Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry.

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2019
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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.
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mutuku2019evaluationscientific Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Mutuku, Shadrack M;Trim, Paul J;Prabhala, Bala K;Irani, Swati;Bremert, Kayla L;Logan, Jessica M;Brooks, Douglas A;Stahl, Jürgen;Centenera, Margaret M;Snel, Marten F;Butler, Lisa M;
Journal Scientific reports
Year 2019
DOI
10.1038/s41598-019-51549-3
URL
Keywords
latinos religiosity faith-based health interventions medical mistrust

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