title: From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier.
abstract: Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG-GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG-GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG-GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co-localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers.
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.|School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Liecheng
authors.initials: L
authors.lastname: Yang
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhong
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.
authors.forename: Xihui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.
authors.forename: Yangyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: School for Radiological and interdisciplinary Sciences (RAD-X).|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions.
authors.forename: Leshuai W
authors.initials: LW
authors.lastname: Zhang
mesh_terms: D065567:Absorption, Physiological; D000818:Animals; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006108:Graphite / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008064:Lipidoses / Q000139:chemically induced* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000009:adverse effects* / Q000737:chemistry / Q000648:ultrastructure; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D000067996:RAW 264.7 Cells; D013499:Surface Properties; D013629:Tamoxifen / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D023382:Toxicity Tests, Acute
chemical_list: D004337:Drug Carriers; D004965:Estrogen Antagonists; D005456:Fluorescent Dyes; C584395:N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D013629:Tamoxifen; D011092:Polyethylene Glycols; D006108:Graphite
keywords: adverse drug effect.; autophagy; cationic amphiphilic drug; graphene oxide; lysosome; phospholipidosis