Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy

Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestatio...

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Autores principales:	Mostafa A. Askar, Noura M. Thabet, Gharieb S. El-Sayyad, Ahmed I. El-Batal, Mohamed Abd Elkodous, Omama E. El Shawi, Hamed Helal, Mohamed K. Abdel-Rafei
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	breast cancer targeted therapy multifunctional core–shell nanoparticles antitumor radio-sensitization Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/30b0e5fd02144a2688abf0d6174f24e9
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spelling	oai:doaj.org-article:30b0e5fd02144a2688abf0d6174f24e92021-11-11T15:35:35ZDual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy10.3390/cancers132155712072-6694https://doaj.org/article/30b0e5fd02144a2688abf0d6174f24e92021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5571https://doaj.org/toc/2072-6694Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGF<sub>low</sub> and P53<sub>high</sub> signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.Mostafa A. AskarNoura M. ThabetGharieb S. El-SayyadAhmed I. El-BatalMohamed Abd ElkodousOmama E. El ShawiHamed HelalMohamed K. Abdel-RafeiMDPI AGarticlebreast cancertargeted therapymultifunctional core–shell nanoparticlesantitumorradio-sensitizationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5571, p 5571 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer targeted therapy multifunctional core–shell nanoparticles antitumor radio-sensitization Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer targeted therapy multifunctional core–shell nanoparticles antitumor radio-sensitization Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mostafa A. Askar Noura M. Thabet Gharieb S. El-Sayyad Ahmed I. El-Batal Mohamed Abd Elkodous Omama E. El Shawi Hamed Helal Mohamed K. Abdel-Rafei Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
description	Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGF<sub>low</sub> and P53<sub>high</sub> signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.
format	article
author	Mostafa A. Askar Noura M. Thabet Gharieb S. El-Sayyad Ahmed I. El-Batal Mohamed Abd Elkodous Omama E. El Shawi Hamed Helal Mohamed K. Abdel-Rafei
author_facet	Mostafa A. Askar Noura M. Thabet Gharieb S. El-Sayyad Ahmed I. El-Batal Mohamed Abd Elkodous Omama E. El Shawi Hamed Helal Mohamed K. Abdel-Rafei
author_sort	Mostafa A. Askar
title	Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
title_short	Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
title_full	Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
title_fullStr	Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
title_full_unstemmed	Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy
title_sort	dual hyaluronic acid and folic acid targeting ph-sensitive multifunctional 2dg@dca@mgo-nano-core–shell-radiosensitizer for breast cancer therapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/30b0e5fd02144a2688abf0d6174f24e9
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Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy

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