Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug

S. Imstepf, V. Pierroz, P. Raposinho, Matthias Bauwens, M. Felber, T. Fox, A.B. Shapiro, R. Freudenberg, C. Fernandes, S. Gama, G. Gasser, Felix Mottaghy, I.R. Santos, R. Alberto

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and (99m)Tc, an Auger and internal conversion electron emitter, into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to (99m)Tc afforded a construct which autonomously ferries a radioactive payload into the cell nucleus. At this site, damage is exerted by dose deposition from Auger radiation. The (99m)Tc-conjugate exhibited a dose-dependent inhibition of survival in a selected panel of cancer cells and an in vivo study in healthy mice evidenced a biodistribution which is comparable to that of the parent drug. The homologous Rhenium conjugate was found to effectively bind to DNA, inhibited human Topoisomerase II, and exhibited cytotoxicity in vitro. The collective in vitro and in vivo data demonstrate that the presented metallo-conjugates closely mimic native Doxorubicin.
Original languageEnglish
Pages (from-to)2397-2407
Number of pages11
JournalBioconjugate Chemistry
Volume26
Issue number12
DOIs
Publication statusPublished - Dec 2015

Keywords

  • ANISOTROPY-BASED ASSAY
  • DOUBLE-STRAND BREAKS
  • CANCER-THERAPY
  • BIOLOGICAL EFFECTIVENESS
  • ORTHOPHOSPHATE HYDROGEL
  • DOXORUBICIN PRODRUG
  • ANTITUMOR-ACTIVITY
  • ENERGY DEPOSITION
  • MAMMALIAN-CELLS
  • DNA

Cite this

Imstepf, S., Pierroz, V., Raposinho, P., Bauwens, M., Felber, M., Fox, T., Shapiro, A. B., Freudenberg, R., Fernandes, C., Gama, S., Gasser, G., Mottaghy, F., Santos, I. R., & Alberto, R. (2015). Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug. Bioconjugate Chemistry, 26(12), 2397-2407. https://doi.org/10.1021/acs.bioconjchem.5b00466