Speaker
Description
Background: Recent advances in lipid nanoparticle delivery (LNP) systems have enabled the development of mRNA vaccines and oligonucleotide therapeutics. Reliable hepatic in vitro systems are essential for the evaluation of metabolism of LNP components and RNA therapeutics.
Methods: The 3D liver spheroid models were constructed using mouse and rat primary hepatocytes as well as HepG2 cell line. After incubation with SM-102 or futisiran, metabolites in spheroid cell lysates and culture media were analyzed separately using liquid chromatography-high resolution mass spectrometry. The 2D hepatocyte incubations were also prepared and analyzed for comparison purposes.
Results: Hydrolysis and β-oxidation were identified as the major metabolic pathways for SM-102 in liver spheroid. The predominant in vivo metabolites of futisiran were detected in the liver spheroid cultures. Additionally, compared with the standard 2D hepatocyte system, the 3D liver spheroid is highly efficient which recapitulated major metabolic pathways using significantly fewer primary cells.
Conclusions: The 3D liver spheroid models represent a promising tool for future investigations into the metabolism of RNA therapeutics.
Acknowledgments:
This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD).
