Rational Design of Naphthalimide-Based Type I Two-Photon Photosensitizers for Photodynamic Therapy

Photodynamic therapy (PDT) still confronts substantial challenges in treating hypoxic tumors within deep-seated tissues, including the lack of oxygen-independent Type I photosensitizers and design principles. In this work, a series of two-photon photosensitizers of naphthalimide-based derivatives are designed by introducing furan/thiophene at the 4-position of NS (1S) and thio/selenocarbonyl modifications and synthesis routes are suggested. Theoretical studies by density functional theory (DFT) suggested that the compounds 1Se-furan2 and 1Se-furan3 exhibit exceptional photodynamic properties including large two-photon absorption cross sections (262.02/183.16 GM in the 650-900 nm therapeutic window), prolonged triplet state lifetimes (828/4487 μs), optimal lipophilicity (logP = 4.53/4.38), and exclusive superoxide anion radical generation via the Type I mechanism with low oxygen dependence. More importantly, the synergistic regulation mechanism of the two-photon response characteristics and type I/II reaction pathways of naphthalimide by heterocyclic substitution and thio/selenocarbonyl modifications is elucidated. A theoretical framework is also presented for the development of two-photon photosensitizers that preferentially undergo Type I reactions, thereby providing stronger tissue penetration and reducing the risk of photodamage.