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Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
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-malei...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251458/ https://www.ncbi.nlm.nih.gov/pubmed/30538458 http://dx.doi.org/10.2147/IJN.S187089 |
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author | Alimoradi, Houman Greish, Khaled Barzegar-Fallah, Anita Alshaibani, Lama Pittalà, Valeria |
author_facet | Alimoradi, Houman Greish, Khaled Barzegar-Fallah, Anita Alshaibani, Lama Pittalà, Valeria |
author_sort | Alimoradi, Houman |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6251458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62514582018-12-11 Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity Alimoradi, Houman Greish, Khaled Barzegar-Fallah, Anita Alshaibani, Lama Pittalà, Valeria Int J Nanomedicine Original Research 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. Dove Medical Press 2018-11-20 /pmc/articles/PMC6251458/ /pubmed/30538458 http://dx.doi.org/10.2147/IJN.S187089 Text en © 2018 Alimoradi et al. 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 (http://creativecommons.org/licenses/by-nc/3.0/). 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. |
spellingShingle | Original Research Alimoradi, Houman Greish, Khaled Barzegar-Fallah, Anita Alshaibani, Lama Pittalà, Valeria Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity |
title | 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_short | Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity |
title_sort | nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251458/ https://www.ncbi.nlm.nih.gov/pubmed/30538458 http://dx.doi.org/10.2147/IJN.S187089 |
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