Title |
Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex
|
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Published in |
International Journal of Nanomedicine, July 2015
|
DOI | 10.2147/ijn.s82255 |
Pubmed ID | |
Authors |
Juan-Juan Yin, Stepan P Shumyak, Christopher Burgess, Zhi-Wei Zhou, Zhi-Xu He, Xue-Ji Zhang, Shu-Ting Pan, Tian-Xin Yang, Wei Duan, Jia-Xuan Qiu, Shu-Feng Zhou |
Abstract |
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) (K d =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 K d 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Canada | 1 | 25% |
Unknown | 3 | 75% |
Demographic breakdown
Type | Count | As % |
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Practitioners (doctors, other healthcare professionals) | 3 | 75% |
Members of the public | 1 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 16 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 4 | 25% |
Student > Ph. D. Student | 4 | 25% |
Professor | 2 | 13% |
Researcher | 2 | 13% |
Other | 1 | 6% |
Other | 1 | 6% |
Unknown | 2 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 19% |
Chemistry | 3 | 19% |
Medicine and Dentistry | 2 | 13% |
Neuroscience | 2 | 13% |
Agricultural and Biological Sciences | 1 | 6% |
Other | 1 | 6% |
Unknown | 4 | 25% |