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

Authors Huang Y, Yang T, Zhang W, Lu Y, Ye P, Yang G, Li B, Qi S, Liu Y, He X, Lee R, Xu C, Xiang G

Received 10 June 2014

Accepted for publication 10 July 2014

Published 29 September 2014 Volume 2014:9(1) Pages 4581—4595


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

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 work

Abstract: 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

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