Development of potent tripodal G-quadruplex DNA binders and their efficient delivery to cancer cells by aptamer functionalised liposomes

Two new ligands, TPB3P and TPB3Py, have been synthesized, demonstrating strong stabilization effects and high selectivity for G-quadruplex (G4) over duplex DNAs. These ligands feature three analogous polyamine pendant arms (TPA3P and TPA3Py) but differ in their central aromatic core: a triphenylbenzene moiety replaces the triphenylamine moiety found in the TPA-based ligands. Unlike TPA-based ligands, which show no significant cytotoxicity, TPB3P and TPB3Py exhibit high cytotoxicity against MCF-7, LN229, and HeLa cancer cells. Furthermore, the most potent G4-binding ligands have been encapsulated in liposomes and AS1411 aptamer-targeted liposomes, achieving nanomolar IC50 values in the most cytotoxic systems.