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A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues

Understanding the pharmacokinetic/pharmacodynamic (PK/PD)-relationship of a drug candidate is key to determine effective, yet safe treatment regimens for patients. However, current testing strategies are inefficient in characterizing in vivo responses to fluctuating drug concentrations during multi-...

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Autores principales: Lohasz, Christian, Loretan, Jacqueline, Sterker, Dario, Görlach, Ekkehard, Renggli, Kasper, Argast, Paul, Frey, Olivier, Wiesmann, Marion, Wartmann, Markus, Rausch, Martin, Hierlemann, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954798/
https://www.ncbi.nlm.nih.gov/pubmed/35342386
http://dx.doi.org/10.3389/fphar.2021.785851
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author Lohasz, Christian
Loretan, Jacqueline
Sterker, Dario
Görlach, Ekkehard
Renggli, Kasper
Argast, Paul
Frey, Olivier
Wiesmann, Marion
Wartmann, Markus
Rausch, Martin
Hierlemann, Andreas
author_facet Lohasz, Christian
Loretan, Jacqueline
Sterker, Dario
Görlach, Ekkehard
Renggli, Kasper
Argast, Paul
Frey, Olivier
Wiesmann, Marion
Wartmann, Markus
Rausch, Martin
Hierlemann, Andreas
author_sort Lohasz, Christian
collection PubMed
description Understanding the pharmacokinetic/pharmacodynamic (PK/PD)-relationship of a drug candidate is key to determine effective, yet safe treatment regimens for patients. However, current testing strategies are inefficient in characterizing in vivo responses to fluctuating drug concentrations during multi-day treatment cycles. Methods based on animal models are resource-intensive and require time, while traditional in vitro cell-culturing methods usually do not provide temporally-resolved information on the effects of in vivo–like drug exposure scenarios. To address this issue, we developed a microfluidic system to 1) culture arrays of three-dimensional spheroids in vitro, to 2) apply specific dynamic drug exposure profiles, and to 3) in-situ analyze spheroid growth and the invoked drug effects in 3D by means of 2-photon microscopy at tissue and single-cell level. Spheroids of fluorescently-labeled T-47D breast cancer cells were monitored under perfusion-culture conditions at short time intervals over three days and exposed to either three 24 h-PK-cycles or a dose-matched constant concentration of the phosphatidylinositol 3-kinase inhibitor BYL719. While the overall efficacy of the two treatment regimens was similar, spheroids exposed to the PK profile displayed cycle-dependent oscillations between regression and regrowth. Spheroids treated with a constant BYL719 concentration regressed at a steady, albeit slower rate. At a single-cell level, the cell density in BYL719-treated spheroids oscillated in a concentration-dependent manner. Our system represents a versatile tool for in-depth preclinical characterization of PK/PD parameters, as it enables an evaluation of drug efficacy and/or toxicity under realistic exposure conditions.
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spelling pubmed-89547982022-03-26 A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues Lohasz, Christian Loretan, Jacqueline Sterker, Dario Görlach, Ekkehard Renggli, Kasper Argast, Paul Frey, Olivier Wiesmann, Marion Wartmann, Markus Rausch, Martin Hierlemann, Andreas Front Pharmacol Pharmacology Understanding the pharmacokinetic/pharmacodynamic (PK/PD)-relationship of a drug candidate is key to determine effective, yet safe treatment regimens for patients. However, current testing strategies are inefficient in characterizing in vivo responses to fluctuating drug concentrations during multi-day treatment cycles. Methods based on animal models are resource-intensive and require time, while traditional in vitro cell-culturing methods usually do not provide temporally-resolved information on the effects of in vivo–like drug exposure scenarios. To address this issue, we developed a microfluidic system to 1) culture arrays of three-dimensional spheroids in vitro, to 2) apply specific dynamic drug exposure profiles, and to 3) in-situ analyze spheroid growth and the invoked drug effects in 3D by means of 2-photon microscopy at tissue and single-cell level. Spheroids of fluorescently-labeled T-47D breast cancer cells were monitored under perfusion-culture conditions at short time intervals over three days and exposed to either three 24 h-PK-cycles or a dose-matched constant concentration of the phosphatidylinositol 3-kinase inhibitor BYL719. While the overall efficacy of the two treatment regimens was similar, spheroids exposed to the PK profile displayed cycle-dependent oscillations between regression and regrowth. Spheroids treated with a constant BYL719 concentration regressed at a steady, albeit slower rate. At a single-cell level, the cell density in BYL719-treated spheroids oscillated in a concentration-dependent manner. Our system represents a versatile tool for in-depth preclinical characterization of PK/PD parameters, as it enables an evaluation of drug efficacy and/or toxicity under realistic exposure conditions. Frontiers Media S.A. 2021-12-21 /pmc/articles/PMC8954798/ /pubmed/35342386 http://dx.doi.org/10.3389/fphar.2021.785851 Text en Copyright © 2021 Lohasz, Loretan, Sterker, Görlach, Renggli, Argast, Frey, Wiesmann, Wartmann, Rausch and Hierlemann. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Lohasz, Christian
Loretan, Jacqueline
Sterker, Dario
Görlach, Ekkehard
Renggli, Kasper
Argast, Paul
Frey, Olivier
Wiesmann, Marion
Wartmann, Markus
Rausch, Martin
Hierlemann, Andreas
A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title_full A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title_fullStr A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title_full_unstemmed A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title_short A Microphysiological Cell-Culturing System for Pharmacokinetic Drug Exposure and High-Resolution Imaging of Arrays of 3D Microtissues
title_sort microphysiological cell-culturing system for pharmacokinetic drug exposure and high-resolution imaging of arrays of 3d microtissues
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954798/
https://www.ncbi.nlm.nih.gov/pubmed/35342386
http://dx.doi.org/10.3389/fphar.2021.785851
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