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

我们已经开发了一种化学控制的超长效递送系统，以支持每周一次至每月一次的肽施用。在该系统中，肽通过可裂解的β-消除性接头共价连接至水凝胶微球贮库;在皮下注射后，接头缓慢裂解并释放药物。如果使用相同的接头将两种不同的肽连接至微球，则它们将以相同的速率释放;释放的相对量可以通过连接至微球的相对量来控制。因此，该递送系统应能够协调“双重激动剂”的药代动力学。该I期提案旨在证明利用双药物递送系统来协调两种肽治疗剂的药代动力学的可行性。我们将使用半衰期约为一周的单一接头将GLP-1受体激动剂依塞那肽和新发现的胰高血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，我们将测定这两种肽的药代动力学。同时，我们将利用DIO小鼠作为肥胖模型，并尝试证明双重激动剂作为抗肥胖药物的功效，以及两种药物的最佳比例。

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.