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

• Published in: International journal of molecular sciences 2022-06, Vol.23 (13), p.7238
• Main Authors: Fernandes, Célia, Palma, Elisa, Silva, Francisco, Belchior, Ana, Pinto, Catarina I. G., Guerreiro, Joana F., Botelho, Hugo M., Mendes, Filipa, Raposinho, Paula, Paulo, António
• Format: Article
• Language: English
• Subjects: auger electron emitters; Bombesin; Cancer therapies; Cell death; Congeners; Copy number; DNA damage; DNA intercalators; Dosimetry; Electrons; Emitters; Emitters (electron); Localization; Medical research; Micronuclei; Mitochondria; Mitochondrial DNA; mitochondrion-tropic probes; Nuclei (cytology); Organelles; Peptides; Prostate cancer; Radiation; Radiation therapy; Radioisotopes; radiopharmaceuticals; Targeted Radionuclide Therapy (TRT); technetium-99m; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23137238

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.