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

Williams, A., Goodfellow, Rhian Mair, Topley, Nicholas, Amos, Nick and Williams, Bryan Davies 2000. The suppression of rat collagen-induced arthritis and inhibition of macrophage derived mediator release by liposomal methotrexate formulations. Inflammation Research 49 (4) , pp. 155-161. 10.1007/s000110050575

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Arthritis, Interleukin-1β, Macrophage, Prostaglandin E2.
Publisher: Springer Verlag
ISSN: 1023-3830
Last Modified: 12 Jun 2019 02:20
URI: http://orca.cf.ac.uk/id/eprint/69362

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