Macrocyclic RGD-peptides with high selectivity for αvβ3 integrin in cancer imaging and therapy†

Integrins, particularly the α_vβ₃ subtype, are critical receptors involved in cell adhesion, migration, and signaling, playing a significant role in tumor progression and metastasis. Despite extensive research into integrin-targeted therapies, challenges remain in developing ligands that exhibit high selectivity for α_vβ₃ over other integrin subtypes, such as α_vβ₅. This study employs a one-pot sortase A-mediated on-resin peptide cleavage and in situ cyclization method to synthesize two generations of macrocyclic RGD-peptide libraries. Systematic screening through surface plasmon resonance and cell-based competition assays identified the lead compound, c-(G5RGDKcLPET), which demonstrated high affinity and selectivity for α_vβ₃. Additionally, the optimized cyclic peptide was functionalized with a fluorescent dye (Cy5) and the cytotoxic drug monomethyl auristatin E (MMAE), enhancing its potential for cancer imaging and targeted therapy. This work contributes a novel platform for developing integrin-targeted diagnostics and therapeutics, highlighting the importance of macrocyclic peptides in cancer treatment strategies.