Ellipticine-aimed polymer-conjugated Auger electron emitter: multistage organelle targeting approach

0360736 - ÚMCH 2012 RIV US eng J - Journal Article
Sedláček, Ondřej - Hrubý, Martin - Studenovský, Martin - Kučka, Jan - Větvička, David - Kovář, Lubomír - Říhová, Blanka - Ulbrich, Karel
Ellipticine-aimed polymer-conjugated Auger electron emitter: multistage organelle targeting approach.
Bioconjugate Chemistry. Roč. 22, č. 6 (2011), s. 1194-1201. ISSN 1043-1802. E-ISSN 1520-4812
R&D Projects: GA ČR GPP207/10/P054; GA ČR GAP108/10/1560; GA AV ČR IAAX00500803; GA MŠMT 1M0505
Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510
Keywords : ellipticine * drug delivery * radiotherapy
Subject RIV: CD - Macromolecular Chemistry
Impact factor: 4.930, year: 2011

We describe an ellipticine derivative-bound iodine-125 attached to hydrazide moieties containing poly[N-(2-hydroxypropyl)methacrylamide]. The system is completely stable at pH 7.4, 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 IC50 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.
Permanent Link: http://hdl.handle.net/11104/0198218