title: Efficacy of multi-functional liposomes containing daunorubicin and emetine for treatment of acute myeloid leukaemia.
abstract: Despite recent advances in chemotherapy against acute myeloid leukaemia (AML), the disease still has high mortality, particularly for patients who tolerate extensive chemotherapy poorly. Nano-formulations have potential to minimise the adverse effects of chemotherapy. We present here a liposomal formulation encapsulating both the anthracycline daunorubicin (DNR) and emetine (Eme) for enhanced cytotoxic effect against AML cells. Eme could be loaded into the PEGylated liposomes together with DNR by the acid precipitation principle, with a loading efficiency of Eme at about 50% of that of DNR. The liposome surface was modified with folate to enhance drug loading into cells, giving higher cytotoxic activity. Both intracellular drug loading and cytotoxic activity could be further increased by anti-folate treatment of AML cells with methotrexate (MTX). The combination of DNR and Eme also increased drug loading in MTX-treated cells compared to DNR alone. Liposomes with both DNR and Eme were particularly efficient against AMLs with deficient p53. In conclusion, we have produced a multi-functional liposomal anti-leukaemic drug formulation designed to overcome some of the problems in anthracycline chemotherapy: (1) Combination of DNR and Eme to diminish drug resistance. (2) Using PEGylated stealth liposomes to minimise adverse side-effects. (3) Molecules on the liposomal surface target proteins on AML-cells ensure selectivity, which was enhanced by priming the leukaemia cells with MTX.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Lene
authors.initials: L
authors.lastname: Myhren
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Ida Mostrøm
authors.initials: IM
authors.lastname: Nilssen
authors.affiliation: Université Paris-Sud11, Plateforme d'Imagerie Cellulaire, IFR141-IPSIT, FR 92296, Chatenay-Malabry, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
authors.affiliation: Insitut Galien Paris-Sud (UMR CNRS 8612), Université Paris-Sud 11, LabEx LERMIT, FR 92296, Chatenay-Malabry, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Barratt
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Translational Signalling Group, Haukeland University Hospital, Bergen, Norway. Electronic address: lars.herfindal@biomed.uib.no.
authors.forename: Lars
authors.initials: L
authors.lastname: Herfindal
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003630:Daunorubicin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004351:Drug Resistance; D004640:Emetine / Q000008:administration & dosage*; D005434:Flow Cytometry; D058976:Folate Receptor 2 / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008027:Light; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D012542:Scattering, Radiation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D004337:Drug Carriers; D058976:Folate Receptor 2; D008081:Liposomes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011092:Polyethylene Glycols; D004640:Emetine; D008727:Methotrexate; D003630:Daunorubicin
keywords: Daunorubicin; Daunorubicin (CID: 30323); Doxorubicin; Doxorubicin (CID: 31703); Emetine; Emetine (CID: 10219); Folic acid; Leukaemia; Methotrexate; Methotrexate (CID: 126941)