Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
Received 11 September 2018
Accepted for publication 27 October 2018
Published 20 November 2018 Volume 2018:13 Pages 7771—7787
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Thomas J Webster
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
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]