A facile approach for preparing dual-agonists with long lifetimes and balanced activities

一种制备具有长寿命和平衡活性的双激动剂的简便方法

• 批准号: 9464014
• 负责人: Gary W Ashley
• 金额: $ 14.96万
• 依托单位: PROLYNX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2019-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9464014
• 关键词: Agonist; Animals; Anti-Obesity Agents; Body Weight decreased; Chemicals; Cleaved cell; Diabetes Mellitus; Drug Delivery Systems; Drug Kinetics; GLP-I receptor; Glucagon; Glucagon Receptor; Half-Life; Hydrogels; Hyperglycemia; Life Extension; Microspheres; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Subcutaneous Injections; System; Technology; Weight Gain; exenatide; glucagon-like peptide 1; in vivo; new technology; novel; peptide drug

We have developed a chemically-controlled ultra-long acting delivery system to support once- weekly to once-monthly administration of peptides. In this system, the peptide is covalently attached to a hydrogel microsphere depot by a cleavable β-eliminative linker; upon subcutaneous injection, the linker slowly cleaves and releases the drug. If the same linker is used to attach two different peptides to microspheres, they will be released at the same rate; the relative amounts released can be controlled by the relative amounts attached to the microspheres. Hence, this delivery system should be capable of coordinating the pharmacokinetics of “dual-agonists”. This Phase I proposal seeks to demonstrate the feasibility of utilizing a two-drug delivery system to coordinate the pharmacokinetics of two peptide therapeutics. We will attach both the GLP-1 receptor agonist exenatide and a newly discovered glucagon agonist to our hydrogel- microspheres using a single linker having a half-life of about one week. After subcutaneous injection of the microspheres in the mouse, we will determine the pharmacokinetics of both these peptides. Concurrently, we will utilize the DIO mice as a model for obesity, and attempt to demonstrate the efficacy of the dual agonist as an anti-obesity drug, as well as the optimal ratio of the two drugs.

我们已经开发了一种化学控制的超长效递送系统，以支持每周一次到每月一次的多肽给药。在这个系统中，多肽通过可切割的β消除连接体共价连接到水凝胶微球储存库；皮下注射时，连接体缓慢切割并释放药物。如果使用相同的连接物将两种不同的多肽连接到微球上，它们将以相同的速度释放；释放的相对量可以由连接到微球上的相对数量控制。因此，这种给药系统应该能够协调“双激动剂”的药代动力学。这个第一阶段的提案试图证明利用两种药物输送系统来协调两种多肽疗法的药代动力学的可行性。我们将使用半衰期约一周的单一连接物将GLP-1受体激动剂埃塞那肽和新发现的胰升糖素激动剂连接到我们的水凝胶微球上。在小鼠皮下注射微球后，我们将测定这两种多肽的药代动力学。同时，我们将利用DIO小鼠作为肥胖模型，并试图证明双激动剂作为减肥药物的有效性，以及两种药物的最佳比例。