Folate‐targeted imaging of activated macrophages in rats with adjuvant‐induced arthritis

• Published in: Arthritis and rheumatism 2002-07, Vol.46 (7), p.1947-1955
• Main Authors: Turk, Mary Jo, Breur, Gert J., Widmer, William R., Paulos, Chrystal M., Xu, Le‐Cun, Grote, Lee Ann, Low, Philip S.
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - diagnostic imaging; Biological and medical sciences; Carrier Proteins - analysis; Chelating Agents; Disease Models, Animal; Female; Folate Receptors, GPI-Anchored; Folic Acid - metabolism; Investigative techniques, diagnostic techniques (general aspects); Macrophages - diagnostic imaging; Medical sciences; Osteoarticular system. Muscles; Radioligand Assay; Radionuclide Imaging; Radionuclide investigations; Rats; Rats, Inbred Lew; Receptors, Cell Surface; Technetium
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.10405

Objective To determine whether overexpression of the high‐affinity folate receptor (FR) on activated macrophages can be exploited to selectively target imaging agents to sites of inflammation in rats with adjuvant‐induced arthritis (AIA). Methods Folic acid was conjugated to a 99mTc chelator (the complex termed EC20), and its distribution was visualized using gamma scintigraphy in healthy rats, rats with AIA, and arthritic rats that had been depleted of macrophages. To confirm that uptake was mediated by the FR, excess folic acid competition studies were conducted, and tissue FR levels were quantitated using a radioligand binding assay. Flow cytometry was also used to investigate uptake of folate conjugates into macrophages of both arthritic and healthy rats. Results EC20 concentrated in the arthritic extremities of diseased rats but not in the extremities of healthy rats. The intensity of images of affected tissues was greatly reduced in the presence of excess competing folic acid. The livers and spleens of arthritic animals also showed enhanced uptake of EC20 and increased levels of FR. Depletion of macrophages from arthritic animals reduced tissue FR content and concomitantly abolished uptake of EC20. In addition, macrophages isolated from livers of rats with AIA exhibited a significantly higher binding capacity for folate conjugates than did macrophages obtained from healthy rats. Conclusion Although EC20 is currently undergoing clinical evaluation for use in the imaging of ovarian carcinomas, the present results suggest that it may also be useful for assaying the participation of activated macrophages in inflammatory processes such as rheumatoid arthritis.