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 epidermal growth factor receptors (EGFR).
Additionally, the selectivity and antitumor properties of the conjugates
were investigated in the 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. This
therapeutic approach, combined with the conjugate’s confirmed
safety profile, highlights its potential for effective and safe cancer
treatment.