Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate


INTRODUCTION Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. METHODS Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. RESULTS EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. CONCLUSIONS EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity.

DOI: 10.1186/ar3304

Extracted Key Phrases

7 Figures and Tables

Citations per Year

309 Citations

Semantic Scholar estimates that this publication has 309 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Lu2011TreatmentOE, title={Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate}, author={Yingjuan Lu and Torian W. Stinnette and Elaine Westrick and Patrick J. Klein and Mark A. Gehrke and Vicky A. Cross and Iontcho R. Vlahov and Philip S Low and Christopher P. Leamon}, booktitle={Arthritis research & therapy}, year={2011} }