Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanofor...

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Autores principales:	Nura A. Mohamed, Haissam Abou-Saleh, Yu Kameno, Isra Marei, Gilberto de Nucci, Blerina Ahmetaj-Shala, Fisnik Shala, Nicholas S. Kirkby, Lewis Jennings, Dana E. Al-Ansari, Robert P. Davies, Paul D. Lickiss, Jane A. Mitchell
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8e7b211a296b4ff6ae224dc791158fee
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spelling	oai:doaj.org-article:8e7b211a296b4ff6ae224dc791158fee2021-12-02T16:23:21ZStudies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension10.1038/s41598-021-83423-62045-2322https://doaj.org/article/8e7b211a296b4ff6ae224dc791158fee2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83423-6https://doaj.org/toc/2045-2322Abstract Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal–organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2–4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.Nura A. MohamedHaissam Abou-SalehYu KamenoIsra MareiGilberto de NucciBlerina Ahmetaj-ShalaFisnik ShalaNicholas S. KirkbyLewis JenningsDana E. Al-AnsariRobert P. DaviesPaul D. LickissJane A. MitchellNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nura A. Mohamed Haissam Abou-Saleh Yu Kameno Isra Marei Gilberto de Nucci Blerina Ahmetaj-Shala Fisnik Shala Nicholas S. Kirkby Lewis Jennings Dana E. Al-Ansari Robert P. Davies Paul D. Lickiss Jane A. Mitchell Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
description	Abstract Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal–organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2–4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.
format	article
author	Nura A. Mohamed Haissam Abou-Saleh Yu Kameno Isra Marei Gilberto de Nucci Blerina Ahmetaj-Shala Fisnik Shala Nicholas S. Kirkby Lewis Jennings Dana E. Al-Ansari Robert P. Davies Paul D. Lickiss Jane A. Mitchell
author_facet	Nura A. Mohamed Haissam Abou-Saleh Yu Kameno Isra Marei Gilberto de Nucci Blerina Ahmetaj-Shala Fisnik Shala Nicholas S. Kirkby Lewis Jennings Dana E. Al-Ansari Robert P. Davies Paul D. Lickiss Jane A. Mitchell
author_sort	Nura A. Mohamed
title	Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
title_short	Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
title_full	Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
title_fullStr	Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
title_full_unstemmed	Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
title_sort	studies on metal–organic framework (mof) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8e7b211a296b4ff6ae224dc791158fee
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Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension

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