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Guiding treatment selection for advanced prostate cancer with biogenic silver nanoparticles
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- Author / Creator
- Rajput, Sunil
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Prostate cancer (PCa) is the second most common cancer in men worldwide. Men with advanced PCa often face poor prognosis and are at high risk for mortality. To improve prognosis in this high risk population, targeting a reliable biological factor or marker that predicts a patient’s response (sensitivity or resistance) to a specific treatment offers therapeutic guidance and clinical benefit. Two major hormonal treatments for advanced PCa are enzalutamide and abiraterone; which either block the binding of a steroid (androgen) to its protein receptor (androgen receptor, AR) or decrease androgen synthesis. Recently, presence of an AR variant (AR-V7) has been linked to resistance of these hormonal treatments. Thus, triaging PCa patients that are AR-V7 positive to other systemic treatments (e.g., taxane-based chemotherapy) can improve progression-free survival and overall survival. However, optimal sequencing available systemic treatments to maximize individual patient benefits remains a critical unmet need in this clinical setting. This work demonstrates a nanomaterial-enhanced antibody sandwich assay for the successful detection of AR-V7 protein in serum of metastatic castration-resistant prostate cancer (mCRPC) patients. Highly sensitive detection is driven by the optical properties of noble metal nanoparticles. Biogenic spherical silver metal nanoparticles, produced by the fungus Fusarium oxysporum, were incorporated as plasmonic labels for enhanced spectroscopy. Biogenic silver nanoparticles are stabilized with a surface corona that is unique relative to their chemically-prepared counterparts. This method produces nanoparticles with a native biological scaffold surrounding the nanoparticles that provides enhanced stability and enables facile antibody attachment. AR-V7 was captured onto a fabricated chip containing specific antibodies immobilized on gold spots and subsequently labelled for detection by antibody coated silver nanoparticles. Measurement of the number of nanoparticles that bind to the chip was accomplished using surface-enhanced Raman scattering (SERS), which provides a unique chemical fingerprint of the label. A prospective pilot scale investigation of clinical utility demonstrated the ability to quantitatively measure AR-V7 in serum of a blinded retrospective cohort of seven advanced PCa patients pre / post treatment with enzalutamide and / or abiraterone. Results presented show distinct separation of PCa patients by AR-V7 status (positive or negative) by a low detection limit established with normal healthy male controls. Presence and amount of AR-V7 in serum offers predictive and prognostic value to inform selection between two classes of systemic treatments (i.e., hormones or taxanes) outlined in the Canadian and American clinical guidelines for managing castration-resistant PCa. Contributions of this work paves the way for a sensitive, rapid, and minimally-invasive SERS-based tool for advanced PCa patients with the aim of better patient outcomes.
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- Graduation date
- Fall 2018
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.