Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice

Abstract

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.

Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis

“…[10][11][12] However, long-term use and high-dose Mtx given by systematic administration have been associated with drug resistance and adverse side effects. 13,14 Therefore, it is desirable to develop a system that can deliver Mtx selectively to target tissues and to release the encapsulated Mtx within a short time. 15 In order to deliver encapsulated drug to target tissues efficiently, efforts have been devoted to the development of intelligent delivery systems that respond to specific stimuli, such as pH level, temperature, and redox potential.…”

Fab antibody fragment-functionalized liposomes for specific targeting of antigen-positive cells

“…([N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoylsn-glycero-3-phosphoethanolamine]) were prepared using a thin film hydration method as previously described. 9,10 Briefly, DOPE, CH and DSPE-MPEG were dissolved in chloroform. After its evaporation, the dried lipid film was dispersed in PBS containing Fab-NDP antibody fragments and Alexa Fluor 647 (AF647).…”

Move to Nano‐Arthrology: Targeted Stimuli‐Responsive Nanomedicines Combat Adaptive Treatment Tolerance (ATT) of Rheumatoid Arthritis

“…In another work, MTX was encapsulated in a liposomal formulation obtained by conjugating a hydrophobic fragment of surfactant protein to the linker and folate to improve their tolerance and efficacy. Both in vivo uptake specificity and clinical effects showed better results than non‐targeted liposomes . Bilthariya et al conjugated folate to albumin nanoparticles for targeted delivery of etoricoxib.…”