INTRODUCTION: Many human disorders display unknown tissues relationships affecting disease progression and drugs response (1). While in vitro assays fail in recapitulating organ-organ connection, animal models reveal species-specific drug outcomes. To this purpose, a novel multi-organ microphysiological system (MIVO®) has been adopted to fluidically connect 3D ovarian cancer tissues with a hepatic cellular model and simulate the systemic cisplatin administration for investigating its anticancer efficacy and simultaneously measuring potential hepatotoxic effects.
METHODS: Human hepatocellular (Hep-G2) and ovarian cancer (SKOV-3) cells line have been used to realize liver models and 2D/3D tumor model (2). Computational fluid-dynamic modeling has been performed to simulate the capillary blood velocity, that was set-up within MIVO® where 3D ovarian cancer and the liver model were cultured fluidically connected. First, a drug concentration (10-100 µM) screening was performed by using 2D and 3D single organ models. Then, drug efficacy and toxicity assays were assessed in MIVO and compared with both static co-cultures and single organ models. Ovarian and liver cells death, half maximal effective concentration (EC50) and median lethal dose (LD50) for Skov-3 cells and Hep-G2 cells were quantitatively assessed. Cisplatin effects were also qualitatively by immunofluorescence.
RESULTS: A linear decay of Hep-G2 and Skov-3 cells viability was observed with increasing cisplatin concentration after 48h of treatment. Furthermore, the 3D ovarian cancer model demonstrated higher drug resistance than the 2D model. Finally, reduced efficacy against the 3D ovarian cancer tissue and hepatotoxicity were observed in the MIVO compared with single organ model (0.5X of EC50 and 2X of LD50).
DISCUSSION AND CONCLUSIONS: Results highlight that the introduction of 3D cells culture and multi-organ fluidic connections resembling the in vivo conditions significantly impact in both drug efficacy and toxicity outcomes, indicating the importance of developing more predictive pre-clinical tools for drug screening.
(1) Trapecar, Martin. "Multiorgan Microphysiological Systems as Tools to Interrogate Interorgan Crosstalk and Complex Diseases." FEBS letters (2021).
(2) Marrella, Alessandra, et al. "3D fluid-dynamic ovarian cancer model resembling systemic drug administration for efficacy assay." ALTEX- 38.1 (2021): 82-94.