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.