Treatment of Type 2 Diabetes with Oral Administration of Nanoencapsulated GLP-1

描述（由申请人提供）：2型糖尿病是世界上导致死亡和残疾的主要原因之一。虽然目前的治疗方法可以预防糖尿病的一些更具破坏性的并发症，但它们既不能恢复正常血糖，也不能消除长期糖尿病造成的所有有害影响。最近的研究表明，在大多数2型糖尿病患者中，持续静脉注射胰高血糖素样肽1 （GLP-1）可以显著降低血糖。然而，由于需要持续输注GLP-1，口服GLP-1肽不能导致血清GLP-1水平升高，目前使用GLP-1的方法不适合长期治疗糖尿病。先进的控释系统为标准的口服、静脉或肌肉给药提供了另一种方法。该应用提出了一种非侵入性糖尿病治疗方法，即口服包裹在可生物降解纳米颗粒中的GLP-1。将不稳定的生物制剂如GLP-1包封在可生物降解的聚合物中，可以保护胃免受酸性环境和蛋白酶的侵害，并允许安全进入胃肠道的管腔进行摄取。本研究旨在确定口服纳米胶囊GLP-1在降低实验动物血糖水平方面是否优于全身给药。为此，提出了3个目标。在目的1中，我们分析了不同的GLP-1包封生物胶粘剂配方的体外释放动力学（ELISA）和释放后肽生物活性（INS-1细胞胰岛素释放/增殖）。目的2是确定体内剂量和动力学。在这个目的中，对照小鼠腹腔注射葡萄糖，然后口服从aim 1的释放和生物活性研究中选择的GLP-1纳米颗粒制剂。在最后的研究中，研究了GLP-1纳米颗粒在空腹和餐后糖尿病小鼠中的治疗效果。2型糖尿病及其长期并发症仅在美国就影响了1820万人。这种疾病的长期并发症导致的死亡使糖尿病成为美国第三大死亡原因。本文提出的口服GLP-1可能对公众健康产生深远的影响，因为它有可能减少与长期糖尿病相关的疾病和死亡。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus is 1 of the leading causes of death and disability in the world. While current treatments prevent some of diabetes' more damaging complications, they can neither restore normoglycemia nor eliminate all the harmful effects caused by long term diabetes. Recent studies have shown that the continuous intravenous (i.v.) administration of Glucagon-like peptide 1 (GLP-1) can lower plasma glucose significantly in a majority of patients with Type 2 diabetes. However, due to the need for the continuous infusion of GLP-1 and the failure of oral GLP-1 peptide to lead to an increase in serum GLP-1 levels, current approaches using GLP-1 are not suitable for long term diabetes treatment. Advanced controlled release systems provide an alternative approach to the standard oral, intravenous or intramuscular delivery of pharmaceutical agents. This application proposes a non-invasive diabetes therapy through the oral administration of GLP-1 encapsulated in biodegradable nanoparticles. Encapsulation of labile biologicals such as GLP-1 into biodegradable polymers provides protection from the acidic environment and proteases of the stomach and allows safe passage into the lumen of the Gl tract for uptake. This proposal is designed to determine whether orally delivered, nano-encapsulated GLP-1 are superior to systemic bolus delivery in reducing blood glucose levels in experimental animals. To this end, 3 aims are proposed. In Aim 1, different bioadhesive formulations of encapsulated GLP-1 are analyzed for release kinetics (ELISA) and post-release peptide bioactivity (INS-1 cell insulin release / proliferation) in vitro. The goal of Aim 2 is to determine in vivo dosing and kinetics. In this aim, control mice are treated with a intra-peritoneal injection of glucose followed by the oral administration of GLP-1 nanoparticle formulations selected from the release and bioactivity studies in Aim 1. In the final Aim, the therapeutic efficacy of GLP-1 nanoparticles is examined in fasting and post-prandial diabetic mice. Type II diabetes mellitus and its long term complications affect 18.2 million people in the United States alone. Deaths due to the long-term complications of this disease make diabetes the third leading cause of death in the US. The orally delivered form of GLP-1 proposed here could have a profound effect on public health due to its potential to reduce the illness and death associated with long term diabetes.