title: Antiandrogen gold nanoparticles dual-target and overcome treatment resistance in hormone-insensitive prostate cancer cells.
abstract: 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.
authors: Department of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive NW, Atlanta, GA 30332-0400, USA.
authors: Erik C
authors: EC
authors: Dreaden
authors: Berkley E
authors: BE
authors: Gryder
authors: Lauren A
authors: LA
authors: Austin
authors: Brice A
authors: BA
authors: Tene Defo
authors: Steven C
authors: SC
authors: Hayden
authors: Min
authors: M
authors: Pi
authors: L Darryl
authors: LD
authors: Quarles
authors: Adegboyega K
authors: AK
authors: Oyelere
authors: Mostafa A
authors: MA
authors: El-Sayed
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006046:Gold / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods*; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D006728:Hormones; D011944:Receptors, Androgen; D006046:Gold