Novel Water‐Soluble, Heavy Atom‐Free Thioxanthene‐Fused Naphthalimide–Polyamine Phototheranostic Conjugates

Photodynamic therapy (PDT) is a promising therapeutic modality based on the combined use of light and photosensitizers (PSs) and approved for treating several types of cancers. Thio‐heterocyclic naphthalimide‐based PSs are particularly attractive as phototheranostic agents, combining fluorescence imaging for diagnosis with reactive oxygen species (ROS)‐mediated cytotoxicity for treatment. However, no effective conjugation strategy for simultaneously endowing naphthalimides with water solubility and efficient ROS production ability currently exists. Herein, novel water‐soluble, heavy atom‐free thioxanthene‐fused naphthalimide–polyamine conjugates 1–4 have been developed. Structural variation in the polyamine moiety, including chain length and nitrogen content, allowed the fine‐tuning of key properties. Conjugates 2 and 3 exhibited (i) favorable photophysical and fluorescent properties, (ii) enhanced water solubility, (iii) improved photodynamic efficacy against MCF‐7 breast cancer cells, and (iv) negligible dark toxicity. This novel class of thioxanthene‐fused naphthalimide–polyamine conjugates provides a promising conjugation strategy for improving the drug‐like properties of PSs.