Controlled Release of the IL-1R Antagonist, Anakinra, from Microgels with an Extended Intra-articular Residence Time

PURPOSE: To establish intra-articularly injected microgel compositions that can control the rate of release of anakinra, a protein-based IL-1R antagonist, at therapeutically relevant concentrations for an extended period of time. METHODS: Uptake and release of the IL-1Ra from microgels was tuned by simple post-synthesis modifications via the addition of calcium chloride after protein loading, or conjugation of small molecules to existing microgels to study the effects of negative (unmodified), positive (dimethylethylenediamine, agmatine), polar (ethanolamine), and non-polar (phenethylamine) side chains on protein delivery. RESULTS: Microgels modified with phenethylamine enhanced the loading capacity of the IL-1Ra to 242%. Both calcium-treated and small molecule-modified microgels had a decrease in initial burst release from the microgel matrix, and both extended the release of IL-1Ra from 6 h for unmodified microgels to over 60 days within the active therapeutic index of the drug. Microgels persist in the joint space for at least 8 weeks, and follow a bi-exponential decay curve with a ß half-life of 93.2 days. CONCLUSIONS: These findings demonstrate the application of simple post-synthesis modifications for improved drug delivery via polyanionic microgels, and support the potential use of poly(acrylic acid) microgels as intra-articular drug delivery vehicles for osteoarthritis treatment.