Radiodynamic Properties of Liposomes Encapsulating a Bi ³⁺ Triple-Decker Phthalocyanine

The development of next-generation radiosensitizing agents is of major interest for enhancing tumor-specific radiation responses while minimizing the toxicity to healthy tissues. Among emerging radiosensitizers, porphyrinoids have attracted attention, as their unique redox properties, further enhanced by specific coordination metals, can augment radiation-induced oxidative tissue damage. While porphyrins and texaphyrins have been widely investigated, it remains unclear whether phthalocyanines are similarly effective. In this work, we report on the design, synthesis, and characterization of a triple-decker bismuth-phthalocyanine complex (<b>BiTD</b>), consisting of three tetra(<i>t</i>-butyl)phthalocyanine ligands coordinated by two Bi centers. To improve biocompatibility and enhance cellular uptake, <b>BiTD</b> was encapsulated in liposomes, where it exhibited excellent stability. Under these conditions, <b>BiTD</b> significantly outperformed free phthalocyanines in radiochemical assays, generating markedly higher levels of reactive oxygen species (ROS) upon ionizing radiation. Importantly, <b>BiTD</b> also increased radiotherapy outcomes in pancreatic cancer spheroids. These results highlight bicoordinated multideck phthalocyanines as a promising metalloorganic radiosensitizer and establish a new molecular design strategy to enhance radiodynamic therapy (RDT) while facilitating the understanding of its hypothetical mechanisms and applications.