The anti-inflammatory drugs, IL-1 receptor antagonist (IL1Ra) and TNF-alpha blocking antibodies, have been shown to dramatically modify the progression of inflammatory joint disease. While these drugs have significant potential to impact treatment of osteoarthritis, serious side effects associated with the required systemic administration protocol limits their application to single joint pathology in osteoarthritis. There is a need for an effective mechanism to deliver these drugs directly to the joint space, while providing for the high concentrations and frequent dosing suggested for drug effectiveness. The objective of this study is to develop a novel intra-articular drug delivery system that will be effective for delivering these disease-modifying drugs directly to the joint space. Elastin-like polypeptides (ELPs) will serve as the basis for the newly developed drug delivery system, whereby ELPs are thermally triggered to form large, micron size aggregates at body temperature upon injection into the joint space. We propose that these aggregates can entrap protein drugs and thus serve as a """"""""depot"""""""" for drug release over time. We further propose two specific mechanisms by which ELPs can serve as drug carriers for these protein drugs: (1) by physical entrapment of the protein drug following mixing and thermally-initiated aggregate formation (> 35 degrees C), or (2) by design of an ELP-drug fusion protein that will undergo aggregate formation when thermally-initiated. In this project, we propose work to study these two concepts applied to the release of one protein drug, IL1Ra, as a first proof-of-concept. We propose work to: (1) synthesize ELPs that physically entrap IL1Ra into aggregates and evaluate the kinetics of IL1Ra biodistribution in a rat model; and (2) synthesize fusion proteins of ELPs and IL1Ra and similarly evaluate IL1Ra biodistribution in the rat. The protein drugs released from the ELPs, either as soluble drug or fusion protein, will also be evaluated in vitro to determine kinetics of release, binding activity to target (IL-1 receptor 1) and biological activity in regulating T-lymphocyte proliferation. It is our central hypothesis that intra-articular injection of an ELP-based """"""""drug depot"""""""" for IL1Ra will increase the half-life of this important disease-modifying drug in the joint space, and thus provide the potential to serve as a highly effective treatment for osteoarthritis. ? ? ?
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