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

Abstract

A pumpless, reconfigurable, multi-organ–on–a–chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non–multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell–derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell–based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.

Digital Twins: Bridging Physical Space and Cyberspace

“…As engineers leverage the growing amounts of available data, we can expect to have our own digital twins that monitor our health and simulate potential cures. Organs on chips 9 are already available to test the effectiveness of drugs. They are very complex systems in operational terms (harvesting cells, cultivating them, printing them to emulate an organ, and keeping them alive), and anything that could simplify the approach to a personalized remedy would be most welcome.…”

Organ-on-a-chip platforms for accelerating the evaluation of nanomedicine

“…Therefore, Multi-Organ Chip and body-on-a-chip (Body Chip) platforms combining different organs are needed to investigate the interactions between multiple tissues following nanomedicine exposure. Although some investigations have shown proof-of-concept applications using Multi-Organ Chip systems consisting of immortalized cell lines [ 128 , 129 ], future endeavors must transition to primary cells, which can provide a more realistic physiological microenvironment for understanding nanomedicine delivery and effects.…”

“…For systemic investigating of nanomedicine, reproducing the architectural complexity of human tissues and organs in a miniaturized fashion and interconnecting them in the right arrangement is a representative challenge. There have been recent advancements in constructing Body Chip or Multi-Organ Chip platforms, but more characterizations are still needed before they can be widely and accurately applied [ 91 , 128 , 129 ]. Similarly, building multiple experimental units arrayed on a single chip to achieve large(r)-scale, high (er)-throughput screening and analysis is also a challenge [ 165 ].…”

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

“…This system provided the concept of obtaining entirely human responses to drug testing. More recently, their multi-OOAC system work has shown pharmacokinetic/pharmacodynamic (PK/PD) profiling of tamoxifen on MCF-7 breast cancer cells in the presence/absence of liver cells, while simultaneously monitoring the effect of tamoxifen on cardiac function [32].…”