Cell uptake and radiotoxicity studies of an nuclear localization signal peptide-intercalator conjugate labeled with [99mTc(CO)3]+

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 [Tc-99m(OH2)(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 Tc-99m. These principal results imply a possible therapeutic strategy based on the use of the low-energy Auger electron-emitting Tc-99m radionuclide attached to nucleus-targeting molecules and comprising an intercalator. Highly efficient DNA targeting vectors could complement the usual role of 99mTc in diagnostic applications. The Auger electrons emitted by the 99mTc nuclide induce DNA damage leading ultimately, through a mitotic catastrophe pathway, to necrotic cell death. Non-DNA-targeting Tc-99m complexes display much lower radiotoxicity.