Therapeutic Efficacy of ¹⁷⁷Lu-Labeled A20FMDV2 Peptides Targeting α_νβ₆

Integrin α_νβ₆ promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting α_νβ₆ with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for α_νβ₆. However, one concern of these α_νβ₆ integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either ⁶⁸Ga for imaging or ¹⁷⁷Lu for therapy. PET imaging with [⁶⁸Ga]Ga-DOTA-(PEG28)₂-A20FMDV2 revealed specific tumor uptake in α_νβ₆-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)₂-A20FMDV2 and IBA-DOTA-(PEG28)₂-A20FMDV2 were radiolabeled with ¹⁷⁷Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both ¹⁷⁷Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an α_νβ₆-positive tumor.