Back to Journals » International Journal of Nanomedicine » Volume 12

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Authors Maranhão RC, Guido MC, de Lima AD, Tavares ER, Marques AF, Tavares de Melo MD, Nicolau JC, Salemi VMC, Kalil-Filho R

Received 3 December 2016

Accepted for publication 17 February 2017

Published 17 May 2017 Volume 2017:12 Pages 3767—3784

DOI https://doi.org/10.2147/IJN.S129324

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alicia Fernandez-Fernandez

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster


Raul C Maranhão,1,2 Maria C Guido,1 Aline D de Lima,1 Elaine R Tavares,1 Alyne F Marques,1 Marcelo D Tavares de Melo,3 Jose C Nicolau,3 Vera MC Salemi,3 Roberto Kalil-Filho3

1Laboratory of Metabolism and Lipids, 2Faculty of Pharmaceutical Sciences, 3Heart Failure Unit, Clinical Cardiology Division, Heart Institute (InCor), Medical School Hospital, University of São Paulo, São Paulo, Brazil

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.

Keywords: lipid particle, drug delivery, adenosine, VEGF, myocardial infarction
 

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]