly consumed under the high glucose level due to the glucose oxidation catalyzed by GOx, which led to a local hypoxic environment. Then, the glucose-responsive vesicles (GRVs) could rapidly dissociate and subsequently release insulin. To achieve ease of administration, we further loaded the GRVs into a microneedle-array-based patch for painless insulin delivery (Figure 1A).
Results and Discussion: This amphiphilic hypoxia-sensitive polymer can self-assemble into the GRVs with the size of 118 nm. In vitro studies demonstrated the insulin release rate from GRVs was effectively correlated with the surrounding glucose concentrations. Moreover, the release rate was remarkably faster when compared to pH-sensitive based glucose-responsive nanoparticles which previously reported in parallel. In vivo studies showed that the blood glucose in the diabetic mice transcutaneously treated with GRV-loaded microneedle (MN) patch quickly declined to a normoglycemic state within 0.5 h(Figure 1B). In addition, the GRV-loaded MN patch could efficiently avoid potential risk to hypoglycemia.

Figure 1. (A) A fluorescence microscopy image of MNs loading GRVs with FITC-labeled insulin. Inset: a zoom-in image of MN. Scale bar is 200 µm. (B) Blood glucose levels in STZ-induced diabetic mice after treatment with MN made of m-HA, MN loaded with human recombinant insulin, MN loaded with GRVs containing insulin and enzyme (GRV(E+I)), MN loaded with GRVs containing insulin and half amount of enzyme (GRV(1/2E+I)), or MN loaded with GRVs containing insulin (GRV(I)).
Conclusions: A “smart insulin patch” with a novel trigger mechanism was developed for closed-loop insulin delivery in a fast glucose-responsiveness, pain-free, and safe manner. It will also guide the development of a useful drug delivery system for treating other diseases using artificial vesicles, the behaviors of which can be “smartly” activated and self-regulated according to the variation of physiological signals.
the grants from the American Diabetes Association (ADA) to Z.G. (1-14-JF-29 and 1-15-ACE-21); the grant from NC TraCS, NIH’s Clinical and Translational Science Awards (CTSA, NIH grant 1UL1TR001111) at UNC-CH
References:
[1] Mo R, Jiang T, Di J, Tai W, Gu Z. Emerging micro-and nanotechnology based synthetic approaches for insulin delivery. Chemical Society Reviews 2014;43(10):3595-3629.
[2] Veiseh O, Tang BC, Whitehead KA, Anderson DG, Langer R. Managing diabetes with nanomedicine: challenges and opportunities. Nature Reviews Drug Discovery 2015;14(1):45-57.
[3] Yu J, Zhang Y, Ye Y, DiSanto R, Sun W, Ranson D, Ligler FS, Buse JB, Gu Z. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proceedings of the National Academy of Sciences 2015;112(27):8260-8265.