Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis.
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 (99m)Tc 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.


CONCLUSIONS
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.
Turk
Mary Jo
MJ
Purdue University, West Lafayette, Indiana 47907, USA.
Breur
Gert J
GJ
Widmer
William R
WR
Paulos
Chrystal M
CM
Xu
Le-Cun
LC
Grote
Lee Ann
LA
Low
Philip S
PS
D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging*; D002352:Carrier Proteins / Q000032:analysis*; D002614:Chelating Agents; D004195:Disease Models, Animal; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D008264:Macrophages / Q000000981:diagnostic imaging*; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D051381:Rats; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface; D013667:Technetium
D002352:Carrier Proteins; D002614:Chelating Agents; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D013667:Technetium; D005492:Folic Acid