A Cyclic-RGD Dinuclear Tb^III Macrocyclic Complex as a Tumor Integrin-Selective Luminescent Probe

To develop small molecular integrin-selective luminescent imaging probes, we have prepared the binary dipicolinate (DPA) Tb^III dinuclear macrocyclic complex, Tb₂(cRGDfK-ODO2A-dimer) (DPA)₂ ^2– or complex I, and reference ligands and Tb^III complexes which were purified by HPLC and characterized by NMR, mass spectrometry and luminescence spectroscopy. Luminescence titrations of the structural and bonding model Tb₂(m-ODO2A-dimer)²⁺ complex by DPA^2– ion confirmed the molecular formula of the adduct was Tb₂(m-ODO2A-dimer)(DPA)₂ ^2–, and the first binary binding constant was determined to be log K₁ = 5.76. At pH 7.4, complex I showed 300 times luminescence enhancement at 544 nm (λ_ex = 278 nm) as compared to that without adding DPA, and was found to bind to α_vβ₃ integrin and human glioblastoma U87MG tumor cells in both specific and non-specific modes, via luminescence spectroscopic and confocal cell imaging competition studies. This makes complex I and its future optimized derivatives potentially feasible for preclinical bioimaging applications, particularly in the time-resolved mode.