Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules
Itraconazole (ITC), a well-tolerated antifungal drug, exerts multiple anticancer effects which justified its preclinical and clinical investigation as potential anti-cancer agent with reduced side effects. Enhancement of ITC anti-cancer efficacy would bring valuable benefits to patients. We propose...
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doaj-3766e56650ec49d39e6083a1c362f6602021-05-13T09:30:27ZengTaylor & Francis GroupDrug Delivery1071-75441521-04642021-01-0128190691910.1080/10717544.2021.19177281917728Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsulesNabila A. El-Sheridy0Riham M. El-Moslemany1Alyaa A. Ramadan2Maged W. Helmy3Labiba K. El-Khordagui4Department of Pharmaceutics, Faculty of Pharmacy, Alexandria UniversityDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria UniversityDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria UniversityDepartment of Pharmacology, Faculty of Pharmacy, Damanhour UniversityDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria UniversityItraconazole (ITC), a well-tolerated antifungal drug, exerts multiple anticancer effects which justified its preclinical and clinical investigation as potential anti-cancer agent with reduced side effects. Enhancement of ITC anti-cancer efficacy would bring valuable benefits to patients. We propose herein lipid nanocapsules (LNCs) modified with a subtherapeutic dose of miltefosine (MFS) as a membrane bioactive amphiphilic additive (M-ITC-LNC) for the development of an ITC nanoformulation with enhanced anticancer activity compared with ITC solution (ITC-sol) and unmodified ITC-LNC. Both LNC formulations showed a relatively small size (43–46 nm) and high entrapment efficiency (>97%), though ITC release was more sustained by M-ITC-LNC. Cytotoxicity studies revealed significantly greater anticancer activity and selectivity of M-ITC-LNC for MCF-7 breast cancer cells compared with ITC-sol and ITC-LNC. This trend was substantiated by in vivo findings following a 14 day-treatment of murine mammary pad Ehrlich tumors. M-ITC-LNC showed the greatest enhancement of the ITC-induced tumor growth inhibition, proliferation, and necrosis. At the molecular level, the tumor content of Gli 1, caspase-3, and vascular endothelial growth factor verified superiority of M-ITC-LNC in enhancing the ITC antiangiogenic, apoptotic, and Hedgehog pathway inhibitory effects. Finally, histopathological and biochemical analysis indicated greater reduction of ITC systemic toxicity by M-ITC-LNC. Superior performance of M-ITC-LNC was attributed to the effect of MFS on the structural and release properties of LNC coupled with its distinct bioactivities. In conclusion, MFS-modified LNC provides a simple nanoplatform integrating the potentials of LNC and MFS for enhancing the chemotherapeutic efficacy of ITC and possibly other oncology drugs.http://dx.doi.org/10.1080/10717544.2021.1917728itraconazolemiltefosinelipid nanocapsulesbreast cancermcf-7 cellsehrlich tumorbiomarkers |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nabila A. El-Sheridy Riham M. El-Moslemany Alyaa A. Ramadan Maged W. Helmy Labiba K. El-Khordagui |
spellingShingle |
Nabila A. El-Sheridy Riham M. El-Moslemany Alyaa A. Ramadan Maged W. Helmy Labiba K. El-Khordagui Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules Drug Delivery itraconazole miltefosine lipid nanocapsules breast cancer mcf-7 cells ehrlich tumor biomarkers |
author_facet |
Nabila A. El-Sheridy Riham M. El-Moslemany Alyaa A. Ramadan Maged W. Helmy Labiba K. El-Khordagui |
author_sort |
Nabila A. El-Sheridy |
title |
Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
title_short |
Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
title_full |
Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
title_fullStr |
Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
title_full_unstemmed |
Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
title_sort |
enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules |
publisher |
Taylor & Francis Group |
series |
Drug Delivery |
issn |
1071-7544 1521-0464 |
publishDate |
2021-01-01 |
description |
Itraconazole (ITC), a well-tolerated antifungal drug, exerts multiple anticancer effects which justified its preclinical and clinical investigation as potential anti-cancer agent with reduced side effects. Enhancement of ITC anti-cancer efficacy would bring valuable benefits to patients. We propose herein lipid nanocapsules (LNCs) modified with a subtherapeutic dose of miltefosine (MFS) as a membrane bioactive amphiphilic additive (M-ITC-LNC) for the development of an ITC nanoformulation with enhanced anticancer activity compared with ITC solution (ITC-sol) and unmodified ITC-LNC. Both LNC formulations showed a relatively small size (43–46 nm) and high entrapment efficiency (>97%), though ITC release was more sustained by M-ITC-LNC. Cytotoxicity studies revealed significantly greater anticancer activity and selectivity of M-ITC-LNC for MCF-7 breast cancer cells compared with ITC-sol and ITC-LNC. This trend was substantiated by in vivo findings following a 14 day-treatment of murine mammary pad Ehrlich tumors. M-ITC-LNC showed the greatest enhancement of the ITC-induced tumor growth inhibition, proliferation, and necrosis. At the molecular level, the tumor content of Gli 1, caspase-3, and vascular endothelial growth factor verified superiority of M-ITC-LNC in enhancing the ITC antiangiogenic, apoptotic, and Hedgehog pathway inhibitory effects. Finally, histopathological and biochemical analysis indicated greater reduction of ITC systemic toxicity by M-ITC-LNC. Superior performance of M-ITC-LNC was attributed to the effect of MFS on the structural and release properties of LNC coupled with its distinct bioactivities. In conclusion, MFS-modified LNC provides a simple nanoplatform integrating the potentials of LNC and MFS for enhancing the chemotherapeutic efficacy of ITC and possibly other oncology drugs. |
topic |
itraconazole miltefosine lipid nanocapsules breast cancer mcf-7 cells ehrlich tumor biomarkers |
url |
http://dx.doi.org/10.1080/10717544.2021.1917728 |
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