Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate 英文参考文献.docVIP

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Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate 英文参考文献.doc

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Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate 英文参考文献

Luetal.ArthritisResearchTherapy2011,13:R56 /content/13/2/R56 RESEARCH ARTICLE OpenAccess Treatmentofexperimentaladjuvantarthritiswith anovelfolatereceptor-targetedfolicacid- aminopterinconjugate YingjuanLu1,TorianWStinnette1,ElaineWestrick1,PatrickJKlein1,MarkAGehrke1,VickyACross1, IontchoRVlahov1,PhilipSLow2andChristopherPLeamon1* Abstract Introduction:Folatereceptor(FR)-expressingmacrophageshavebeenshowntoaccumulateatsitesof inflammation,wheretheypromotedevelopmentofinflammatorysymptoms.Totargetsuchamacrophage population,wedesignedandevaluatedthebiologicactivityofEC0746,anovelfolicacidconjugateofthehighly potentantifolate,aminopterin. Methods:UsingaFR-positivesubcloneofmurinemacrophage-derivedRAW264.7cellsandratthioglycollate- elicitedmacrophages,westudiedtheeffectofEC0746ondihydrofolatereductaseactivity,cellproliferation,and cellularresponsetowardsbacteriallipopolysaccharideaswellasIFNgactivation.TheEC0746anti-inflammatory activity,pharmacokinetics,andtoxicitywerealsoevaluatedinnormalratsorinratswithadjuvant-inducedarthritis; thatis,aFR-positivemacrophagemodelthatcloselyresemblesrheumatoidarthritisinhumans. Results:EC0746suppressestheproliferationofRAW264.7cellsandpreventstheabilityofnonproliferatingrat macrophagestorespondtoinflammatorystimuli.Inthemacrophage-richratarthritismodel,brieftreatmentwith subcutaneouslyadministeredEC0746isshowntomediateanFR-specificanti-inflammatoryresponsethatismore potentthaneitherorallyadministeredmethotrexateorsubcutaneouslydeliveredetanercept.Moreimportantly, EC0746therapyisalsoshowntobe~40-foldlesstoxicthanunmodifiedaminopterin,withfewerbonemarrow andgastrointestinalproblems. Conclusions:EC0746isthefirsthighFR-bindingdihydrofolatereductaseinhibitorthatdemonstratesFR-specific anti-inflammatoryactivitiesbothinvitroandinvivo.Ourdatarevealthatarelativelytoxicanti-inflammatorydrug, suchasaminopterin,canbetargetedwithfolicacidtoinflammatorymacrophagesandtherebyrelieve inflammatorysymptomswithgreatlyreducedtoxicity. Introduction rolei