EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy

Zixuan Ye,1,* Yue Zhang,1,* Yuanfen Liu,2,* Yanyan Liu,1 Jiasheng Tu,1 Yan Shen1 1Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Jiangsu Health Vocational College, Nanjing, People’s Rep...

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Autores principales:	Ye Z, Zhang Y, Liu Y, Tu J, Shen Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	bovine serum albumin antibody-drug conjugate cetuximab doxorubicin colonic carcinoma epidermal growth factor receptor Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/74db8e037a8e4f8ca0a375138df1018e
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spelling	oai:doaj.org-article:74db8e037a8e4f8ca0a375138df1018e2021-12-02T13:50:20ZEGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy1178-2013https://doaj.org/article/74db8e037a8e4f8ca0a375138df1018e2021-03-01T00:00:00Zhttps://www.dovepress.com/egfr-targeted-cetuximab-valine-citrulline-vc-doxorubicin-immunoconjuga-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Zixuan Ye,1,* Yue Zhang,1,* Yuanfen Liu,2,* Yanyan Liu,1 Jiasheng Tu,1 Yan Shen1 1Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Jiangsu Health Vocational College, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Shen; Jiasheng TuDepartment of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, People’s Republic of ChinaTel +86 25 83271305Email shenyan@cpu.edu.cn; jiashengtu@aliyun.comBackground: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab–valine–citrulline (vc)–doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells.Methods: Maleimidocaproyl–valine–citrulline–p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody–drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs.Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR–overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPsConclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.Keywords: bovine serum albumin, antibody–drug conjugate, cetuximab, doxorubicin, colonic carcinoma, epidermal growth factor receptorYe ZZhang YLiu YLiu YTu JShen YDove Medical Pressarticlebovine serum albuminantibody-drug conjugatecetuximabdoxorubicincolonic carcinomaepidermal growth factor receptorMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 2443-2459 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bovine serum albumin antibody-drug conjugate cetuximab doxorubicin colonic carcinoma epidermal growth factor receptor Medicine (General) R5-920
spellingShingle	bovine serum albumin antibody-drug conjugate cetuximab doxorubicin colonic carcinoma epidermal growth factor receptor Medicine (General) R5-920 Ye Z Zhang Y Liu Y Liu Y Tu J Shen Y EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
description	Zixuan Ye,1,* Yue Zhang,1,* Yuanfen Liu,2,* Yanyan Liu,1 Jiasheng Tu,1 Yan Shen1 1Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Jiangsu Health Vocational College, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Shen; Jiasheng TuDepartment of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, People’s Republic of ChinaTel +86 25 83271305Email shenyan@cpu.edu.cn; jiashengtu@aliyun.comBackground: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab–valine–citrulline (vc)–doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells.Methods: Maleimidocaproyl–valine–citrulline–p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody–drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs.Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR–overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPsConclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.Keywords: bovine serum albumin, antibody–drug conjugate, cetuximab, doxorubicin, colonic carcinoma, epidermal growth factor receptor
format	article
author	Ye Z Zhang Y Liu Y Liu Y Tu J Shen Y
author_facet	Ye Z Zhang Y Liu Y Liu Y Tu J Shen Y
author_sort	Ye Z
title	EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
title_short	EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
title_full	EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
title_fullStr	EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
title_full_unstemmed	EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy
title_sort	egfr targeted cetuximab-valine-citrulline (vc)-doxorubicin immunoconjugates- loaded bovine serum albumin (bsa) nanoparticles for colorectal tumor therapy
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/74db8e037a8e4f8ca0a375138df1018e
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EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy

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