Developing Chlorin/Arylaminoquinazoline Conjugates with Nanomolar Activity for Targeted Photodynamic Therapy: Design, Synthesis, SAR, and Biological Evaluation

In this report, we developed novel chlorin/arylaminoquinazoline conjugates for targeted photodynamic therapy of cancer. The synthesized photosensitizers consisted of chlorin-e6 metallocomplexes (Zn, In, or Pd) conjugated with arylaminoquinazoline ligands with high affinity for EGFR receptors. Through the incorporation of cationic moieties, we successfully prepared water-soluble conjugated drugs suitable for intravenous administration. Comprehensive SAR studies were conducted to evaluate the influence of structural features on the photodynamic activity of these conjugates. Additionally, the selectivity and antitumor properties of the conjugates were investigated in EGFR-expressing A431 human tumor cell line in vitro. Among the tested molecules, the In-containing conjugate effectively inhibited tumor cell proliferation at nanomolar concentrations, a rare property for conventional photosensitizers. In in vivo experiments, the conjugates rapidly accumulated at the tumor site in nude mice bearing A431 xenograft tumors. Subsequent distribution analysis among different tissues was carried out using fluorescence imaging and elemental analysis. Finally, we demonstrated that the most promising In-containing conjugate was capable of inhibiting xenograft tumor growth in mice through combinational therapy.