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 ?-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.
Public Health Relevance Statement: We have developed a technology platform for half-life extension that is chemically controlled by a linker used to connect the drug to a carrier. We propose that by using the same linker to attach two different drugs to the same carrier, we can confer the same half-life to both drugs and coordinate their in vivo concentrations. We will develop these concepts and apply them to produce a peptidic dual-agonist for treatment of diabetes and obesity.
Project Terms: Agonist; Animals; Anti-Obesity Agents; Body Weight decreased; Chemicals; Cleaved cell; Diabetes Mellitus; Drug Delivery Systems; Drug Kinetics; exenatide; GLP-I receptor; Glucagon; Glucagon Receptor; glucagon-like peptide 1; Half-Life; Hydrogels; Hyperglycemia; in vivo; Life Extension; Microspheres; Modeling; Mus; new technology; Non-Insulin-Dependent Diabetes Mellitus; novel; Obesity; peptide drug; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Subcutaneous Injections; System; Technology; Weight Gain
