- Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
-
Purpose: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. Materials and methods: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. Results: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.
- Maranh?o, Raul C.,Guido, Maria C.,de Lima, Aline D.,Tavares, Elaine R.,Marques, Alyne F.,de Melo, Marcelo D. Tavares,Nicolau, Jose C.,Salemi, Vera M. C.,Kalil-Filho, Roberto
-
-
Read Online
- Methotrexate Analogues. 21. Divergent Influence of Alkyl Chain Length on the Dihydrofolate Reductase Affinity and Cytotoxicity of Methotrexate Monoesters
-
n-Octyl, n-dodecyl, and n-hexadecyl α- and γ-esters of methotrexate (MTX) were compared with the previously described α- and γ-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in cultu
- Rosowsky, Andre,Forsch, Ronald A.,Yu, Cheng-Sein,Lazarus, Herbert,Beardsley, G. Peter
-
p. 605 - 609
(2007/10/02)
-
- Methotrexate Analogues. 18. Enhancement of the Antitumor Effect of Methotrexate and 3',5'-Dichloromethotrexate by the Use of Lipid-Soluble Diesters
-
Lipophilic methotrexate (MTX) and 3',5'-dichloromethotrexate (DCM) diesters were prepared by HCl-catalyzed esterification or by neutral esterification using cesium carbonate and an alkyl or aralkyl halide in Me2SO.The products were tested for in vivo antitumor activity against L1210 leukemia in mice to test whether all MTX and DCM diesters are therapeutically equivalent in this species.Contrary to what has been found with simple primary dialkyl esters, ortho-substituted dibenzyl esters of MTX produce longer survival on a q3d*3 schedule than does MTX itself and show a dose-sparing effect comparable to that of MTX at shorter treatment intervals.Thus, MTX bis(6-chloropiperonyl) ester at an MTX-equivalent dose of 5.5 mg/kg gave a +88percent increase in median life span (ILS), whereas for MTX a +88percent ILS required 30 mg/kg.When the MTX-equivalent dose of MTX bis(6-chloropiperonyl) ester was increased to 40 mg/kg, a +167percent ILS was observed, as compared with a +100percent ILS with 60 mg/kg of the parent drug.High activity (>100percent ILS) was likewise shown by the bis(2,5-dimethylbenzyl), bis(2,6-dichlorobenzyl), and di-3-picolyl esters of MTX and by the bis(1-methylbutyl) ester of DCM.The results of this study indicate that MTX and DCM esters are not therapeutically equivalent in mice, despite the high serum esterase activity in this species, and that an up to 10-fold reduction in total administered dose on the q3d*3 schedule is feasible by this approach.
- Rosowsky, A.,Yu, C.-S.
-
p. 1448 - 1452
(2007/10/02)
-