Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.
Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance.
Eugénia
E
Nogueira
Franck
F
Lager
Delphine
D
Le Roux
Patrícia
P
Nogueira
Jaime
J
Freitas
Celine
C
Charvet
Gilles
G
Renault
Ana
A
Loureiro
Catarina R
CR
Almeida
Anna
A
Ohradanova-Repic
Christian
C
Machacek
Gonçalo J L
GJ
Bernardes
Alexandra
A
Moreira
Hannes
H
Stockinger
Michael
M
Burnet
Alexandre M
AM
Carmo
Andreia C
AC
Gomes
Ana
A
Preto
Georges
G
Bismuth
Artur
A
Cavaco-Paulo
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002460:Cell Line; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice
D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D005492:Folic Acid; D008727:Methotrexate