Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells. (1st May 2019)

• Record Type: Journal Article
• Authors: Indra, Radek; Černá, Tereza; Heger, Zbyněk; Hraběta, Jan; Wilhelm, Marek; Dostálová, Simona; Lengálová, Alžběta; Martínková, Markéta; Adam, Vojtěch; Eckschlager, Tomáš; Schmeiser, Heinz H.; Arlt, Volker M.; Stiborová, Marie
• Is Part Of: Toxicology. Volume 419(2019)
• Page Start: 40
• Page End: 54
• Publication Date: 2019-05-01
• Subjects: Apo apoferritin -- ApoElli apoferritin-containing encapsulated ellipticine -- CI cell index -- CYP cytochrome P450 -- CTCF corrected total cell fluorescence -- DAP 4′6-diamidino-2-phenylindole, dihydrochloride -- DLPC dilauroyl phosphatidylcholine -- DLS quasielastic dynamic light scattering -- DMEM Dulbecco's Modified Eagle Medium -- DMSO dimethyl sulfoxide -- Elli ellipticine -- EPR enhanced permeability and retention -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HDFn neonatal human dermal fibroblasts -- HPLC high performance liquid chromatography -- IMDM Iscove's modified Dulbecco's medium -- PEI polyethylenimine -- POR NADPH:cytochrome P450 oxidoreductase -- RAL relative adduct labelling -- RBC red blood cells -- RES reticuloendothelial system -- SCARA5 scavenger receptor class A member 5 -- TEM transmission electron microscopy -- TLC thin-layer chromatography -- TfR1 transferrin receptor 1; Ellipticine -- Apoferritin nanoparticles -- Cytochrome P450-mediated metabolism -- DNA adducts -- Neuroblastoma -- Cytotoxicity; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2019.03.009
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Although ellipticine (Elli) is an efficient anticancer agent, it exerts several adverse effects. One approach to decrease the adverse effects of drugs is their encapsulation inside a suitable nanocarrier, allowing targeted delivery to tumour tissue whereas avoiding healthy cells. We constructed a nanocarrier from apoferritin (Apo) bearing ellipticine, ApoElli, and subsequently characterized. The nanocarrier exhibits a narrow size distribution suggesting its suitability for entrapping the hydrophobic ellipticine molecule. Ellipticine was released from ApoElli into the water environment under pH 6.5, but only less than 20% was released at pH 7.4. The interaction of ApoElli with microsomal membrane particles containing cytochrome P450 (CYP) biotransformation enzymes accelerated the release of ellipticine from this nanocarrier making it possible to be transferred into this membrane system even at pH 7.4 and facilitating CYP-mediated metabolism. Reactive metabolites were formed not only from free ellipticine, but also from ApoElli, and both generated covalent DNA adducts. ApoElli was toxic in UKF-NB-4 neuroblastoma cells, but showed significantly lower cytotoxicity in non-malignant fibroblast HDFn cells. Ellipticine either free or released from ApoElli was concentrated in the nuclei of neuroblastoma cells, concentrations of which being significantly higher in nuclei of UKF-NB-4 than in HDFn cells. In HDFn the higher amounts of ellipticine were sequestrated in lysosomes. The extent of ApoElli entering the nuclei in UKF-NB-4 cells was lower than that of free ellipticine and correlated with the formation of ellipticine-derived DNA adducts. Our study indicates that the ApoElli form of ellipticine seems to be a promising tool for neuroblastoma treatment.