Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria
For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. Howev...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/2/441 |
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| author | Diogo Figueiredo Célia Fernandes Francisco Silva Elisa Palma Paula Raposinho Ana Belchior Pedro Vaz António Paulo |
| author_facet | Diogo Figueiredo Célia Fernandes Francisco Silva Elisa Palma Paula Raposinho Ana Belchior Pedro Vaz António Paulo |
| author_sort | Diogo Figueiredo |
| collection | DOAJ |
| description | For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. However, there is a growing body of evidence that other targets, such as the mitochondria, could be relevant subcellular targets in Auger therapy. Thus, we developed dual-targeted <sup>99m</sup>Tc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of <sup>99m</sup>Tc in the mitochondria, and a bombesin peptide to provide specificity towards the gastrin releasing peptide receptor (GRPr) overexpressed in prostate cancer cells. The designed dual-targeted complex, <b><sup>99m</sup>Tc-TPP-BBN</b>, is efficiently internalized by human prostate cancer PC3 cells through a specific GRPr-mediated mechanism of uptake. Moreover, the radioconjugate provided an augmented accumulation of <sup>99m</sup>Tc in the mitochondria of the target tumor cells, most probably following its intracellular cleavage by cathepsin B. In addition, <b><sup>99m</sup>Tc-TPP-BBN</b> showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner. |
| first_indexed | 2024-03-09T04:37:33Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:37:33Z |
| publishDate | 2021-01-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f7bff5e5207f44f1b10a0680c2e9fbc62023-12-03T13:27:10ZengMDPI AGMolecules1420-30492021-01-0126244110.3390/molecules26020441Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral MitochondriaDiogo Figueiredo0Célia Fernandes1Francisco Silva2Elisa Palma3Paula Raposinho4Ana Belchior5Pedro Vaz6António Paulo7C2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalC2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, PortugalFor effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. However, there is a growing body of evidence that other targets, such as the mitochondria, could be relevant subcellular targets in Auger therapy. Thus, we developed dual-targeted <sup>99m</sup>Tc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of <sup>99m</sup>Tc in the mitochondria, and a bombesin peptide to provide specificity towards the gastrin releasing peptide receptor (GRPr) overexpressed in prostate cancer cells. The designed dual-targeted complex, <b><sup>99m</sup>Tc-TPP-BBN</b>, is efficiently internalized by human prostate cancer PC3 cells through a specific GRPr-mediated mechanism of uptake. Moreover, the radioconjugate provided an augmented accumulation of <sup>99m</sup>Tc in the mitochondria of the target tumor cells, most probably following its intracellular cleavage by cathepsin B. In addition, <b><sup>99m</sup>Tc-TPP-BBN</b> showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner.https://www.mdpi.com/1420-3049/26/2/441radiopharmaceuticalsauger emitterstechnetium-99mtargeted radionuclide therapy (TRT)mitochondria targeting |
| spellingShingle | Diogo Figueiredo Célia Fernandes Francisco Silva Elisa Palma Paula Raposinho Ana Belchior Pedro Vaz António Paulo Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria Molecules radiopharmaceuticals auger emitters technetium-99m targeted radionuclide therapy (TRT) mitochondria targeting |
| title | Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria |
| title_full | Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria |
| title_fullStr | Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria |
| title_full_unstemmed | Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria |
| title_short | Synthesis and Biological Evaluation of <sup>99m</sup>Tc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria |
| title_sort | synthesis and biological evaluation of sup 99m sup tc i tricarbonyl complexes dual targeted at tumoral mitochondria |
| topic | radiopharmaceuticals auger emitters technetium-99m targeted radionuclide therapy (TRT) mitochondria targeting |
| url | https://www.mdpi.com/1420-3049/26/2/441 |
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