Photodynamic Therapy by Glucose Transporter 1-Selective Light Inactivation

[Image: see text] Chromophore-assisted light inactivation (CALI) was applied to molecule-targeted photodynamic therapy (PDT). In order to identify organic photosensitizers suitable for CALI, the carbonic anhydrase II (CAII) ligand, 4-sulfamoylbenzoic acid 1, was conjugated with several photosensitizers to produce compounds 2–7, whose CALI ability was evaluated by measuring their effect on CAII enzymatic activity. Di-iodinated BODIPY (I(2)BODIPY) exhibited excellent CAII inactivation ability, similar to that of Ru(bpy)(3). The glucose–I(2)BODIPY conjugate (8) was synthesized as an inactivation of glucose transporter 1 (GLUT1), a protein overexpressed in many cancer cells. Under light irradiation, 8 exhibited concentration-dependent cytotoxicity with half maximal inhibitory concentration (IC(50)) values of 5.49, 11.14, and 8.73 μM, against human cervical carcinoma (HeLa), human lung carcinoma (A549), and human hepatocellular carcinoma (HepG2) cell lines, respectively. The GLUT1 inhibitor phloretin suppressed the cytotoxicity induced by 8 under light irradiation in a concentration-dependent manner. Western blot analysis indicated that GLUT1 was not detected in cell lines treated with 10 μM 8 under light irradiation. Furthermore, 8 reduced the levels of epidermal growth factor receptor tyrosine kinase (EGFR), phospho-ERK (Y204), and GLUT1 without affecting ERK, α-tubulin, and PCNA protein levels, whereas talaporfin sodium, a clinically approved photosensitizer for PDT, nonspecifically reduced intracellular protein levels in HeLa cells, indicating that 8 has a GLUT1-specific inactivation ability and causes light-induced cytotoxicity by modulating the EGFR/MAPK signaling pathway.