Selective Integrin Ligands Promote Cell Internalization of the Antineoplastic Agent Fluorouracil

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 α₄β₁ or α₅β₁ 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 α₅β₁ Integrin agonist, is able to selectively deliver 5-FU into tumor cells, successfully leading to Cancer cell death.