Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus
Although <sup>99m</sup>Tc 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 radiocon...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/13/7238 |
| Summary: | Although <sup>99m</sup>Tc 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 <b><sup>99m</sup>Tc-TPP-BBN</b> and <b><sup>99m</sup>Tc-AO-BBN</b> (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. <b><sup>99m</sup>Tc-TPP-BBN</b> and <b><sup>99m</sup>Tc-AO-BBN</b> caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener <b><sup>99m</sup>Tc-BBN</b>, leading to an augmented formation of γH2AX foci and micronuclei. <b><sup>99m</sup>Tc-TPP-BBN</b> 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 <b><sup>99m</sup>Tc-TPP-BBN</b> in the mitochondria and enhanced uptake of <b><sup>99m</sup>Tc-AO-BBN</b> in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by <sup>99m</sup>Tc. In particular, the results obtained for <b><sup>99m</sup>Tc-TPP-BBN</b> reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates. |
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| ISSN: | 1661-6596 1422-0067 |