title: Cationic nanoemulsion as a delivery system for oligonucleotides targeting malarial topoisomerase II.
abstract: A promising strategy based on the antisense oligonucleotides against the Plasmodium falciparum topoisomerase II has been considered using cationic nanoemulsion as oligonucleotide delivery system. Phosphodiester and chemically modified phosphorothioate oligonucleotides bearing negative charges were adsorbed on positively charged emulsion composed of medium chain triglycerides, egg lecithin, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and water, at different +/- charge ratios (positive charges from cationic lipid/negative charges from oligonucleotide): +0.5/-, +2/-, +4/- and +6/-. The physicochemical properties of the complexes were determined, as well as their stability in culture medium. Their interaction with erythrocytes through hemolysis, binding experiments and confocal microscopy were also evaluated. Finally, the in vitro evaluation of parasite growth and reinfection capacity was performed. The overall results showed that antisense oligonucleotides against P. falciparum topoisomerase II gene can be efficiently adsorbed onto a cationic nanoemulsion forming complexes. Whereas unloaded nanoemulsion displayed an hemolytic effect due to the presence of the cationic lipid, this was not the case of loaded nanoemulsion at low +/- ratios. Oligonucleotide-loaded nanoemulsions were found to be located inside the infected erythrocytes, inhibiting efficiently parasite growth (until 80%) and causing a delay in P. falciparum life cycle.
authors.affiliation: Université Paris-Sud, CNRS UMR 8612, Physico-chimie - Pharmacotechnie - Biopharmacie, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, Châtenay-Malabry F-92296, France.
authors.forename: F
authors.initials: F
authors.lastname: Bruxel
authors.forename: S
authors.initials: S
authors.lastname: Cojean
authors.forename: A
authors.initials: A
authors.lastname: Bochot
authors.forename: H
authors.initials: H
authors.lastname: Teixeira
authors.forename: C
authors.initials: C
authors.lastname: Bories
authors.forename: P-M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: E
authors.initials: E
authors.lastname: Fattal
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002412:Cations; D004250:DNA Topoisomerases, Type II / Q000187:drug effects*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D004912:Erythrocytes / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D053758:Nanoparticles; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology
chemical_list: D000962:Antimalarials; D002412:Cations; D004655:Emulsions; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D004250:DNA Topoisomerases, Type II