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

Shadrack M. Mutuku, Paul Trim, Bala K. Prabhala, Swati Irani, Kayla Bremert, Jessica M. Logan, Douglas A. Brooks, Jürgen Stahl, Margaret M. Centenera, Marten Snel, Lisa Butler

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article number15008
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

ASJC Scopus subject areas

  • General

Cite this

Mutuku, Shadrack M. ; Trim, Paul ; Prabhala, Bala K. ; Irani, Swati ; Bremert, Kayla ; Logan, Jessica M. ; Brooks, Douglas A. ; Stahl, Jürgen ; Centenera, Margaret M. ; Snel, Marten ; Butler, Lisa. / Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry. / Mutuku, Shadrack M.; Trim, Paul; Prabhala, Bala K.; Irani, Swati; Bremert, Kayla; Logan, Jessica M.; Brooks, Douglas A.; Stahl, Jürgen; Centenera, Margaret M.; Snel, Marten; Butler, Lisa.

In: Scientific Reports, Vol. 9, No. 1, 15008, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Trim, Paul

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AU - Irani, Swati

AU - Bremert, Kayla

AU - Logan, Jessica M.

AU - Brooks, Douglas A.

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AU - Butler, Lisa

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