Modular late-stage vectorization of Fe(II)-terpyridine complexes for photoacoustic and photothermal applications

The development of vectorized molecular photothermal agents is often limited by the lack of modular synthetic strategies that allow the introduction of biological vectors without compromising the properties of the previously engineered agents. Herein, we report a late-stage vectorization synthetic strategy where pyridinium quaternization of a preformed Fe(II)-terpyridine complex provides a straightforward and versatile access to libraries of vectorized agents while preserving their intrinsic photophysical and photothermal properties. This Fe(II)-terpyridine complex was used as a common synthetic intermediate for the final step introduction of biotin vectors bearing different linkers to afford the desired bis-vectorized complexes. Importantly, the quaternization strategy was designed to enhance the electron-withdrawing character of the ligand, hence reducing the energy of the metal-to-ligand charge-transfer transition for red shifting it toward the near-infrared region, thereby making them relevant for irradiation in photobiology. Beyond enhancing these previously engineered optical properties, late-stage vectorization substantially improved the in vitro biological behavior of the complexes. The vectorized complexes displayed enhanced cellular accumulation, confirmed by photoacoustic imaging, together with negligible in vitro dark toxicity, efficient photothermal conversion and cytotoxicity under irradiation, while maintaining high chemical and photostability. Overall, this work establishes late-stage functionalization by quaternization of a pre-formed Fe(II)-terpyridine complex as a modular design strategy to decorrelate functionalization with a vector as the final synthetic step from engineering the photothermal core, for producing performant vectorized Fe(II)-based agents active in photoacoustic imaging and photothermal therapy.