Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

Qin Zeng, Jianfeng Han, Dong Zhao, Tao Gong, Zhirong Zhang, Xun SunKey Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People&#39;s Republic of ChinaBackground: The generation of anti-adenovirus neutra...

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Autores principales:	Sun X, Zhang Z, Gong T, Zhao D, Han J, Zeng Q
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/9852db1ffa3445119a39cb50a00bcbaa
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spelling	oai:doaj.org-article:9852db1ffa3445119a39cb50a00bcbaa2021-12-02T04:52:25ZProtection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus1176-91141178-2013https://doaj.org/article/9852db1ffa3445119a39cb50a00bcbaa2012-02-01T00:00:00Zhttp://www.dovepress.com/protection-of-adenovirus-from-neutralizing-antibody-by-cationic-peg-de-a9365https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Qin Zeng, Jianfeng Han, Dong Zhao, Tao Gong, Zhirong Zhang, Xun SunKey Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People&#39;s Republic of ChinaBackground: The generation of anti-adenovirus neutralizing antibody (NAb) in humans severely restricts the utilization of recombinant adenovirus serotype 5 (Ad5) vectors in gene therapy for a wide range of clinical trials. To overcome this limitation, we ionically complexed Ad5 with a newly synthesized copolymer, which we called APC, making an adenovirus shielded from NAb.Methods: APC, a cationic polyethylene glycol derivative, was synthesized via two steps of ring-opening copolymerization of ethylene oxide and allyl glycidyl ether, followed by the addition of 2-mercaptoethylamine. The copolymer or the control PEI-2k was ionically complexed to anionic Ad5 in 5% glucose, and in vitro transduction assays were carried out in coxsackievirus and adenovirus receptor-positive cells (A549) and coxsackievirus and adenovirus receptor-negative cells (B16 and SKOV3). The physical properties and morphology of adenovirus alone or the complexes were investigated respectively by zeta potential, size distribution, and transmission electron microscopy image. Then cytotoxicity of APC was examined using 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Finally, the ability of APC to protect adenovirus from NAb was evaluated by transfection assays after a neutralizing effect.Results: APC was successfully synthesized and showed a low cytotoxicity. Positively charged Ad5/APC exhibited slightly increased diameter (130.2 &plusmn; 0.60 nm) than naked Ad5 (115.6 &plusmn; 5.46 nm) while Ad5/PEI-2k showed severe aggregation (1382 &plusmn; 79.9 nm). Ad5/APC achieved a gene transfection level as high as Ad5/PEI-2k in A549 or B16 cells, and significantly higher than Ad5/PEI-2k in SKOV3 cells. Most importantly, after the exposure to the neutralizing antibody, naked Ad5 and Ad5/PEI-2k exhibited poor gene expression while Ad5/APC still showed significantly efficient gene expression.Conclusion: Our results demonstrated that Ad5/APC complex offered good protection for Ad5 against NAb in vitro and suggested a potential strategy of resistance to NAb in vivo.Keywords: adenovirus, cationic PEG derivative, anti-adenovirus neutralizing antibodySun XZhang ZGong TZhao DHan JZeng QDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 985-997 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Sun X Zhang Z Gong T Zhao D Han J Zeng Q Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
description	Qin Zeng, Jianfeng Han, Dong Zhao, Tao Gong, Zhirong Zhang, Xun SunKey Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People&#39;s Republic of ChinaBackground: The generation of anti-adenovirus neutralizing antibody (NAb) in humans severely restricts the utilization of recombinant adenovirus serotype 5 (Ad5) vectors in gene therapy for a wide range of clinical trials. To overcome this limitation, we ionically complexed Ad5 with a newly synthesized copolymer, which we called APC, making an adenovirus shielded from NAb.Methods: APC, a cationic polyethylene glycol derivative, was synthesized via two steps of ring-opening copolymerization of ethylene oxide and allyl glycidyl ether, followed by the addition of 2-mercaptoethylamine. The copolymer or the control PEI-2k was ionically complexed to anionic Ad5 in 5% glucose, and in vitro transduction assays were carried out in coxsackievirus and adenovirus receptor-positive cells (A549) and coxsackievirus and adenovirus receptor-negative cells (B16 and SKOV3). The physical properties and morphology of adenovirus alone or the complexes were investigated respectively by zeta potential, size distribution, and transmission electron microscopy image. Then cytotoxicity of APC was examined using 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Finally, the ability of APC to protect adenovirus from NAb was evaluated by transfection assays after a neutralizing effect.Results: APC was successfully synthesized and showed a low cytotoxicity. Positively charged Ad5/APC exhibited slightly increased diameter (130.2 &plusmn; 0.60 nm) than naked Ad5 (115.6 &plusmn; 5.46 nm) while Ad5/PEI-2k showed severe aggregation (1382 &plusmn; 79.9 nm). Ad5/APC achieved a gene transfection level as high as Ad5/PEI-2k in A549 or B16 cells, and significantly higher than Ad5/PEI-2k in SKOV3 cells. Most importantly, after the exposure to the neutralizing antibody, naked Ad5 and Ad5/PEI-2k exhibited poor gene expression while Ad5/APC still showed significantly efficient gene expression.Conclusion: Our results demonstrated that Ad5/APC complex offered good protection for Ad5 against NAb in vitro and suggested a potential strategy of resistance to NAb in vivo.Keywords: adenovirus, cationic PEG derivative, anti-adenovirus neutralizing antibody
format	article
author	Sun X Zhang Z Gong T Zhao D Han J Zeng Q
author_facet	Sun X Zhang Z Gong T Zhao D Han J Zeng Q
author_sort	Sun X
title	Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
title_short	Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
title_full	Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
title_fullStr	Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
title_full_unstemmed	Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus
title_sort	protection of adenovirus from neutralizing antibody by cationic peg derivative ionically linked to adenovirus
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/9852db1ffa3445119a39cb50a00bcbaa
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Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

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