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High-Throughput Screening of Drug-Transporter Interactions in a 3D Microfluidic Renal Proximal Tubule on a Chip

Autor/Autorin
Vriend, Jelle
Nieskens, Tom T.G.
Vormann, Marianne K.
van den Berge, Batholomeus T.
van den Heuvel, Angelique
Russel, Frans G.M.
Suter-Dick, Laura
Lanz, Henriette
Vulto, Paul
Masereeuw, Rosalinde
Wilmer, Martijn
Datum
07.2018
Metadata
Zur Langanzeige
Type
01 - Zeitschriftenartikel, Journalartikel oder Magazin
Zusammenfassung
Drug-transporter interactions could impact renal drug clearance and should ideally be detected in early stages of drug development to avoid toxicity-related withdrawals in later stages. This requires reliable and robust assays for which current high-throughput screenings have, however, poor predictability. Kidney-on-a-chip platforms have the potential to improve predictability, but often lack compatibility with high-content detection platforms. Here, we combined conditionally immortalized proximal tubule epithelial cells overexpressing organic anion transporter 1 (ciPTEC-OAT1) with the microfluidic titer plate OrganoPlate to develop a screenings assay for renal drug-transporter interactions. In this platform, apical localization of F-actin and intracellular tight-junction protein zonula occludens-1 (ZO-1) indicated appropriate cell polarization. Gene expression levels of the drug transporters organic anion transporter 1 (OAT1; SLC22A6), organic cation transporter 2 (OCT2; SLC22A2), P-glycoprotein (P-gp; ABCB1), and multidrug resistance-associated protein 2 and 4 (MRP2/4; ABCC2/4) were similar levels to 2D static cultures. Functionality of the efflux transporters P-gp and MRP2/4 was studied as proof-of-concept for 3D assays using calcein-AM and 5-chloromethylfluorescein-diacetate (CMFDA), respectively. Confocal imaging demonstrated a 4.4 ± 0.2-fold increase in calcein accumulation upon P-gp inhibition using PSC833. For MRP2/4, a 3.0 ± 0.2-fold increased accumulation of glutathione-methylfluorescein (GS-MF) was observed upon inhibition with a combination of PSC833, MK571, and KO143. Semi-quantitative image processing methods for P-gp and MRP2/4 was demonstrated with corresponding Z'-factors of 0.1 ± 0.3 and 0.4 ± 0.1, respectively. In conclusion, we demonstrate a 3D microfluidic PTEC model valuable for screening of drug-transporter interactions that further allows multiplexing of endpoint read-outs for drug-transporter interactions and toxicity
Link
https://link.springer.com/article/10.1208%2Fs12248-018-0247-0
https://www.ncbi.nlm.nih.gov/pubmed/30051196
URI
http://hdl.handle.net/11654/26933
DOI der Originalausgabe
https://doi.org/10.1208/s12248-018-0247-0
Übergeordnetes Werk
The APPS Journal (An official Journal of the American Association of Pharmaceutical Scientists)
Jahrgang
20
Ausgabe
5
Zitation

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