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

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 Cardiolog...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maranhão RC, Guido MC, de Lima AD, Tavares ER, Marques AF, Tavares de Melo MD, Nicolau JC, Salemi VMC, Kalil-Filho R
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	lipid particle drug delivery adenosine VEGF myocardial infarction. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/5eb10b109f4f4710b90836ab239702b9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5eb10b109f4f4710b90836ab239702b9
record_format	dspace
spelling	oai:doaj.org-article:5eb10b109f4f4710b90836ab239702b92021-12-02T05:10:41ZMethotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats1178-2013https://doaj.org/article/5eb10b109f4f4710b90836ab239702b92017-05-01T00:00:00Zhttps://www.dovepress.com/methotrexate-carried-in-lipid-core-nanoparticles-reduces-myocardial-in-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Raul 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 Maranhão RCGuido MCde Lima ADTavares ERMarques AFTavares de Melo MDNicolau JCSalemi VMCKalil-Filho RDove Medical Pressarticlelipid particledrug deliveryadenosineVEGFmyocardial infarction.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 3767-3784 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	lipid particle drug delivery adenosine VEGF myocardial infarction. Medicine (General) R5-920
spellingShingle	lipid particle drug delivery adenosine VEGF myocardial infarction. Medicine (General) R5-920 Maranhão RC Guido MC de Lima AD Tavares ER Marques AF Tavares de Melo MD Nicolau JC Salemi VMC Kalil-Filho R Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
description	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
format	article
author	Maranhão RC Guido MC de Lima AD Tavares ER Marques AF Tavares de Melo MD Nicolau JC Salemi VMC Kalil-Filho R
author_facet	Maranhão RC Guido MC de Lima AD Tavares ER Marques AF Tavares de Melo MD Nicolau JC Salemi VMC Kalil-Filho R
author_sort	Maranhão RC
title	Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
title_short	Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
title_full	Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
title_fullStr	Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
title_full_unstemmed	Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
title_sort	methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/5eb10b109f4f4710b90836ab239702b9
work_keys_str_mv	AT maranhaorc methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT guidomc methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT delimaad methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT tavareser methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT marquesaf methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT tavaresdemelomd methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT nicolaujc methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT salemivmc methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats AT kalilfilhor methotrexatecarriedinlipidcorenanoparticlesreducesmyocardialinfarctionsizeandimprovescardiacfunctioninrats
_version_	1718400531989266432

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

Ejemplares similares