Selective Integrin Ligands Promote Cell Internalization of the Antineoplastic Agent Fluorouracil

[Image: see text] Drug conjugates consisting of an antineoplastic drug and a targeting receptor ligand could be effective to overcome the heavy side effects of unselective anticancer agents. To address this need, we report here the results of a project aimed to study agonist and antagonist integrin ligands as targeting head of molecular cargoes for the selective delivery of 5-fluorouracil (5-FU) to cancer or noncancer cells. Initially, two fluorescent β-lactam-based integrin ligands were synthesized and tested for an effective and selective internalization mediated by α(4)β(1) or α(5)β(1) integrins in Jurkat and K562 cells, respectively. No cellular uptake was observed for both fluorescent compounds in HEK293 noncancerous control cells. Afterward, three conjugates composed of the β-lactam-based integrin ligand, suitable linkers, and 5-FU were realized. The best compound E, acting as α(5)β(1) integrin agonist, is able to selectively deliver 5-FU into tumor cells, successfully leading to cancer cell death.