Affiliation: | 1. Institute of Pathology, Technische Universität München, Trogerstrasse 18, 81675 München, Germany
These authors contributed equally to this work.;2. Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
These authors contributed equally to this work.;3. Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy;4. Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, Via A. Vivaldi 43, 81100 Caserta, Italy;5. Institute of Pathology, Technische Universität München, Trogerstrasse 18, 81675 München, Germany;6. Klinik für Nuklearmedizin and TranslaTUM, Central Institute for Translational Cancer Research, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany |
Abstract: | αvβ6 Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with αvβ6 integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the αvβ6-specific cyclic pentapeptide SDM17 (cycloRGD-Chg-E]-CONH2) to enhance αvβ6 integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)3 showed a 28-fold higher αvβ6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC50 of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC50-based selectivity over the related integrin αvβ8 (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)3 holds promise for improved clinical PET diagnostics of carcinomas and fibrosis. |