title: Cell uptake and radiotoxicity studies of an nuclear localization signal peptide-intercalator conjugate labeled with [99mTc(CO)3]+.
abstract: A trifunctional bioconjugate consisting of the SV40 nuclear localization signal (NLS) peptide, an aliphatic triamine ligand, and the DNA intercalating pyrene has been synthesized and quantitatively labeled with [(99m)Tc(OH(2))(3)(CO)(3)](+). The radiotoxicity of the resulting nucleus-targeting radiopharmaceutical on B16F1 mouse melanoma cells has been investigated to evaluate the activity of Auger and Coster-Kronig electrons on the viability of cells. We found a dose-dependent significant radiotoxicity of the nucleus-targeting radiopharmaceutical clearly related to the low energy decay of (99m)Tc. These principal results imply a possible therapeutic strategy based on the use of the low-energy Auger electron-emitting (99m)Tc radionuclide attached to nucleus-targeting molecules and comprising an intercalator. Highly efficient DNA targeting vectors could complement the usual role of (99m)Tc in diagnostic applications. The Auger electrons emitted by the (99m)Tc nuclide induce DNA damage leading ultimately, through a mitotic catastrophe pathway, to necrotic cell death. Non-DNA-targeting (99m)Tc complexes display much lower radiotoxicity.
authors.affiliation: Institute of Inorganic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Haefliger
authors.forename: Nikos
authors.initials: N
authors.lastname: Agorastos
authors.forename: Annabelle
authors.initials: A
authors.lastname: Renard
authors.forename: Guya
authors.initials: G
authors.lastname: Giambonini-Brugnoli
authors.forename: Cornelia
authors.initials: C
authors.lastname: Marty
authors.forename: Roger
authors.initials: R
authors.lastname: Alberto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D007364:Intercalating Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D051379:Mice; D015394:Molecular Structure; D019913:Nuclear Localization Signals / Q000737:chemistry* / Q000493:pharmacokinetics*; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D007364:Intercalating Agents; D019913:Nuclear Localization Signals; D015609:Organotechnetium Compounds