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98d

A Micro Cell Culture Analog (μCCA) with 3-D Hydrogel Culture to Assess Metabolism-Dependent Cytotoxicity of Anti-Cancer Drugs

Jong H. Sung and Michael Shuler. Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, NY 14853

Development of a high-throughput in vitro system that can closely mimic human response to a drug is crucial for reducing the cost and the time of developing new drugs. Current cell-based assay system in a multi-well format is a static system which consists of a single cell type, and lack the important aspect of biotransformation and multi-organ interactions. In addition, 2-D monolayer cell culture does not provide a physiologically realistic environment and alter the behavior of cells, making the conventional cell-based assay systems inadequate for prediction of human response to a drug. A multi-chamber, microfluidic device utilizing 3-D constructs of cell-embedded hydrogel was developed and used to test the effect of anti-cancer drugs and their metabolites. A microscale cell culture analog (μCCA) is a physical realization of a physiologically-based pharmacokinetic (PBPK) model, where chambers representing key organs are fabricated on a silicon chip and interconnected by microchannels for medium recirculation which emulates blood flow. We tested Tegafur, an oral prodrug of 5-FU which is a chemotherapeutic agent for colon cancer, using the μCCA device with the HepG2/C3A cells and HCT-116 cells embedded in Matrigel constructs cultured in the liver and the tumor compartment, respectively. Tegafur is non-toxic to cells and is converted to 5-FU in the liver by cytochrome P450 enzymes, which then exerts a toxic effect on cells. The results show that the μCCA device was able to capture the metabolism in the liver compartment and consequent damages to the tumor cells, which was not observed in a traditional, static 96-well plate assay. This 3-D μCCA system was able to reproduce the action of a drug that could only be observed in animal or human model before. It can mimic the dynamic multiple organ interactions and enables the study of pharmacokinetic/pharmacodynamic properties of a drug in vitro in a more physiologically realistic microenvironment.