LAUSR

ABSTRACT 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 (CAD). Previously, we have reported that PEGylated graphene oxide (PEG‐GO) loaded with several CAD 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 CAD can alter DIP. Twenty‐two CAD 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. HighlightsNanocarrier loaded with drug changes the strength of drug induced phospholipidosis.Nanocarrier has strong potentiation effect on Ifenprodil induced phospholipidosis.Primary hepatocytes and spheroids validated the potentiation effect of nanocarriers.Guidance need to be drafted by FDA for the safe use of nanocarrier in drug delivery.