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Preclinical Charact...
Preclinical Characterization of a Stabilized Gastrin-Releasing Peptide Receptor Antagonist for Targeted Cancer Theranostics
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- Abouzayed, Ayman (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Kanellopoulos, Panagiotis (författare)
- Uppsala universitet,Institutionen för läkemedelskemi,NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece.
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- Gorislav, Alisa (författare)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Maina, Theodosia (författare)
- NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece.
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- Nock, Berthold A. (författare)
- NCSR Demokritos, Mol Radiopharm, INRaSTES, Athens 15310, Greece.
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- Orlova, Anna, 1960- (författare)
- Uppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- MDPI, 2023
- 2023
- Engelska.
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:7
- Relaterad länk:
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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/10.3...
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Abstract
Ämnesord
Stäng
- Radiolabeled gastrin-releasing peptide receptor (GRPR) antagonists have shown great promise for the theranostics of prostate cancer; however, their suboptimal metabolic stability leaves room for improvements. It was recently shown that the replacement of Gly(11) with Sar(11) in the peptidic [D-Phe(6),Leu(13)-NHEt,des-Met(14)]BBN(6-14) chain stabilized the [Tc-99m]Tc-DB15 radiotracer against neprilysin (NEP). We herein present DOTAGA-PEG(2)-(Sar(11))RM26 (AU-RM26-M1), after Gly(11) to Sar(11)-replacement. The impact of this replacement on the metabolic stability and overall biological performance of [In-111]In-AU-RM26-M1 was studied using a head-to-head comparison with the unmodified reference [In-111]In-DOTAGA-PEG(2)-RM26. In vitro, the cell uptake of [In-111]In-AU-RM26-M1 could be significantly reduced in the presence of a high-excess GRPR-blocker that demonstrated its specificity. The cell uptake of both radiolabeled GRPR antagonists increased with time and was superior for [In-111]In-AU-RM26-M1. The dissociation constant reflected strong affinities for GRPR (500 pM for [In-111]In-AU-RM26-M1). [In-111]In-AU-RM26-M1 showed significantly higher stability in peripheral mice blood at 5 min pi (88 & PLUSMN; 8% intact) than unmodified [In-111]In-DOTAGA-PEG(2)-RM26 (69 & PLUSMN; 2% intact; p < 0.0001). The administration of a NEP inhibitor had no significant impact on the Sar(11)-compound (91 & PLUSMN; 2% intact; p > 0.05). In vivo, [In-111]In-AU-RM26-M1 showed high and GRPR-mediated uptake in the PC-3 tumors (7.0 & PLUSMN; 0.7%IA/g vs. 0.9 & PLUSMN; 0.6%IA/g in blocked mice) and pancreas (2.2 & PLUSMN; 0.6%IA/g vs. 0.3 & PLUSMN; 0.2%IA/g in blocked mice) at 1 h pi, with rapid clearance from healthy tissues. The tumor uptake of [In-111]In-AU-RM26-M1 was higher than for [In-111]In-DOTAGA-PEG(2)-RM26 (at 4 h pi, 5.7 & PLUSMN; 1.8%IA/g vs. 3 & PLUSMN; 1%IA/g), concordant with its higher stability. The implanted PC-3 tumors were visualized with high contrast in mice using [In-111]In-AU-RM26-M1 SPECT/CT. The Gly(11) to Sar(11)-substitution stabilized [In-111]In-DOTAGA-PEG(2)-(Sar(11))RM26 against NEP without negatively affecting other important biological features. These results support the further evaluation of AU-RM26-M1 for prostate cancer theranostics after labeling with clinically relevant radionuclides.
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
- theranostics
- PC-3 cells
- neprilysin
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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