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Towards Glucose Transporter-Mediated Glucose-Responsive Insulin Delivery with Fast Response

实现快速响应的葡萄糖转运蛋白介导的葡萄糖反应性胰岛素输送

基本信息

批准号：
10425401
负责人：
Song Li
金额：
$ 41.88万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425401
关键词：
Animal Model Behavior Binding Biological Availability Blindness Blood Glucose Brain Injuries Caliber Caring Cell membrane Cells Cessation of life Chronic Complications of Diabetes Mellitus Devices Diabetes Mellitus Diabetic mouse Drops Emulsions Encapsulated Engineering Erythrocytes Formulation Glucose Glucose Transporter Glycolates Goals Health Human Hyaluronic Acid Hyperglycemia Hypoglycemia Implant In Vitro Injections Insulin Insulin-Dependent Diabetes Mellitus Intravenous Kidney Failure Length Lipids Liposomes Mediating Membrane Methods Modality Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Pain Painless Pancreas Polymers Property Public Health Quality of life Regulation Risk SLC2A1 gene Seizures Self Administration Sprague-Dawley Rats Streptozocin Structure of beta Cell of islet System Testing Transdermal substance administration Translations Type 2 diabetic Unconscious State base biomaterial compatibility blood glucose regulation clinically relevant design diabetes mellitus therapy diabetic patient diabetic rat effectiveness evaluation glucose monitor improved in vivo innovation limb amputation male multidisciplinary nanoparticle physical property response standard care type I diabetic

项目摘要

PROJECT SUMMARY Glucose-responsive delivery of insulin mimicking the function of pancreatic β-cells to achieve meticulous control of blood glucose (BG) would revolutionize type 1 and advanced type 2 diabetes care. However, it is extremely challenging to demonstrate a system which would combine fast response, reversible activation, ease of administration and excellent biocompatibility. In this proposal, we aim to establish an innovative glucose-responsive insulin delivery system based on the interaction between the glucose derivative- modified insulin (Glu-insulin) and glucose transporters (GLUTs) on red blood cells (RBCs). This binding interaction is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of blood glucose levels. We will exploit two conjugation formulations of Glu-insulin and glucose transporters (GIGTer): 1) polymeric nanoparticles (NPs; ~100 nm in diameter) coated with the RBC membrane (with GLUTs) and loaded with Glu-insulin; and 2) liposomal NPs integrated with exogenously expressed glucose transporters and Glu-insulin. We will further integrate these two glucose-responsive formulations into a painless microneedle (MN)-array based transcutaneous patch to obtain the “smart insulin patch” (SIP). Glu-insulin encapsulated NPs will also be incorporated inside SIP for serving as insulin reservoir to “recharge” GIGTers for up to 48 h regulation within a normoglycemic range. In vivo potency of smart insulin patch will be evaluated using the streptozotocin (STZ)-induced type 1 diabetic male C57B6 mice and Sprague Dawley rats. In Aim 1, we will validate and optimize the glucose-responsive capability of the GIGTers based on our preliminary study. In Aim 2, we will evaluate the effectiveness of SIPs integrated with GIGTers, determining the feasibility of utilizing the GIGTer as a new administration modality. In Aim 3, we will optimize the physicochemical properties of the GIGTer-integrated patches in type 1 diabetic mouse and rat (implanted with the Continuous Glucose Monitoring System, CGMS) models; we will substantiate the glucose-responsive capability as well as the biocompatibility of SIPs with GIGTers. The proposed goal, when successfully realized, will be a significant upgrade over the current insulin-dependent diabetes therapy options and have a profound impact to improve health and quality of life of diabetic patients.

项目总结模拟胰腺β细胞功能的葡萄糖响应性胰岛素递送实现细致血糖(BG)的控制将使1型糖尿病和高级2型糖尿病的治疗发生革命性变化。然而，它是展示一种结合了快速响应、可逆激活、易于管理和良好的生物兼容性。在这项建议中，我们的目标是建立一个创新的基于葡萄糖衍生物-胰岛素之间相互作用的葡萄糖响应型胰岛素递送系统修饰的胰岛素(谷氨酸-胰岛素)和葡萄糖转运体(GLUT)在红细胞(RBC)上。此装订相互作用在高血糖的环境中是可逆的，导致胰岛素的快速释放和随后的血糖水平的下降。我们将开发两种谷氨酸-胰岛素和葡萄糖的偶联配方转运体(GIGTer)：1)包裹在红细胞上的聚合物纳米颗粒(NPs；直径约100 nm) 膜(有谷氨酸)和负载谷氨酸-胰岛素；和2)脂质体纳米粒与外源整合表达葡萄糖转运蛋白和谷氨酸胰岛素。我们将进一步整合这两个对葡萄糖有反应的配制成基于无痛微针(MN)阵列的经皮贴片，以获得胰岛素贴片“(SIP)。谷氨酸-胰岛素包裹的NPs也将被纳入到SIP中作为胰岛素蓄水池在正常血糖范围内对GIGTER进行长达48小时的“充电”。黄曲霉毒素的体内效力智能胰岛素贴片将使用链脲佐菌素(STZ)诱导的1型糖尿病男性C57B6进行评估小鼠和SD大鼠。在目标1中，我们将验证和优化葡萄糖响应能力 GIGTers基于我们的初步研究。在目标2中，我们将评估sips集成的有效性。通过GIGTers，确定将GIGTer作为一种新的管理模式的可行性。在《目标3》中，我们将优化GIGTer整合贴片在1型糖尿病小鼠身上的物理化学性质和大鼠(植入连续血糖监测系统，CGMS)模型；我们将证实 SIPs与GIGTers的葡萄糖反应能力和生物相容性。提出的目标是，一旦成功实现，将是对目前胰岛素依赖型糖尿病的重大升级治疗方案的选择对改善糖尿病患者的健康和生活质量有着深远的影响。