One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto
Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor upta...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/12/1145 |
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| author | Panagiotis Kanellopoulos Aikaterini Kaloudi Maritina Rouchota George Loudos Marion de Jong Eric P. Krenning Berthold A. Nock Theodosia Maina |
| author_facet | Panagiotis Kanellopoulos Aikaterini Kaloudi Maritina Rouchota George Loudos Marion de Jong Eric P. Krenning Berthold A. Nock Theodosia Maina |
| author_sort | Panagiotis Kanellopoulos |
| collection | DOAJ |
| description | Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [<sup>99m</sup>Tc]Tc-DB4 (DB4, N<sub>4</sub>-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH<sub>2</sub>) and [<sup>111</sup>In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH<sub>2</sub>) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK<sub>2</sub>R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [<sup>99m</sup>Tc] Tc-DB4 and [<sup>111</sup>In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [<sup>99m</sup>Tc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [<sup>111</sup>In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK<sub>2</sub>R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in mice, paving the way for clinical translation of this approach. |
| first_indexed | 2024-03-10T14:33:09Z |
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| id | doaj.art-913efcbdc8024b118187142e3a6f530a |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T14:33:09Z |
| publishDate | 2020-11-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-913efcbdc8024b118187142e3a6f530a2023-11-20T22:25:18ZengMDPI AGPharmaceutics1999-49232020-11-011212114510.3390/pharmaceutics12121145One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with EntrestoPanagiotis Kanellopoulos0Aikaterini Kaloudi1Maritina Rouchota2George Loudos3Marion de Jong4Eric P. Krenning5Berthold A. Nock6Theodosia Maina7Molecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, GreeceMolecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, GreeceBIOEMTECH, Lefkippos Attica Technology Park NCSR “Demokritos”, 15310 Athens, GreeceBIOEMTECH, Lefkippos Attica Technology Park NCSR “Demokritos”, 15310 Athens, GreeceDepartment of Radiology & Nuclear Medicine Erasmus MC, 3015 CN Rotterdam, The NetherlandsCyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The NetherlandsMolecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, GreeceMolecular Radiopharmacy, INRASTES, NCSR “Demokritos”, 15341 Athens, GreeceBackground: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [<sup>99m</sup>Tc]Tc-DB4 (DB4, N<sub>4</sub>-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH<sub>2</sub>) and [<sup>111</sup>In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH<sub>2</sub>) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK<sub>2</sub>R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [<sup>99m</sup>Tc] Tc-DB4 and [<sup>111</sup>In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [<sup>99m</sup>Tc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [<sup>111</sup>In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK<sub>2</sub>R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in mice, paving the way for clinical translation of this approach.https://www.mdpi.com/1999-4923/12/12/1145tumor-targetingpeptide radioligand[<sup>99m</sup>Tc]Tc-DB4gastrin-releasing peptide receptor[<sup>111</sup>In]In-SG4cholecystokinin subtype 2 receptor |
| spellingShingle | Panagiotis Kanellopoulos Aikaterini Kaloudi Maritina Rouchota George Loudos Marion de Jong Eric P. Krenning Berthold A. Nock Theodosia Maina One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto Pharmaceutics tumor-targeting peptide radioligand [<sup>99m</sup>Tc]Tc-DB4 gastrin-releasing peptide receptor [<sup>111</sup>In]In-SG4 cholecystokinin subtype 2 receptor |
| title | One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto |
| title_full | One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto |
| title_fullStr | One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto |
| title_full_unstemmed | One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto |
| title_short | One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [<sup>99m</sup>Tc]Tc-DB4 and [<sup>111</sup>In]In-SG4 in Mice Treated with Entresto |
| title_sort | one step closer to clinical translation enhanced tumor targeting of sup 99m sup tc tc db4 and sup 111 sup in in sg4 in mice treated with entresto |
| topic | tumor-targeting peptide radioligand [<sup>99m</sup>Tc]Tc-DB4 gastrin-releasing peptide receptor [<sup>111</sup>In]In-SG4 cholecystokinin subtype 2 receptor |
| url | https://www.mdpi.com/1999-4923/12/12/1145 |
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