Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel-impregnated...

Paclitaxel is a chemotherapeutic agent that suppresses cellular proliferation and angiogenesis and has been effective in suppressing proliferative synovitis in animal models. Local joint delivery ofpaclitaxel is being pursued as a treatment for rheumatoid arthritis in humans, to avoid systematic toxicity of the drug. We used an extracorporeal, isolated metacarpophalangeal joint preparation that uniquely permitted the simultaneous evaluation of codependent hemodynamic, microvascular, and transsynovial flow responses of a joint. Specifically in this study, the isolated joint preparation provided quantitative assessment of vascular flow, transsynovial flow, and morphologic changes in response to intraarticular injection of paclitaxel (50 ng) in poly-(DL)-lactide co-glycolide 50:50 microspheres (50 microm diameter) to assess initial intra-articular biocompatibility. Control joints were isolated but not injected. Serial hemodynamic measurements, transsynovial fluid forces, synovial fluid analysis, synovial and capillary permeability, and oxygen metabolism were measured every 30 min during a subsequent 3-h isolation period. At termination, synovium and cartilage were harvested from bilateral metacarpophalangeal joints for histopathologic assessment. Intra-articular injection of this formulation of paclitaxel did not significantly affect hemodynamic parameters in the joint during this short-term study, and early joint inflammatory reaction was minimal. However, transsynovial fluid forces were significantly greater in treated joints as evidenced by greater synovial fluid flow, intra-articular pressure, transitional microvascular pressure, and permeability to fluid transport. Gross and histologic morphology of synovium and articular cartilage were normal in all isolated joints. In conclusion, this extracorporeal in vivo isolated joint model permitted investigation of the early changes in joint physiology induced by this microsphere formulation and dose ofpaclitaxel in joints and could provide a more physiologic and dynamic model for study of the pharmacokinetics of drug absorption following intra-articular administration. Due to the minimal inflammation and lack of evidence of gross or histologic change in the joint, this formulation of paclitaxel should be adequately biocompatible for use in an in vivo animal model for further study of its feasibility for human use.