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Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment

Yin, Juan-Juan, Sharma, Sonali, Shumyak, Stepan P., Wang, Zhi-Xin, Zhou, Zhi-Wei, Zhang, Yangde, Guo, Peixuan, Li, Chen-Zhong, Kanwar, Jagat R., Yang, Tianxin, Mohapatra, Shyam S., Liu, Wanqing, Duan, Wei, Wang, Jian-Cheng, Li, Qi, Zhang, Xueji, Tan, Jun, Jia, Lee, Liang, Jun, Wei, Ming Q., Li, Xiaotian and Zhou, Shu-Feng 2013, Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment, PLOS one, vol. 8, no. 5, Article e62289, pp. 1-20.

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Title Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment
Author(s) Yin, Juan-Juan
Sharma, Sonali
Shumyak, Stepan P.
Wang, Zhi-Xin
Zhou, Zhi-Wei
Zhang, Yangde
Guo, Peixuan
Li, Chen-Zhong
Kanwar, Jagat R.
Yang, Tianxin
Mohapatra, Shyam S.
Liu, Wanqing
Duan, Wei
Wang, Jian-Cheng
Li, Qi
Zhang, Xueji
Tan, Jun
Jia, Lee
Liang, Jun
Wei, Ming Q.
Li, Xiaotian
Zhou, Shu-Feng
Journal name PLOS one
Volume number 8
Issue number 5
Season Article e62289
Start page 1
End page 20
Total pages 20
Publisher Public Library of Science
Place of publication San Francisco, California
Publication date 2013-05-02
ISSN 1932-6203
Summary Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant Ka was 1,639 M-1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.
Language eng
Field of Research 111504 Pharmaceutical Sciences
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2013, Public Library of Science
Persistent URL http://hdl.handle.net/10536/DRO/DU:30059549

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.