Protease Operated Depots

In this project we focus on the delivery of peptide drugs by the formation of injectable depots of ELPSs. Peptides are an exciting class of pharmaceuticals currently in development for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections. We have developed a novel peptide delivery approach –Protease Operated Depots (PODs)– to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We have recently demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes peptide drug, and a thermoresponsive, depot-forming elastin-like-polypeptide (ELP) that undergoes its thermally triggered inverse phase transition between room temperature and body temperature, thereby forming an injectable depot. We constructed synthetic genes for GLP-1 PODs and demonstrated their high-yield expression in E. coli and facile purification by a non-chromatographic scalable scheme we had previously developed. Remarkably, a single injection of GLP-1 PODs was able to reduce blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide drug. These findings suggest that the PODs may offer a cost effective and modular genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.


Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. M. Amiram; K.M. Luginbuhl; X. Li; M.N. Feinglos; A. Chilkoti. (2013).