title: Receptor-mediated DNA-targeted photoimmunotherapy.
abstract: 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.
authors.affiliation: Molecular Radiation Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Karagiannis
authors.forename: Pavel N
authors.initials: PN
authors.lastname: Lobachevsky
authors.forename: Brenda K Y
authors.initials: BK
authors.lastname: Leung
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Roger F
authors.initials: RF
authors.lastname: Martin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D020014:K562 Cells; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011990:Receptors, Transferrin / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D017319:Photosensitizing Agents; D011990:Receptors, Transferrin; D004247:DNA; D066246:ErbB Receptors