Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle

Chao Zhang,1 Mengnan Han,1 Fanghua Zhang,1 Xueli Yang,1 Jie Du,1 Honglei Zhang,1 Wei Li,1 Shengxi Chen2 1College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei...

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Autores principales:	Zhang C, Han M, Zhang F, Yang X, Du J, Zhang H, Li W, Chen S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	5-fluorodeoxyuridine targeting therapy her2 breast cancer affibody dna nanoparticle Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/4800d443b36b4f73bb230223ee2805e6
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spelling	oai:doaj.org-article:4800d443b36b4f73bb230223ee2805e62021-12-02T03:36:31ZEnhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle1178-2013https://doaj.org/article/4800d443b36b4f73bb230223ee2805e62020-02-01T00:00:00Zhttps://www.dovepress.com/enhancing-antitumor-efficacy-of-nucleoside-analog-5-fluorodeoxyuridine-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Chao Zhang,1 Mengnan Han,1 Fanghua Zhang,1 Xueli Yang,1 Jie Du,1 Honglei Zhang,1 Wei Li,1 Shengxi Chen2 1College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People’s Republic of China; 2Biodesign Center for BioEnergetics, Arizona State University, Tempe, AZ 85287, USACorrespondence: Honglei Zhang; Wei LiCollege of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People’s Republic of ChinaTel/Fax +86 312 592 9009Email zhanghonglei@hbu.edu.cn; liweihebeilab@163.comBackground: Chemotherapy, as an adjuvant treatment strategy for HER2-positive breast cancer, can effectively improve clinical symptoms and overcome the drug resistance of therapeutic monoclonal antibodies. Nucleoside analogues are a class of traditional chemotherapeutic drugs that are widely applied in adjuvant therapy. However, there are many critical issues that limit their clinical efficiency, including poor selectivity and stability, severe side effects and suboptimal therapeutic efficacy. Hence, this work aims to develop a new DNA nanocarrier for targeted drug delivery to solve the above problems.Methods: Four 41-mer DNA strands were synthesized and 10 FUdR molecules were attached to 5ʹ end of each DNA strand by DNA solid-phase synthesis. An affibody molecule was connected to the end of polymeric FUdR through a linker in one of the four strands. The affibody-FUdR-tetrahedral DNA nanostructures (affi-F/TDNs) were self-assembled through four DNA strands, in which one vertex was connected to an affibody at the end of a polymeric FUdR tail and three vertices were only polymeric FUdR tails. In vitro cellular uptake of affi-F/TDNs was examined visually with confocal fluorescence microscopy and flow cytometry, and the cytotoxicity of affi-F/TDNs against cancer cells was investigated with MTT assay. Cell apoptosis was detected by Annexin V-FITC/PI double staining method. Using NOD/SCID (Mus Musculus) mice model, the targeted killing efficacy of affi-F/TDNs was also evaluated.Results: The drug-loading of FUdR in affi-TDNs was 19.6% in mole ratio. The in vitro results showed that affi-F/TDNs had high selectivity and inhibition (81.2%) for breast cancer BT474 cells overexpressing HER2 and low toxicity in MCF-7 cells with low HER2 expression. During the in vivo application, affi-F/TDNs displayed good stability in the blood circulation, achieved specific accumulation in tumor region and the best antitumor efficacy (inhibition ratio of 58.1%), and showed excellent biocompatibility.Conclusions: The affibody-DNA tetrahedrons, as a simple and effective active targeting delivery nanocarrier, provided a new avenue for the transport of nucleoside antitumor drugs.Keywords: 5-fluorodeoxyuridine, targeting therapy, her2, breast cancer, affibody, DNA nanoparticleZhang CHan MZhang FYang XDu JZhang HLi WChen SDove Medical Pressarticle5-fluorodeoxyuridinetargeting therapyher2breast canceraffibodydna nanoparticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 885-900 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	5-fluorodeoxyuridine targeting therapy her2 breast cancer affibody dna nanoparticle Medicine (General) R5-920
spellingShingle	5-fluorodeoxyuridine targeting therapy her2 breast cancer affibody dna nanoparticle Medicine (General) R5-920 Zhang C Han M Zhang F Yang X Du J Zhang H Li W Chen S Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
description	Chao Zhang,1 Mengnan Han,1 Fanghua Zhang,1 Xueli Yang,1 Jie Du,1 Honglei Zhang,1 Wei Li,1 Shengxi Chen2 1College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People’s Republic of China; 2Biodesign Center for BioEnergetics, Arizona State University, Tempe, AZ 85287, USACorrespondence: Honglei Zhang; Wei LiCollege of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People’s Republic of ChinaTel/Fax +86 312 592 9009Email zhanghonglei@hbu.edu.cn; liweihebeilab@163.comBackground: Chemotherapy, as an adjuvant treatment strategy for HER2-positive breast cancer, can effectively improve clinical symptoms and overcome the drug resistance of therapeutic monoclonal antibodies. Nucleoside analogues are a class of traditional chemotherapeutic drugs that are widely applied in adjuvant therapy. However, there are many critical issues that limit their clinical efficiency, including poor selectivity and stability, severe side effects and suboptimal therapeutic efficacy. Hence, this work aims to develop a new DNA nanocarrier for targeted drug delivery to solve the above problems.Methods: Four 41-mer DNA strands were synthesized and 10 FUdR molecules were attached to 5ʹ end of each DNA strand by DNA solid-phase synthesis. An affibody molecule was connected to the end of polymeric FUdR through a linker in one of the four strands. The affibody-FUdR-tetrahedral DNA nanostructures (affi-F/TDNs) were self-assembled through four DNA strands, in which one vertex was connected to an affibody at the end of a polymeric FUdR tail and three vertices were only polymeric FUdR tails. In vitro cellular uptake of affi-F/TDNs was examined visually with confocal fluorescence microscopy and flow cytometry, and the cytotoxicity of affi-F/TDNs against cancer cells was investigated with MTT assay. Cell apoptosis was detected by Annexin V-FITC/PI double staining method. Using NOD/SCID (Mus Musculus) mice model, the targeted killing efficacy of affi-F/TDNs was also evaluated.Results: The drug-loading of FUdR in affi-TDNs was 19.6% in mole ratio. The in vitro results showed that affi-F/TDNs had high selectivity and inhibition (81.2%) for breast cancer BT474 cells overexpressing HER2 and low toxicity in MCF-7 cells with low HER2 expression. During the in vivo application, affi-F/TDNs displayed good stability in the blood circulation, achieved specific accumulation in tumor region and the best antitumor efficacy (inhibition ratio of 58.1%), and showed excellent biocompatibility.Conclusions: The affibody-DNA tetrahedrons, as a simple and effective active targeting delivery nanocarrier, provided a new avenue for the transport of nucleoside antitumor drugs.Keywords: 5-fluorodeoxyuridine, targeting therapy, her2, breast cancer, affibody, DNA nanoparticle
format	article
author	Zhang C Han M Zhang F Yang X Du J Zhang H Li W Chen S
author_facet	Zhang C Han M Zhang F Yang X Du J Zhang H Li W Chen S
author_sort	Zhang C
title	Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
title_short	Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
title_full	Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
title_fullStr	Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
title_full_unstemmed	Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle
title_sort	enhancing antitumor efficacy of nucleoside analog 5-fluorodeoxyuridine on her2-overexpressing breast cancer by affibody-engineered dna nanoparticle
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/4800d443b36b4f73bb230223ee2805e6
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Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle

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