title: Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis.
abstract: Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MTX equivalent dose of 4.95 μmol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.
authors: Rong
authors: R
authors: Qi
authors: Istvan
authors: I
authors: Majoros
authors: Asish C
authors: AC
authors: Misra
authors: Alisa E
authors: AE
authors: Koch
authors: Phil
authors: P
authors: Campbell
authors: Hubert
authors: H
authors: Marotte
authors: Ingrid L
authors: IL
authors: Bergin
authors: Zhengyi
authors: Z
authors: Cao
authors: Sascha
authors: S
authors: Goonewardena
authors: Jingga
authors: J
authors: Morry
authors: Shuai
authors: S
authors: Zhang
authors: Michael
authors: M
authors: Beer
authors: Paul
authors: P
authors: Makidon
authors: Alina
authors: A
authors: Kotlyar
authors: Thommey P
authors: TP
authors: Thomas
authors: James R
authors: JR
authors: Baker
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000378:metabolism*; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry*; D004058:Diffusion; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome
chemical_list: D050091:Dendrimers; D058973:Folate Receptors, GPI-Anchored; D053769:Nanocapsules; D058726:Nanoconjugates; C104700:PAMAM Starburst; D005492:Folic Acid; D008727:Methotrexate