Questing for Integrin Targeting Theranostics for Cancer Cell-Selective Molecules

Small molecules may play a significant role as theranostic agents for the diagnosis and treatment of some severe disorders, such as cancer. A theranostic agent must have a therapeutic moiety, an imaging group for diagnostics, and a targeting portion for specific cell recognition. In this study, we synthesized two new molecules, D and E, as potential theranostic agents, consisting of a β-lactam portion acting as a selective α₄β₁ integrin agonist, a fluorescent imaging probe for diagnostics purposes, and a cytotoxic portion for anticancer activity. Compound D incorporates a 1,8-naphthylimide fluorophore for imaging and the 5-FU cytotoxic unit, whereas compound E features BODIPY moiety serving both as a photosensitizer and as a cytotoxic agent. Both compounds were evaluated for their photophysical properties. The binding assays for α₄β₁ integrin revealed that only E had a good affinity (K _D 68.2 ± 1.0 μM). In adhesion assays with Jurkat E6.1, K562, HT-29, and HEK-293 cells, E retained the selective agonist activity for α₄β₁ integrin (EC₅₀ 0.92 ± 0.14 μM) as the parental β-lactam ligand A. Upon photosensitization, compound E induced a significant concentration-dependent reduction in cell viability across all tested cell lines, regardless of integrin expression. Internalization experiments indicated a nonselective cellular uptake of compound E, likely due to its high lipophilicity, which may outweigh the contribution of structural elements responsible for specific integrin recognition.