Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 27; pp. 8260 - 8265
• Main Authors: Yu, Jicheng, Yuqi Zhang, Yanqi Ye, Rocco DiSanto, Wujin Sun, Davis Ranson, Frances S. Ligler, John B. Buse, Zhen Gu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.07.2015; National Acad Sciences
• Subjects: anaerobic conditions; animal models; Animals; Biological Sciences; blood glucose; Blood Glucose - analysis; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; dissociation; drug delivery; Drug delivery systems; Drug Delivery Systems - instrumentation; Drug Delivery Systems - methods; Glucose; Glucose - metabolism; glucose oxidase; Glucose Oxidase - metabolism; glucose-responsive; Humans; hyaluronic acid; Hyaluronic Acid - chemistry; Hyaluronic Acid - metabolism; hydrophilicity; Hydrophobic surfaces; hydrophobicity; hyperglycemia; hypoglycemia; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoxia; Hypoxia - metabolism; hypoxia-sensitive; Insulin; Insulin - administration & dosage; Insulin - chemistry; Insulin - metabolism; insulin-dependent diabetes mellitus; Male; Mice, Inbred C57BL; microneedle; Microscopy, Electron, Transmission; Molecular Structure; oxidation; Oxidation-Reduction; Quality of life; Reproducibility of Results; therapeutics; Transdermal medication; glucose-responsive; microneedle; drug delivery; hypoxia-sensitive; diabetes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1505405112

A glucose-responsive “closed-loop” insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (“smart insulin patch”) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO ₓ) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.