International Journal of Molecular Sciences (Jun 2022)

Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus

  • Célia Fernandes,
  • Elisa Palma,
  • Francisco Silva,
  • Ana Belchior,
  • Catarina I. G. Pinto,
  • Joana F. Guerreiro,
  • Hugo M. Botelho,
  • Filipa Mendes,
  • Paula Raposinho,
  • António Paulo

Journal volume & issue
Vol. 23, no. 13
p. 7238


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Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available “model” radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates 99mTc-TPP-BBN and 99mTc-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. 99mTc-TPP-BBN and 99mTc-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener 99mTc-BBN, leading to an augmented formation of γH2AX foci and micronuclei. 99mTc-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of 99mTc-TPP-BBN in the mitochondria and enhanced uptake of 99mTc-AO-BBN in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by 99mTc. In particular, the results obtained for 99mTc-TPP-BBN reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates.