title: Ellipticine-aimed polymer-conjugated auger electron emitter: multistage organelle targeting approach.
abstract: Radioactive decay of some radionuclides produces a shower of Auger electrons, potent ionizing radiation within a very short range in living tissue (typically ca. 100 nm). Therefore, they must be brought to DNA-containing cell compartments and preferentially directly to DNA to be fully biologically effective. They may be used for a triple-targeting approach (first targeting, polymer-based system targeting into tumor tissue due to EPR effect; second targeting, pH-controlled release of intercalator-bound Auger electron emitter in slightly acidic tumor tissue or endosome; third targeting, into DNA in cell nucleus by the intercalator) minimizing radiation burden of healthy tissues. We describe a first system of this type, an ellipticine derivative-bound iodine-125 attached to hydrazide moieties containing poly[N-(2-hydroxypropyl)methacrylamide]. The system is stable at pH 7.4 (0% intercalator released after 24 h incubation), while iodine-containing biologically active intercalator is released upon decrease of pH (25% intercalator released after 24 h incubation at pH 5.0-model of late endosomes). Both 2-N-(2-oxobutyl)-9-iodoellipticinium bromide and the noniodinated 2-N-(2-oxobutyl)ellipticinium bromide are potent intercalators, as proven by direct titration with DNA and ethidium displacement assay, and readily penetrate into cell nuclei, as proven by confocal microscopy. They retain chemotherapeutical antiproliferative properties of ellipticine against Raji, EL-4, and 4T1cells with IC(50) in the range 0.27-8.8 μmol/L. Polymer conjugate of 2-N-(2-oxobutyl)-9-iodoellipticinium bromide is internalized into endosomes, releases active drug, possesses cytotoxic activity, and the drug accumulates in cell nuclei.
authors.affiliation: Institute of Macromolecular Chemistry AS CR , v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Sedlacek
authors.forename: Martin
authors.initials: M
authors.lastname: Hruby
authors.forename: Martin
authors.initials: M
authors.lastname: Studenovsky
authors.forename: Jan
authors.initials: J
authors.lastname: Kucka
authors.forename: David
authors.initials: D
authors.lastname: Vetvicka
authors.forename: Lubomir
authors.initials: L
authors.lastname: Kovar
authors.forename: Blanka
authors.initials: B
authors.lastname: Rihova
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004583:Electrons; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007457:Iodine Radioisotopes; D051379:Mice; D015394:Molecular Structure; D015388:Organelles / Q000737:chemistry* / Q000187:drug effects; D011109:Polymethacrylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D004611:Ellipticines; D006834:Hydrazines; D007457:Iodine Radioisotopes; D011109:Polymethacrylic Acids; C034192:ellipticine; C011533:Duxon; D004247:DNA