Osteoarthritis is the most common joint disease, adversely effecting more than 80% of individuals older than 75 years of age. Osteoarthritis is, therefore, a major cause of pain and disability in the elderly. Furthermore, the economic impact of osteoarthritis is immense. In addition to direct medical costs (costs associated with physician visits, diagnostic testing, medications, adaptive aids and devices, physical and occupation therapy, hospitalizations and surgery), patients with osteoarthritis in the United States loose greater than 68 million days of work per year. Current techniques at evaluating osteroarthritis are either qualitative in nature - simply asking the patient how he/she feels - or impractical, such as a series of biochemical and histological analyses of biopsy samples of cartilage in the joint of the patient. Radiography with special macroscopic techniques has proven valuable for measuring cartilage thickness changes in osteoarthritis, however, these techniques cannot detect the earliest changes of osteoarthritis i.e. proteoglycan loss from the cartilage matrix. We have previously shown that MRI in combination positively-charged nitroxides, as a contrast enhancing agent, may be a reliable method to evaluate proteoglycan loss in cartilage. Poor relaxivity of nitroxides diminishes their selectivity. To overcome this limitation, it is proposed in this SBIR to develop dendrimeric-linked nitroxides, as selective contrast enhancing agents to assist MRI in evaluating cartilage status in humans with osteoarthritis. This Phase I grant will (a) synthesize dendrimer-linked nitroxides that are positively charged at physiological pH, determining their in vitro stability and (b)test for their ability to bind to cartilage in vitro and measuring the in vivo pharmacokinetics of dendrimer-linked nitroxides that selectively bind to proteoglycans in cartilage. PROPOSED COMMERCIAL APPLICATIONS: If the proposed research in the Phase I and Phase II program is successful - the development of dendrimer-linked nitroxides and MRI - will allow physicians to monitor the progress of osteoarthritis in a non-invasive manner. Further, with the large number of pharmaceutical companies engaged in the development of therapeutic agents that will retard the progression of osteoarthritis by inhibiting the breakdown of proteoglycan, this technology can be used to monitor the efficacy of these new therapeutic agents
Thesaurus Terms: chemical synthesis, contrast media, magnetic resonance imaging, nitric oxide, osteoarthritis dendrite, diagnosis design /evaluation, pharmacokinetics, polymer, proteoglycan, skeletal disorder diagnosis, skeletal visualization, technology /technique development bioimaging /biomedical imaging
