You are not logged in.

Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex

Yin, Juan-Juan, Shumyak, Stepan P., Burgess, Christopher, Zhou, Zhi-Wei, He, Zhi-Xu, Zhang, Xue-Ji, Pan, Shu-Ting, Yang, Tian-Xin, Duan, Wei, Qiu, Jia-Xuan and Zhou, Shu-Feng 2015, Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex, International journal of nanomedicine, vol. 10, no. 1, pp. 4717-4730, doi: 10.2147/IJN.S82255.

Attached Files
Name Description MIMEType Size Downloads

Title Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex
Author(s) Yin, Juan-Juan
Shumyak, Stepan P.
Burgess, Christopher
Zhou, Zhi-Wei
He, Zhi-Xu
Zhang, Xue-Ji
Pan, Shu-Ting
Yang, Tian-Xin
Duan, Wei
Qiu, Jia-Xuan
Zhou, Shu-Feng
Journal name International journal of nanomedicine
Volume number 10
Issue number 1
Start page 4717
End page 4730
Total pages 14
Publisher Dove Press
Place of publication Auckland, N. Z.
Publication date 2015-07-27
ISSN 1178-2013
Keyword(s) breast cancer
drug vector
functionalized
membrane estrogen receptor
polysaccharide
targeted drug delivery
antineoplastic agents
breast neoplasms
cyclodextrins
receptor-alpha
Summary Breast cancer is a leading killer of women worldwide. Cyclodextrin-based estrogen receptor-targeting drug-delivery systems represent a promising direction in cancer therapy but have rarely been investigated. To seek new targeting therapies for membrane estrogen receptor-positive breast cancer, an estrogen-anchored cyclodextrin encapsulating a doxorubicin derivative Ada-DOX (CDE1-Ada-DOX) has been synthesized and evaluated in human breast cancer MCF-7 cells. First, we synthesized estrone-conjugated cyclodextrin (CDE1), which formed the complex CDE1-Ada-DOX via molecular recognition with the derivative adamantane-doxorubicin (Ada-DOX) (Kd =1,617 M(-1)). The structure of the targeting vector CDE1 was fully characterized using (1)H- and (13)C-nuclear magnetic resonance, mass spectrometry, and electron microscopy. CDE1-Ada-DOX showed two-phase drug-release kinetics with much slower release than Ada-DOX. The fluorescence polarization analysis reveals that CDE1-Ada-DOX binds to recombinant human estrogen receptor α fragments with a Kd of 0.027 µM. Competition assay of the drug complex with estrogen ligands demonstrated that estrone and tamoxifen competed with CDE1-Ada-DOX for membrane estrogen receptor binding in MCF-7 cells. Intermolecular self-assembly of CDE1 molecules were observed, showing tail-in-bucket and wire-like structures confirmed by transmission electronic microscopy. CDE1-Ada-DOX had an unexpected lower drug uptake (when the host-guest ratio was >1) than non-targeting drugs in MCF-7 cells due to ensconced ligands in cyclodextrins cavities resulting from the intermolecular self-assembly. The uptake of CDE1-Ada-DOX was significantly increased when the host-guest ratio was adjusted to be less than half at the concentration of CDE1 over 5 µM due to the release of the estrone residues. CDE1 elicited rapid activation of mitogen-activated protein kinases (p44/42 MAPK, Erk1/2) in minutes through phosphorylation of Thr202/Tyr204 in MCF-7 cells. These results demonstrate a targeted therapeutics delivery of CDE1-Ada-DOX to breast cancer cells in a controlled manner and that the drug vector CDE1 can potentially be employed as a molecular tool to differentiate nongenomic from genomic mechanism.
Language eng
DOI 10.2147/IJN.S82255
Field of Research 111204 Cancer Therapy (excl Chemotherapy and Radiation Therapy)
1115 Pharmacology And Pharmaceutical Sciences
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30080717

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 2 times in TR Web of Science
Scopus Citation Count Cited 2 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 81 Abstract Views, 3 File Downloads  -  Detailed Statistics
Created: Thu, 14 Jan 2016, 11:10:53 EST

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.