Folate-Targeted Liposomal Formulations Improve Effects of Methotrexate in Murine Collagen-Induced Arthritis

Abstract

Methotrexate (MTX) is first-line therapy for the treatment of rheumatoid arthritis (RA), however, its use may be limited by side effects notably post-injection malaise. When patients are intolerant or become unresponsive, second-line or antibody therapy may be indicated. A folate-targeted liposomal formulation of MTX (FL-MTX) is tropic to arthritic paws and prevents the onset of collagen-induced arthritis (CIA) in the mouse. We optimized the drug-to-lipid molar ratio to 0.15 and demonstrated the therapeutic efficacy of this form at 2 mg/kg MTX intraperitoneal (i.p.) twice a week. These improved liposomes were present in inflamed joints in proportion to the degree of swelling of the paw and bone remodeling activity. FL-MTX had lower hepatic and renal elimination of MTX than the free substance. FL-MTX provided equivalent results when given i.p. or subcutaneous (s.c.) and FL-MTX 2 mg/kg (drug/lipid 0.15), twice weekly, was similar to or more effective than 35 mg/kg MTX (same route and schedule) in reducing the incidence and swelling in the murine CIA model. These results suggest that FL-MTX is a more potent nanotherapeutic formulation than free MTX treatment. Its potential benefits for patients may include reduced frequency of treatment and lower overall doses for a given response.

Evaluation of Folate-Functionalized Nanoparticle Drug Delivery Systems—Effectiveness and Concerns

“…The nanoparticle accumulation in normal tissues or organs may lead to unfavorable side effects. In a study using folate-targeted liposomes loaded with methotrexate to treat rheumatoid arthritis [17], the nanoparticles highly accumulated in the arthritic mice joints (male 6-week-old DBA/1 mice, vulnerable to collagen-induced arthritis). Interestingly, the liposomes were formulated using a folate-peptide, which claimed to be more efficient than the traditional system linking the folic acid to PEG in liposomes.…”

“…A simple diagram illustrating the structure of liposomes: (A) The phospholipid bilayer forms the liposomes' shell; (B) Folate-DSPE-PEG. It is a typical component used in formulating folate-targeted liposomes[17,22,25]. The hydrophobic tails are highlighted in green.…”