Flexible 3D cell-based platforms for the discovery and profiling of novel drugs targeting plasmodium hepatic infection

The restricted pipeline of drugs targeting the liver stage of; Plasmodium; infection reflects the scarcity of cell models that mimic the human hepatic phenotype and drug metabolism, as well as; Plasmodium; 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; Plasmodium berghei; infection platforms that relied on static or dynamic culture conditions.; P. berghei; 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; in vitro; minimum inhibitory concentration of M5717, a compound under clinical development, with; in vivo; plasma concentrations that clear liver stage; P. berghei; 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.