A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo

Yifei Huang,1,* Tan Yang,2,* Wendian Zhang,2 Yao Lu,2 Peng Ye,2 Guang Yang,2 Bin Li,2 Shibo Qi,2 Yong Liu,2 Xingxing He,3 Robert J Lee,4 Chuanrui Xu,2 Guangya Xiang2 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People&...

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Autores principales:	Huang Y, Yang T, Zhang W, Lu Y, Ye P, Yang G, Li B, Qi S, Liu Y, He X, Lee RJ, Xu C, Xiang G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/ea689734401e4c5a9d88af4e36e65a77
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spelling	oai:doaj.org-article:ea689734401e4c5a9d88af4e36e65a772021-12-02T00:07:20ZA novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo1178-2013https://doaj.org/article/ea689734401e4c5a9d88af4e36e65a772014-09-01T00:00:00Zhttp://www.dovepress.com/a-novel-hydrolysis-resistant-lipophilic-folate-derivative-enables-stab-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013 Yifei Huang,1,* Tan Yang,2,* Wendian Zhang,2 Yao Lu,2 Peng Ye,2 Guang Yang,2 Bin Li,2 Shibo Qi,2 Yong Liu,2 Xingxing He,3 Robert J Lee,4 Chuanrui Xu,2 Guangya Xiang2 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 4Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA*These authors contributed equally to this workAbstract: Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.Keywords: liposome, doxorubicin, folate ligand, FR-targeting, stabilityHuang YYang TZhang WLu YYe PYang GLi BQi SLiu YHe XLee RJXu CXiang GDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2014, Iss Issue 1, Pp 4581-4595 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Huang Y Yang T Zhang W Lu Y Ye P Yang G Li B Qi S Liu Y He X Lee RJ Xu C Xiang G A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
description	Yifei Huang,1,* Tan Yang,2,* Wendian Zhang,2 Yao Lu,2 Peng Ye,2 Guang Yang,2 Bin Li,2 Shibo Qi,2 Yong Liu,2 Xingxing He,3 Robert J Lee,4 Chuanrui Xu,2 Guangya Xiang2 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 4Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA*These authors contributed equally to this workAbstract: Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.Keywords: liposome, doxorubicin, folate ligand, FR-targeting, stability
format	article
author	Huang Y Yang T Zhang W Lu Y Ye P Yang G Li B Qi S Liu Y He X Lee RJ Xu C Xiang G
author_facet	Huang Y Yang T Zhang W Lu Y Ye P Yang G Li B Qi S Liu Y He X Lee RJ Xu C Xiang G
author_sort	Huang Y
title	A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
title_short	A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
title_full	A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
title_fullStr	A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
title_full_unstemmed	A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
title_sort	novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/ea689734401e4c5a9d88af4e36e65a77
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A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo

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