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Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system
Liang Ma1, Jeremy Barker, Changchun Zhou
1Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Abstract:
A three-dimensional micro-scale perfusion-based two-chamber (3D-microPTC) 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-microPTC 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.
Insights
A novel 3D-microPTC system models liver metabolism and brain cancer, enhancing anticancer drug cytotoxicity testing. This platform improves prediction of drug efficacy and dosage for personalized medicine.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Oncology
Background:
- Current 2D cell culture models lack physiological relevance for drug testing.
- Liver metabolism significantly influences anticancer drug efficacy and toxicity.
- Glioblastoma multiforme (GBM) drug response is complex and requires better in vitro models.
Purpose of the Study:
- To develop and validate a three-dimensional micro-scale perfusion-based two-chamber (3D-microPTC) tissue model.
- To assess the metabolism-dependent cytotoxicity of anticancer drugs on GBM cells using the 3D-microPTC system.
- To compare the predictive power of the 3D-microPTC model against traditional 2D cell cultures.
Main Methods:
- Fabrication of a 3D tissue engineering scaffold using biodegradable poly(lactic acid) (PLA).
- Co-culture of liver cells with varying cytochrome P450 (CYP) subtypes and GBM cells in a tandem two-chamber system.
- Testing cytotoxicity of temozolomide (TMZ) and ifosfamide (IFO) in the 3D-microPTC model and 2D cultures.
Main Results:
- TMZ exhibited lower toxicity to GBM cells in the 3D model compared to 2D cultures, with higher GBM cell viability.
- IFO's metabolism-dependent cytotoxicity was strongly influenced by CYP3A4 expression levels in liver cells.
- The 3D-microPTC system demonstrated significant metabolism-dependent effects on drug-induced GBM cell death.
Conclusions:
- The 3D-microPTC system offers a more physiologically relevant in vitro platform for evaluating drug metabolism and toxicity.
- This model system can enhance the prediction of anticancer drug dosing and scheduling for personalized medicine.
- The developed model holds promise for improving preclinical drug screening and reducing attrition rates in drug development.
