duan-controllabledrug-2015.pdf (2.6 MB)
Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex
journal contribution
posted on 2015-07-27, 00:00 authored by J J Yin, S P Shumyak, C Burgess, Z W Zhou, Z X He, X J Zhang, S T Pan, T X Yang, Wei DuanWei Duan, J X Qiu, S F ZhouBreast 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.
History
Journal
International journal of nanomedicineVolume
10Issue
1Pagination
4717 - 4730Publisher
Dove PressLocation
Auckland, N. Z.Publisher DOI
Link to full text
eISSN
1178-2013Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2015, The AuthorsUsage metrics
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No categories selectedKeywords
breast cancerdrug vectorfunctionalizedmembrane estrogen receptorpolysaccharidetargeted drug deliveryantineoplastic agentsbreast neoplasmscyclodextrinsreceptor-alphaScience & TechnologyLife Sciences & BiomedicineNanoscience & NanotechnologyPharmacology & PharmacyScience & Technology - Other TopicsBREAST-CANCERKINASE PATHWAYSRECEPTORMEMBRANEACTIVATIONMECHANISMSDELIVERYDOXORUBICINRECOGNITIONBINDING
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