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Preclinical evaluat...
Preclinical evaluation of new GRPR-antagonists with improved metabolic stability for radiotheranostic use in oncology
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- Kanellopoulos, Panagiotis (författare)
- Uppsala universitet,Theranostics,NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15341, Greece.
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- Mattsson, Adam (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Abouzayed, Ayman (författare)
- Uppsala universitet,Theranostics
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- Obeid, Karim (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Nock, Berthold A. (författare)
- NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15341, Greece.
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Cancerprecisionsmedicin
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- Maina, Theodosia (författare)
- NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15341, Greece.
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- Orlova, Anna, 1960- (författare)
- Uppsala universitet,Theranostics,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- Springer Nature, 2024
- 2024
- Engelska.
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Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer Nature. - 2365-421X. ; 9
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: p-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP). The new analogues carry the DOTAGA-chelator (1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid) through different linkers at the N-terminus to allow for labeling with the theranostic radionuclide pair In-111/Lu-177. After labeling with In-111 the following radioligands were evaluated: (i) [111In]In-AU-SAR-M1 ([111In]In-DOTAGA-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt), (ii) [111In]In-AU-SAR-M2 ([111In]In-[DOTAGA-Arg]AU-SAR-M1) and (iii) [111In]In-AU-SAR-M3 ([111In]In-[DOTAGA-DArg]AU-SAR-M1).Results: These radioligands were compared in a series of in vitro assays using prostate adenocarcinoma PC-3 cells and in murine models. They all displayed high and GRPR-specific uptake in PC-3 cells. Analysis of mice blood collected 5 min post-injection (pi) revealed similar or even higher metabolic stability of the new radioligands compared with [99mTc]Tc-DB15. The stability could be further increased when the mice were treated with Entresto (R) to in situ induce NEP-inhibition. In PC-3 xenograft-bearing mice, [111In]In-AU-SAR-M1 displayed the most favourable biodistribution profile, combining a good tumor retention with the highest tumor-to-organ ratios, with the kidneys as the dose-limiting organ.Conclusions: These findings strongly point at AU-SAR-M1 as a promising radiotherapeutic candidate when labeled with Lu-177, or other medically appealing therapeutic radiometals, especially when combined with in situ NEP-inhibition. To this goal further investigations are currently pursued.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Prostate cancer
- GRPR-antagonist
- Radiotheranostics
- PC-3 tumors
- Metabolic stability
- NEP-inhibition
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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