Albumin-Binding Modification Improves Tumor Retention of Hydrophilic αvβ6-Targeting Radiotheranostic Tracers

Abstract

Integrin αvβ6 is an attractive theranostic target for pancreatic ductal adenocarcinoma (PDAC). Existing αvβ6-targeting tracers are limited by relatively low tumor uptake and rapid tumor washout, compromising theranostic efficacy. In this study, a series of αvβ6-targeting ligands with different hydrophilic linkers and/or albumin-binding moiety were designed and evaluated with molecular docking and MD simulations. Among them, NOTA-Asp2-IPB-αvβ6L was selected for further theranostic evaluation due to its favorable targeting capability, enhanced tumor uptake and favorable pharmacokinetic properties. NOTA-Asp2-IPB-αvβ6L was labeled with 18F, 68Ga, and 177Lu, and showed favorable in vitro properties, including high hydrophilicity, αvβ6 affinity, and albumin binding. In PET/CT imaging, [18F]AlF/[68Ga]Ga-Asp2-IPB-αvβ6L exhibited enhanced tumor uptake and prolonged retention while maintaining favorable pharmacokinetics, showing favorable diagnostic efficiency. In therapeutic studies, [177Lu]Lu-Asp2-IPB-αvβ6L effectively inhibited tumor growth with no apparent toxicity. These results demonstrated [18F]AlF/[68Ga]Ga-Asp2-IPB-αvβ6L and [177Lu]Lu-Asp2-IPB-αvβ6L as promising radiotheranostic pairs for PDAC.