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Article

Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy

1
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166-15731, Iran
2
Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
3
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
4
Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5166-15731, Iran
5
Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
6
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 5166-15731, Iran
7
McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
8
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
9
Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz 51666-16471, Iran
*
Authors to whom correspondence should be addressed.
Authors equal contribution.
Academic Editors: Robert Winqvist and Paolo Cinelli
Received: 15 February 2021 / Revised: 10 July 2021 / Accepted: 16 July 2021 / Published: 20 July 2021
(This article belongs to the Special Issue Transcription Factors in Cancer Progression)
The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target delivery. Here, methotrexate (MTX)- modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time- and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the folate receptor expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer. View Full-Text
Keywords: apoptosis; dendrimer; HMGA2 siRNA; methotrexate; breast cancer apoptosis; dendrimer; HMGA2 siRNA; methotrexate; breast cancer
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MDPI and ACS Style

Abedi Gaballu, F.; Cho, W.C.-S.; Dehghan, G.; Zarebkohan, A.; Baradaran, B.; Mansoori, B.; Abbaspour-Ravasjani, S.; Mohammadi, A.; Sheibani, N.; Aghanejad, A.; Ezzati Nazhad Dolatabadi, J. Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy. Genes 2021, 12, 1102. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071102

AMA Style

Abedi Gaballu F, Cho WC-S, Dehghan G, Zarebkohan A, Baradaran B, Mansoori B, Abbaspour-Ravasjani S, Mohammadi A, Sheibani N, Aghanejad A, Ezzati Nazhad Dolatabadi J. Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy. Genes. 2021; 12(7):1102. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071102

Chicago/Turabian Style

Abedi Gaballu, Fereydoon, William C.-S. Cho, Gholamreza Dehghan, Amir Zarebkohan, Behzad Baradaran, Behzad Mansoori, Soheil Abbaspour-Ravasjani, Ali Mohammadi, Nader Sheibani, Ayuob Aghanejad, and Jafar Ezzati Nazhad Dolatabadi. 2021. "Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy" Genes 12, no. 7: 1102. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071102

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