A three-dimensional micro-scale perfusion-based two-chamber (3D-μPTC) tissue model system was developed to test the cytotoxicity of anticancer drugs in conjunction with liver metabolism. Liver cells with different cytochrome P450 (CYP) subtypes and glioblastoma multiforme (GBM) brain cancer cells were cultured in two separate chambers connected in tandem. Both chambers contained a 3D tissue engineering scaffold fabricated with biodegradable poly(lactic acid) (PLA) using a solvent-free approach. We used this model system to test the cytotoxicity of anticancer drugs, including temozolomide (TMZ) and ifosfamide (IFO). With the liver cells, TMZ showed a much lower toxicity to GBM cells under both 2D and 3D cell culture conditions. Comparing 2D, GBM cells cultured in 3D had much high viability under TMZ treatment. IFO was used to test the CYP-related metabolic effects. Cells with different expression levels of CYP3A4 differed dramatically in their ability to activate IFO, which led to strong metabolism-dependent cytotoxicity to GBM cells. These results demonstrate that our 3D-μPTC system could provide a more physiologically realistic in vitro environment than the current 2D monolayers for testing metabolism-dependent toxicity of anticancer drugs. It could therefore be used as an important platform for better prediction of drug dosing and schedule towards personalized medicine.

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A cell culture microfluidic device has been developed to test the cytotoxicity of anticancer drugs while reproducing multi-organ interactions in vitro. Cells were cultured in separate chambers representing the liver and tumor. The two chambers were connected through a channel to mimick the blood flow. Glioblastoma (GBM) cancer cells (M059K) and hepatoma cells (HepG2) were cultured in the tumor and the liver chambers, respectively. The cytotoxic effect of cancer treatment drug Temolozomide (TMZ) was tested using this two chamber system. The experimental results showed that with the liver cells, the cancer cells showed much higher viability than those without the liver cells. This indicates that the liver metabolism has strong effect on the toxicity of the anticancer drug. The results demonstrated that the perfused two chamber cell culture system has the potential to be used as a platform for drug screening in a more physiologically realistic environment.