Folate Receptor beta as a Potential Delivery Route for Novel Folate Antagonists to Macrophages in the Synovial Tissue of Rheumatoid Arthritis Patients
van der Heijden, JW
van der Laken, CJ
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Objective. To determine the expression of folate receptor beta (FR beta) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FR beta than methotrexate (MTX). Methods. Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FR beta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FR beta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FR beta for folate antagonists were assessed by competition experiments for 3 H-folic acid binding on FR beta-transfected cells. Efficacy of FR beta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FR beta-transfected cells. Results. Immunohistochemical staining of RA synovial tissue showed high expression of FR beta on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FR beta mRNA levels were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new-generation folate antagonists revealed 4 compounds for which FR beta had a high binding affinity (20-77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FR beta-transfected cells. Conclusion. Abundant FRP beta expression on activated macropliages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high-affinity-binding folate antagonists, of which BCG 945 may be a prototypical representative.
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ARTHRITIS AND RHEUMATISM, 2009, 60 pp. 12 - 21