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The suppression of rat collagen-induced arthritis and inhibition of macrophage derived mediator release by liposomal methotrexate formulations

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Objective and Design: This study was designed to determine whether liposomes are suitable vehicles for the delivery of methotrexate (MTX-γ-DMPE) for arthritis therapy.¶Material or Subjects: Liposomal formulations containing either egg lecithin (EPC), cholesterol (CHOL) and phosphatidic acid (PA) (MTX-EPC) or distearoylphosphatidylcholine (DSPC), CHOL and distearoylphosphatidylethanolamine conjugated to polyethyleneglycol (PEG) (MTX-PEG) were employed. Rat peritoneal macrophages (rPMφ) were used to test the mechanism of action of these liposomes in vitro, whilst, the rat collagen-induced arthritis (CIA) model was used to evaluate the in vivo efficacy of MTX-EPC and MTX-PEG.¶Treatment: In vitro, rPMφ were incubated with liposomal MTX concentrations ranging from 0 to 15 μg/well. In vivo, rats were given 4 daily intravenous injections of liposomal MTX (2.5 mg/Kg).¶Methods: IL-1β and prostaglandin-E2 (PGE2) release from rPMφ were quantified by immunoradiometric assay. Arthritis progression, in vivo, was measured by serial clinical score and hind paw diameter measurements.¶Results: MTX-EPC and MTX-PEG respectively (15 μg of MTX and 0.15 mg of lipid) were powerful inhibitors of both IL-1β (77 ± 2.3%; 79 ± 4.0%) and PGE2 (75.5 ± 4.9%; 68.5 ± 2.3%) release (mean ± SEM % inhibition) from lipopolysaccaride stimulated rPMφ. In vivo, only MTX-EPC exerted an anti-inflammatory effect, clinical score (p < 0.001) and paw diameter (p < 0.001) measurements being significantly lower than in control rats, after 2 days treatment.¶Conclusions: MTX-EPC and MTX-PEG are potent inhibitors of pro-inflammatory mediators in vitro, but liposomes with long circulation times do not appear to have therapeutic potential for treating arthritis in vivo.

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Received 23 September 1999; returned for revision 9 November 1999; accepted by W. B. van den Berg 9 December 1999

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Williams, A., Goodfellow, R., Topley, N. et al. The suppression of rat collagen-induced arthritis and inhibition of macrophage derived mediator release by liposomal methotrexate formulations. Inflamm. res. 49, 155–161 (2000). https://doi.org/10.1007/s000110050575

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  • DOI: https://doi.org/10.1007/s000110050575

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