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Antiandrogen Gold Nanoparticles Dual-Target and Overcome Treatment Resistance in Hormone-Insensitive Prostate Cancer Cells

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Department of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive NW, Atlanta, Georgia 30332-0400, United States
§ Parker H. Petit Institute for Bioengineering and Biosciences, Department of Chemistry and Biochemistry, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332-0230, United States
Department of Medicine, University of Tennessee Health Science Center, 19 South Manassas Street, Memphis, Tennessee 38163, United States
*Prof. Mostafa A. El-Sayed: E-mail [email protected]. Prof. Adegboyega K. Oyelere: E-mail [email protected]
Cite this: Bioconjugate Chem. 2012, 23, 8, 1507–1512
Publication Date (Web):July 9, 2012
https://doi.org/10.1021/bc300158k
Copyright © 2012 American Chemical Society

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    Abstract

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    Prostate cancer is the most commonly diagnosed cancer among men in the developed countries. (1) One in six males in the U.S. (2) and one in nine males in the U.K. (3) will develop the disease at some point during their lifetime. Despite advances in prostate cancer screening, more than a quarter of a million men die from the disease every year (1) due primarily to treatment-resistance and metastasis. Colloidal nanotechnologies can provide tremendous enhancements to existing targeting/treatment strategies for prostate cancer to which malignant cells are less sensitive. Here, we show that antiandrogen gold nanoparticles—multivalent analogues of antiandrogens currently used in clinical therapy for prostate cancer—selectively engage two distinct receptors, androgen receptor (AR), a target for the treatment of prostate cancer, as well as a novel G-protein coupled receptor, GPRC6A, that is also upregulated in prostate cancer. These nanoparticles selectively accumulated in hormone-insensitive and chemotherapy-resistant prostate cancer cells, bound androgen receptor with multivalent affinity, and exhibited greatly enhanced drug potency versus monovalent antiandrogens currently in clinical use. Further, antiandrogen gold nanoparticles selectively stimulated GPRC6A with multivalent affinity, demonstrating that the delivery of nanoscale antiandrogens can also be facilitated by the transmembrane receptor in order to realize increasingly selective, increasingly potent therapy for treatment-resistant prostate cancers.

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    Antiandrogen ligand synthesis; nanoparticle synthesis, conjugation, and characterization; docking methods, cell culture/in vitro analysis, radioligand binding, GPRC6A expression/stimulation, and imaging methods. This material is available free of charge via the Internet at http://pubs.acs.org.

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