Precision peptide theranostics: developing N- to C-terminus optimized theranostics targeting cholecystokinin-2 receptor
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Date
2024-01-01
Source Title
Theranostics
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IVYSPRING INT PUBL
Melbourne Authors
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Sir Peter MacCallum Department of Oncology
Bio21
Bio21
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Journal Article
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Rahimi, M. N., Corlett, A., Van Zuylekom, J., Sani, M. A., Blyth, B., Thompson, P., Roselt, P. D. & Haskali, M. B. (2024). Precision peptide theranostics: developing N- to C-terminus optimized theranostics targeting cholecystokinin-2 receptor. Theranostics, 14 (5), pp.1815-1828. https://doi.org/10.7150/thno.89701.
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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 [68Ga]Ga-DOTA-GA1 ([D-Glu]6-Ala-Tyr-NMeGly-Trp-NMeNle-Asp-Nal-NH2) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK2R). 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-CCK2 tumors, and their biodistribution was quantitated ex vivo. Results: We identified and confirmed that D-Glu3 to D-Ala3 substitution produced 2 optimal candidates, [68Ga]Ga-DOTA-GA12 and [68Ga]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 CCK2R. Their high tumor uptake and reduced renal accumulation warrant clinical translation.