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The radiobiological effects induced by Auger electron (AE) emitters might include hardly repairable and severe DNA damage in the targeted tumor cells, if the AEs are emitted in close proximity to a radiosensitive cellular target, such as the nuclear DNA or the mitochondria. Towards this goal, we have designed organelle-targeted 99mTc-complexes with the ability to selectively recognize prostate cancer cells, using 99mTc as a readily available model radionuclide to validate the design of new classes of AE emitting radioconjugates for targeted radionuclide therapy (TRT) of cancer. The designed compounds include dual-targeted complexes carrying a bombesin (BBN) peptide recognizing the gastrin releasing peptide receptor (GRPr) and an acridine orange (AO) or a triphenylphosphonium (TPP) group. The GRPr is overexpressed in a variety of cancers, namely prostate cancer (PCa). The AO group is a well-known DNA intercalator and the TPP group has well-recognized mitotropic properties. Thus, we have anticipated that the presence of these groups should enhance, respectively, the accumulation of the 99mTc radionuclide in the nucleus or mitochondria of the targeted PCa cells (Fig. 1). In this communication, we will report on the cellular internalization and subcellular localization of each type of dual-targeted radioconjugates, as well as on the study of their radiobiological effects in PC3 human PCa cells. In particular, this included the study of the influence of the different 99mTc-complexes in: i) the cellular proliferation rate; ii) the induction of DNA damage; iii) the mitochondrial function. The results obtained have since encouraged the application of this dual-target approach to other AE emitters more suitable for Auger therapy of cancer, such as 111In and 161Tb, as explored by us within a recently approved FCT-funded project.
[1] D. Figueiredo et al., Molecules 26(2), 441 (2021).
[2] A. Belchior et al., EJNMMI Research 10, 79 (2020)
[3] E. Pereira et al., Scientific Reports 7, 42544 (2017).
Acknowledgments: This work was supported by Fundação para a Ciência e Tecnologia (projects UID/Multi/04349/2019 and PTDC/MED-QUI/1554/2020).
