Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Effect of Peptide Length on in Vitro and in Vivo Properties of 177Lu-labeled Peptide Analogs Targeting CCK2R

Anton Amadeus Hörmann
* ,
Maximilian Klingler
,
Christine Rangger
ORCID logo ,
Christian Mair
,
Lieke Joosten
ORCID logo ,
Gerben M. Franssen
,
Peter Laverman
,
Elisabeth von Guggenberg
* ORCID logo
Version 1 : Received: 12 September 2022 / Approved: 14 September 2022 / Online: 14 September 2022 (08:39:42 CEST)

A peer-reviewed article of this Preprint also exists.

Hörmann, A.A.; Klingler, M.; Rangger, C.; Mair, C.; Joosten, L.; Franssen, G.M.; Laverman, P.; von Guggenberg, E. Effect of N-Terminal Peptide Modifications on In Vitro and In Vivo Properties of 177Lu-Labeled Peptide Analogs Targeting CCK2R. Pharmaceutics 2023, 15, 796. Hörmann, A.A.; Klingler, M.; Rangger, C.; Mair, C.; Joosten, L.; Franssen, G.M.; Laverman, P.; von Guggenberg, E. Effect of N-Terminal Peptide Modifications on In Vitro and In Vivo Properties of 177Lu-Labeled Peptide Analogs Targeting CCK2R. Pharmaceutics 2023, 15, 796.

Abstract

Minigastrin (MG) analogs for therapy of CCK2R-expressing malignancies are limited by low stability in vivo or excessive accumulation in non-target organs. By modifying the C-terminal receptor-binding sequence, metabolization could be prevented and tumor targeting significantly improved. In this work, N-terminal changes of the peptide length were evaluated. Based on the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2), two new MG analogs were synthesized, by either introduction of a penta-DGlu moiety or depletion of the four N-terminal amino acids and introduction of a non-charged hydrophilic linker. Two CCK2R-expressing cell lines were used to demonstrate receptor interaction. Stability of the 177Lu-labeled peptide analogs was evaluated in human serum up to 24 h after incubation and in BALB/c mice up to 30 min after injection. The biodistribution profile and tumor targeting potential was evaluated in xenografted BALB/c nude mice. For both new MG analogs, the combination of strong receptor-specific cell interaction, high stability and enhanced tumor targeting could be demonstrated. Shortening of the peptide sequence lowered the absorption in the dose-limiting organs, whereas elongation increased uptake in renal tissue.

Keywords

Cholecystokinin-2 receptor; minigastrin; peptide receptor radionuclide therapy; lutetium-177, theranostics

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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