Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

Houman Alimoradi,1,* Khaled Greish,2,3,* Anita Barzegar-Fallah,1 Lama Alshaibani,2 Valeria Pittalà4 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, P...

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Autores principales:	Alimoradi H, Greish K, Barzegar-Fallah A, Alshaibani L, Pittalà V
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	Biological barriers nanoparticles nitric oxide doxorubicin synergistic cytotoxicity SMA-tDodSNO Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/cad656ae37a74358a089c7c18bf9bac0
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spelling	oai:doaj.org-article:cad656ae37a74358a089c7c18bf9bac02021-12-02T03:20:26ZNitric oxide-releasing nanoparticles improve doxorubicin anticancer activity1178-2013https://doaj.org/article/cad656ae37a74358a089c7c18bf9bac02018-11-01T00:00:00Zhttps://www.dovepress.com/nitric-oxide-releasing-nanoparticles-improve-doxorubicin-anticancer-ac-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Houman Alimoradi,1,* Khaled Greish,2,3,* Anita Barzegar-Fallah,1 Lama Alshaibani,2 Valeria Pittalà4 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Centre for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain; 3Department of Oncology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 4Department of Drug Science, University of Catania, Catania, Italy *These authors contributed equally to this work Purpose: Anticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier. Materials and methods: Effects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues. Results: Combination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs control), without causing significant toxicity as monitored through body weight loss. Conclusion: Taken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC. Keywords: biologic barriers, nanoparticles, nitric oxide, doxorubicin, synergistic cytotoxicity, SMA-tDodSNOAlimoradi HGreish KBarzegar-Fallah AAlshaibani LPittalà VDove Medical PressarticleBiological barriersnanoparticlesnitric oxidedoxorubicinsynergistic cytotoxicitySMA-tDodSNOMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 7771-7787 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biological barriers nanoparticles nitric oxide doxorubicin synergistic cytotoxicity SMA-tDodSNO Medicine (General) R5-920
spellingShingle	Biological barriers nanoparticles nitric oxide doxorubicin synergistic cytotoxicity SMA-tDodSNO Medicine (General) R5-920 Alimoradi H Greish K Barzegar-Fallah A Alshaibani L Pittalà V Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
description	Houman Alimoradi,1,* Khaled Greish,2,3,* Anita Barzegar-Fallah,1 Lama Alshaibani,2 Valeria Pittalà4 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Centre for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain; 3Department of Oncology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 4Department of Drug Science, University of Catania, Catania, Italy *These authors contributed equally to this work Purpose: Anticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier. Materials and methods: Effects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues. Results: Combination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs control), without causing significant toxicity as monitored through body weight loss. Conclusion: Taken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC. Keywords: biologic barriers, nanoparticles, nitric oxide, doxorubicin, synergistic cytotoxicity, SMA-tDodSNO
format	article
author	Alimoradi H Greish K Barzegar-Fallah A Alshaibani L Pittalà V
author_facet	Alimoradi H Greish K Barzegar-Fallah A Alshaibani L Pittalà V
author_sort	Alimoradi H
title	Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
title_short	Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
title_full	Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
title_fullStr	Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
title_full_unstemmed	Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
title_sort	nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/cad656ae37a74358a089c7c18bf9bac0
work_keys_str_mv	AT alimoradih nitricoxidereleasingnanoparticlesimprovedoxorubicinanticanceractivity AT greishk nitricoxidereleasingnanoparticlesimprovedoxorubicinanticanceractivity AT barzegarfallaha nitricoxidereleasingnanoparticlesimprovedoxorubicinanticanceractivity AT alshaibanil nitricoxidereleasingnanoparticlesimprovedoxorubicinanticanceractivity AT pittalav nitricoxidereleasingnanoparticlesimprovedoxorubicinanticanceractivity
_version_	1718401820784590848

Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity

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