The importance of tyrosines in multimers of cyclic RGD nonapeptides: towards αvβ6-integrin targeted radiotherapeutics.

Autor:	Quigley NG; Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany., Zierke MA; Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany., Ludwig BS; Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany., Richter F; Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany., Nguyen NT; Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany., Reissig F; TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany jn@trimt.de., Šimeček J; TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany jn@trimt.de., Kossatz S; Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany., Notni J; Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany.; TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany jn@trimt.de.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2024 Apr 19; Vol. 15 (6), pp. 2018-2029. Date of Electronic Publication: 2024 Apr 19 (Print Publication: 2024).
DOI:	10.1039/d4md00073k
Abstrakt:	In a recent paper in this journal ( RSC Med. Chem. , 2023, 14 , 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp( N Me)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol-water distribution coefficient (log  D ). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the in vivo performance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the in vitro characteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred. Competing Interests: N. G. Q. and J. N. are inventors on patent applications related to αvβ6-integrin binding peptide conjugates and 68Ga-Trivehexin. J. N. and J. Š. are CSO and CEO, respectively, and co-founders of TRIMT GmbH (Radeberg, Germany) who has licensed IP from TU Munich. J. N. is furthermore a member of the Scientific Advisory Board of Radiopharm Theranostics LLC (Carlton, Australia) who has licensed IP from TRIMT GmbH. S. K. receives research support from TRIMT GmbH. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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