We show the efficacy of a therapeutic strategy that combines the potency of
a DNA-binding
photosensitizer, UV(A)Sens, with the
tumor-targeting potential of receptor-mediated endocytosis. The
photosensitizer is an iodinated bibenzimidazole, which, when bound in the minor groove of
DNA and excited by UV(A) irradiation, induces cytotoxic lesions attributed to a radical species resulting from photodehalogenation. Although reminiscent of
photochemotherapy using
psoralens and UV(A) irradiation, an established treatment modality in dermatology particularly for the treatment of
psoriasis and
cutaneous T-cell lymphoma, a critical difference is the extreme photopotency of the iodinated bibenzimidazole, approximately 1,000-fold that of
psoralens. This feature prompted consideration of combination with the specificity of receptor-mediated targeting. Using two in vitro model systems, we show the UV(A) cytotoxicity of iodo
ligand/
protein conjugates, implying binding of the conjugate to cell receptors, internalization, and degradation of the conjugate-receptor complex, with release and translocation of the
ligand to nuclear
DNA. For
ligand-
transferrin conjugates,
phototoxicity was inhibited by coincubation with excess native
transferrin. Receptor-mediated UV(A)-induced cytotoxicity was also shown with the iodo
ligand conjugate of an anti-human
epidermal growth factor receptor monoclonal antibody, exemplifying the potential application of the strategy to other
cancer-specific targets to thus improve the specificity of
phototherapy of superficial lesions and for extracorporeal treatments.