Evaluation Of Hepatotoxicity Of Nanomaterial And Chinese Herbal Monomers Based On Hepatic Cells And Microtissue

Liver is the main site of metabolism in the body,and it is also the target organ of many drugs and nanomaterials.Drug-induced liver injury is often the most important reason for the failure of new drug development,restricted use or even withdrawal after the drug is marketed.Considerable effort has been made to develop nanocarriers for controlled drug delivery over the last decade,while it remains unclear how the strength of adverse drug effect will be altered when a drug is loaded on the nanocarrier.Drug-induced phospholipidosis(DIP)is characterized with excessive accumulation of phospholipids in cells and is common for cationic amphiphilic drugs(CADs).Previously,we have reported that PEGylated graphene oxide(PEG-GO)loaded with several CADs can potentiate DIP.In current study,we extended our study on newly identified phospholipidosis(PLD)inducers that had been identified from the Library of Pharmacologically Active Compounds(LOPAC),to investigate if PEO-GO loaded with these CADs can alter DIP.Twenty-two CADs were respectively loaded on PEG-GO and incubated with RAW264.7,a macrophage cell line.The results showed that when a CAD was loaded on PEG-GO,its strength of PLD induction can be enhanced,unchanged or attenuated.PEG-GO loaded with Ifenprodil exhibited the highest PEG-GO potentiation effect compared to Ifenprodil treatment alone in RAW264.7 cells,and this effect was confirmed in human hepatocellular carcinoma HepG2,another cell line model for PLD induction.Primary hepatocyte culture and spheroids mimicking in vivo conditions were used to further validate nanocarrier potentiation on DIP by Ifenprodil.Stronger phospholipid accumulation was found in PEG-GO/Ifenprodil treated hepatocytes or spheroids than Ifenprodil treatment alone.Therefore,evidences were provided by us that nanocarriers may increase the adverse drug effects and guidance by regulatory agencies need to be drafted for the safe use of nanotechnology in drug delivery.In addition,we used the primary hepatocyte spheroids to evaluate the hepatotoxicity of five Polygonum multiflorum monomers,and found that hepatotoxicity:single anthrone>rheinic acid>emodin>emodin-8-O-?-D-glucoside>Physcion,providing a certain experimental data reference for the study of the biological mechanism and major toxic substances of polygonum multiflorum hepatotoxicity.