Flexible 3D Cell-Based Platforms for the Discovery and Profiling of Novel Drugs Targeting Hepatic Infection.

The restricted pipeline of drugs targeting the liver stage of infection reflects the scarcity of cell models that mimic the human hepatic phenotype and drug metabolism, as well as hepatic infection. Using stirred-tank culture systems, spheroids of human hepatic cell lines were generated, sustaining a stable hepatic phenotype over 4 weeks of culture. Spheroids were employed in the establishment of 3D infection platforms that relied on static or dynamic culture conditions. invasion and development were recapitulated in the hepatic spheroids, yielding blood-infective merozoites. The translational potential of the 3D platforms was demonstrated by comparing the minimum inhibitory concentration of M5717, a compound under clinical development, with plasma concentrations that clear liver stage in mice. Our results show that the 3D platforms are flexible and scalable and can predict the efficacy of antiplasmodial therapies, constituting a powerful tool for integration in drug discovery programs.