Use of methotrexate carried in lipid core nanoparticles in rats with endotoxemia: a possible new strategy for the treatment of the cardiac dysfunction in sepsis

Cardiac dysfunction is a major cause of death in endotoxemia. Previously, we showed that methotrexate (MTX) carried in lipid-core nanoparticles (LDE) can modulate immune response and increase myocardial angiogenesis. The aim was to test the effects of LDE-methotrexate (LDEMTX) in rats with endotoxemia. Twenty male rats received I.P. injections of lipopolysaccharides (LPS, 10 mg/kg twice, 24h interval) and were allocated to 3 groups: LPS-LDEMTX, injected I.P. with 1 mg/kg MTX associated with LDE; LPS-MTX with conventional MTX (1 mg/kg, I.P.); LPS-LDE, injected with LDE only. A control group (CT) without endotoxemia was included. Echocardiography was performed 72h after endotoxemia induction. Animals were euthanized for analysis. LPS-LDE developed LV diastolic dysfunction, which was prevented in both LPS-LDEMTX and LPS-MTX groups. LPS-LDEMTX, but not LPS-MTX, developed compensatory LV hypertrophy. In LPS-LDEMTX, cellular hypoxia was lower, and angiogenesis was higher than in LPS-MTX and LPS-LDE, indicated by expression of hypoxia-inducible factor 1α, vascular endothelial growth factor and angiopoietin 1/2, respectively. Intracellular adenosine was increased in LPS-LDEMTX, with higher adenosine receptor expression. LPS-MTX but not LPS-LDEMTX showed hepatic toxicity. In conclusion, both LDEMTX and MTX prevented diastolic dysfunction in endotoxemia, but LDEMTX was further capable of improving several other parameters and had no toxicity.