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

我们开发了一种化学控制的超长作用递送系统，以支持每周一次到每月一次的肽管理。在该体系中，肽通过可切割的β-消除连接物共价连接到水凝胶微球库；皮下注射后，连接物缓慢分裂并释放药物。如果用相同的连接物将两种不同的肽连接到微球上，它们将以相同的速度释放；释放的相对量可以通过附着在微球上的相对量来控制。因此，这种递送系统应该能够协调“双重激动剂”的药代动力学。本I期提案旨在证明利用两种药物传递系统来协调两种肽疗法的药代动力学的可行性。我们将把GLP-1受体激动剂艾塞那肽和一种新发现的胰高血糖素激动剂结合到我们的水凝胶微球上，使用半衰期约为一周的单一连接剂。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，试图证明双激动剂作为抗肥胖药物的功效，以及两种药物的最佳配比。

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.