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，连续静脉内（i.v.）胰高血糖素样肽1（GLP-1）的给药可以显著降低大多数2型糖尿病患者的血糖。然而，由于需要连续输注GLP-1和口服GLP-1肽不能导致血清GLP-1水平增加，目前使用GLP-1的方法不适合长期糖尿病治疗。先进的控制释放系统提供了一种替代的方法，以标准的口服，静脉内或肌内输送药剂。本申请提出了一种非侵入性糖尿病治疗，通过口服给药的GLP-1封装在可生物降解的纳米颗粒。将不稳定的生物制剂如GLP-1包封到可生物降解的聚合物中提供了免受酸性环境和胃蛋白酶的保护，并允许安全进入胃肠道的内腔以供摄取。该提案旨在确定口服递送的纳米胶囊化GLP-1在降低实验动物的血糖水平方面是否优于全身推注递送。为此，提出了三个目标。在目的1中，分析包封的GLP-1的不同生物粘附制剂的体外释放动力学（ELISA）和释放后肽生物活性（INS-1细胞胰岛素释放/增殖）。目的2的目标是确定体内给药和动力学。在该目的中，对照小鼠用腹膜内注射葡萄糖处理，随后口服施用选自目的1中的释放和生物活性研究的GLP-1纳米颗粒制剂。在最终目的中，在禁食和餐后糖尿病小鼠中检查GLP-1纳米颗粒的治疗功效。II型糖尿病及其长期并发症仅在美国就影响了1820万人。由于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。本文提出的口服形式的GLP-1可能对公共卫生产生深远的影响，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.