Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics

Area of Science:

• Biomedical Engineering
• Pharmacology
• Toxicology

Background:

• Current preclinical drug testing relies heavily on animal models, which have limitations in predicting human responses.
• Developing in vitro systems that mimic human organ functions is crucial for efficient and accurate drug evaluation.

Purpose of the Study:

• To develop and validate a pumpless, reconfigurable multi-organ-on-a-chip system for predicting drug efficacy and toxicity.
• To assess the on-target efficacy and off-target toxicity of drugs and their metabolites using human cells.

Main Methods:

• Utilized a multi-organ-on-a-chip system with recirculating serum-free medium and functional biological microelectromechanical systems.
• Configured the system with primary human hepatocytes and cancer cell lines for antileukemia drug analysis.
• Incorporated hepatocytes, cancer cell lines, and induced pluripotent stem cell-derived cardiomyocytes for broader drug testing.

Main Results:

• Diclofenac showed a cytostatic effect on bone marrow cancer cells and reduced liver viability by 30%, while imatinib had a cytostatic effect without impacting liver viability.
• Tamoxifen demonstrated efficacy against breast cancer cells post-metabolite generation and showed off-target cardiac effects (reduced contractility, beat frequency, and conduction velocity) without affecting viability.
• The system successfully predicted differential drug responses and metabolite-dependent effects.

Conclusions:

• The developed organ-on-a-chip system effectively evaluates on-target efficacy and off-target toxicity of drugs and metabolites using human cells.
• This in vitro system can augment and reduce animal use in preclinical studies, enhancing drug evaluation efficiency.