Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system

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.