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https://hdl.handle.net/2440/121654
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Type: | Journal article |
Title: | Evaluation of small molecule drug uptake in patient-derived prostate cancer explants by mass spectrometry |
Author: | Mutuku, S.M. Trim, P.J. Prabhala, B.K. Irani, S. Bremert, K.L. Logan, J.M. Brooks, D.A. Stahl, J. Centenera, M.M. Snel, M.F. Butler, L.M. |
Citation: | Scientific Reports, 2019; 9(1):15008-15008 |
Publisher: | Nature Publishing Group |
Issue Date: | 2019 |
ISSN: | 2045-2322 2045-2322 |
Statement of Responsibility: | Shadrack M. Mutuku, Paul J. Trim, Bala K. Prabhala, Swati Irani, Kayla L. Bremert, Jessica M. Logan, Douglas A. Brooks, Jürgen Stahl, Margaret M. Centenera, Marten F. Snel, Lisa M. Butler |
Abstract: | Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10 µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24-0.50 ng/µg protein after 48 h culture. Time dependent uptake of enzalutamide (50 µM) in PDEs was visualized using MALDI MSI over 24-48 h, with complete penetration throughout tissues evident by 6 h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data. |
Keywords: | Cells, Cultured Humans Prostatic Neoplasms Benzamides Nitriles Phenylthiohydantoin Antineoplastic Agents Chromatography, Liquid Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Cohort Studies Drug Evaluation, Preclinical Aged Middle Aged Male Tandem Mass Spectrometry Androgen Receptor Antagonists Absorption, Physicochemical |
Rights: | © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
DOI: | 10.1038/s41598-019-51549-3 |
Grant ID: | http://purl.org/au-research/grants/arc/FT130101004 |
Published version: | http://dx.doi.org/10.1038/s41598-019-51549-3 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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