Editors' ChoiceRheumatoid Arthritis

Escorted for Efficacy

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Science Translational Medicine  30 Nov 2011:
Vol. 3, Issue 111, pp. 111ec196
DOI: 10.1126/scitranslmed.3003458

In a new or unfamiliar setting, it is often helpful to have an escort. Roaming without direction could lead to situations that are simply embarrassing—such as not knowing the difference between men’s and women’s restrooms in a foreign country—or downright dangerous. Similarly, Thomas et al. describe an appropriate drug-delivery strategy that escorts molecules to a target tissue to prevent the drug from wandering into unwanted locations, where it could provoke dangerous side effects.

Although the drug methotrexate can be used to treat rheumatoid arthritis (RA), two-thirds of patients either respond poorly or experience toxic side effects. Normally, methotrexate enters cells via the reduced folate carrier. To ensure that more of the drug gets inside diseased cells, Thomas and colleagues linked methotrexate to a nanosized dendrimer decorated with folic acid. Folic acid promoted the uptake of this drug–dendrimer conjugate by means of the folate receptor β (FRβ), which is expressed on activated macrophages in inflamed, arthritic joints. Because the expression of FRβ is negligible in other cell types, the dendrimer can escort methotrexate directly to the macrophages involved in the inflammatory response, keeping it away from other unwelcome sites.

In vitro studies first confirmed preferential uptake of the folic acid-conjugated dendrimers into macrophages. Next, Thomas and colleagues administered methotrexate-containing dendrimers to rats with collagen-induced RA. Treated rats experienced reduced ankle diameters and paw weights as compared with those of untreated controls, and histopathology showed significant reductions in inflammation, cartilage damage, and bone resorption (all hallmarks of RA). Although free methotrexate can reverse arthritic symptoms at its maximum tolerated dose, the dendrimer conjugates can achieve the same results at just 60% of this dose. It is anticipated that such advances in drug nanotechnology will lead to improved therapy for rheumatoid arthritis and other inflammatory diseases.

T. P. Thomas et al., Folate-targeted nanoparticles show efficacy in the treatment of inflammatory arthritis. Arthritis Rheum. 63, 2671–2680 (2011). [PubMed]

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