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

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。

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.