Development of Gold Nanocarriers for the Treatment ofRheumatoid Arthritis

About This Grant

Abstract Rheumatoid arthritis (RA) is a disease with no cure that affects approximately 1% of the world's population. It is characterized by inflammation, cartilage/bone destruction, and disorders of the cardiovascular, pulmonary, and skeletal systems. Disease-modifying antirheumatic drugs such as methotrexate (MTX) effectively manage the symptoms. Clinically, methotrexate is administered in a high dose once a week due both to the rapid renal clearance and toxic side effects. Studies show that patients undergoing treatment experience a twenty-six percent reduction in the number of inflamed joints. While the MTX is highly effective, some patients experience articulations that do not respond to systemic treatment with the drug. To address this issue, we will create nanocarriers to deliver MTX to specific joints that do not respond well to its systemic delivery. The conjugation chemistry will be developed to bind MTX to gold nanoparticles through environmentally responsive linkers, which will serve as a slow-release nanocarrier system when injected into the targeted joints. Colloidal gold has demonstrated anti-inflammatory properties when used to treat RA. The gold nanocarriers, along with MTX and linkers sensitive to environmental cues like reactive oxygen species and the acidic conditions of the synovial fluid, are expected to have a synergistic and pronounced effect in reducing inflammation. The acid and reactive oxygen species release mechanisms of the nanocarriers will be studied along with their cytotoxicity. Next, the efficacy of the gold nanocarriers will be determined by analyzing the levels of reactive oxygen species, tumor necrosis factor (TNF-), interleukin 6 (IL-6) and interleukin 1 (IL-1) produced by RAW 264.7 macrophages upon in vitro inflammatory stimulation. RAW 264.7 macrophages are used as a model cell line to study inflammation responses of other gold nanoparticle formulations. It is expected that the inflammatory variables evaluated will be reduced in vitro. This research will lay the groundwork for testing in animal models and may eventually lead to changes in the administration of methotrexate to patients.