Precision peptide theranostics: developing N- to C-terminus optimized theranostics targeting cholecystokinin-2 receptor
Details
Publication Year 2024,Volume 14,Issue #5,Page 1815-1828
Journal Title
Theranostics
Publication Type
Research article
Abstract
Peptides are ideal for theranostic development as they afford rapid target accumulation, fast clearance from background tissue, and exhibit good tissue penetration. Previously, we developed a novel series of peptides that presented discreet folding propensity leading to an optimal candidate [(68)Ga]Ga-DOTA-GA1 ([D-Glu](6)-Ala-Tyr-NMeGly-Trp-NMeNle-Asp-Nal-NH(2)) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK(2)R). However, we were confronted with challenges of unfavorably high renal uptake. Methods: A structure activity relationship study was undertaken of the lead theranostic candidate. Prudent structural modifications were made to the peptide scaffold to evaluate the contributions of specific N-terminal residues to the overall biological activity. Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK(2) tumors, and their biodistribution was quantitated ex vivo. Results: We identified and confirmed that D-Glu(3) to D-Ala(3) substitution produced 2 optimal candidates, [(68)Ga]Ga-DOTA-GA12 and [(68)Ga]Ga-DOTA-GA13. These radiopeptides presented with high target/background ratios, enhanced tumor retention, excellent metabolic stability in plasma and mice organ homogenates, and a 4-fold reduction in renal uptake, significantly outperforming their non-alanine counterparts. Conclusions: Our study identified novel radiopharmaceutical candidates that target the CCK(2)R. Their high tumor uptake and reduced renal accumulation warrant clinical translation.
Publisher
Ivyspring International Publisher
Keywords
Mice; Animals; *Receptor, Cholecystokinin B/metabolism; *Gallium Radioisotopes/chemistry; Precision Medicine; Mice, Nude; Tissue Distribution; Cell Line, Tumor; Peptides/chemistry
Department(s)
Cancer Imaging; Laboratory Research
Open Access at Publisher's Site
https://doi.org/10.7150/thno.89701
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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