Hafnium-Based\nMetal–Organic Framework Nanosystems\nEntrapping Squaraines for Efficient NIR-Responsive Photodynamic Therapy

In\nthis study, we present for the first time the incorporation\nof two distinct nonsymmetrical squaraines (SQ) into hierarchically\nporous Hafnium-based UiO-66 Metal–Organic Frameworks (MOFs),\neach functionalized with various moieties, for application as photosensitizers\nin photodynamic therapy. SQs are meticulously designed to feature\nCOOH moieties for interaction with the MOF’s metallic cluster\nand bromine atoms to enhance intersystem crossing and reactive oxygen\nspecies (ROS) production. The distinct central functionalizations,\none with squaric acid and the other with a dicyanovinyl-substituted\nsquaric acid derivative, result in unique geometric conformations.\nThe latter, as well as the molecular size and density, have been analyzed\nby computational methods, facilitating the optimal design of MOF cavities\nfor SQ accommodation. Our synthetic methodology involves the production\nof hierarchically porous Hf-MOFs that integrate both micro- and mesopores.\nThe resultant SQ@MOF systems preserve photosensitizing properties,\nenhancing solubility and stability without compromising ROS generation\nor MOF structural integrity. As proof of concept, <i>in vitro</i> evaluations against PANC-1 cells were evaluated, demonstrating the\ncytocompatibility of SQ@MOFs in the dark up to concentrations of 200\nμg mL<sup>–1</sup>. Photoactivity is assessed using a\nstatistical multivariate design, enabling identification of the SQ@MOF\nsystem with the highest phototoxicity and determination of the variables\nthat significantly influence phototoxicity.