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High-throughput Screening for Mitochondrial Hepatotoxicants in 3D HepG2 C3A Spheroid Cultures

Abstract

Effective early prediction of drug induced liver injury (DILI) induced by compounds exhibiting mitochondrial and cytotoxic liabilities remains a key challenge in the reduction of drug attrition rates and the selection of desirable lead candidates. 3D culture systems are increasingly being utilised as screening tools to predict hepatic toxicity due to their ability to maintain hepatocyte function in vitro, and more accurately than 2D cultures to reflect in vivo hepatic responses. Sygnature Discovery is increasingly adopting such 3D assay platforms as part of our expanding Bioscience and Discovery Toxicology capabilities. Here we describe the application of scaffold free 3D spheroid technology in the screening of HepG2 C3A, a clonal derivative of HepG2 with enhanced hepatic growth and functional characteristics. We highlight the incorporation of 3D C3A spheroid cultures into a validated high throughput screening workflow utilising automated compound delivery via the Biomek NXP liquid handler, with high content imaging and quantitation of mitochondrial toxicity markers by the ImageXpress Micro Confocal Additionally, we demonstrate the highly predictive capacity of this multi-parametric assay platform to screen for mitochondrial hepatotoxicants and potential DILI risk following repeat, long term compound dosing. Development of more complex 3D assay screening platforms forms part of an ongoing commitment at Sygnature Discovery to provide more in vivo relevant models across our integrated drug discovery programmes.

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