Mitochondria-Targeted Photodynamic Therapy with a Galactodendritic Chlorin to Enhance Cell Death in Resistant Bladder Cancer Cells

Here, we report the rational design of a new third-generation photosensitizer (PS), a chlorin conjugated with galactodendritic units, ChlGal₈, to improve the effectiveness of bladder cancer treatment. ChlGal₈ shows better photochemical and photophysical properties than a recently reported homologous porphyrin, PorGal₈. In addition to inheriting excellent photostability, the ability to generate singlet oxygen, and the ability to interact with the proteins galectin-1 and human serum albumin (HSA), ChlGal₈ exhibits high absorption in the red region of the electromagnetic spectrum. In vitro studies of anticancer activity of ChlGal₈ revealed that once this PS is taken up by UM-UC-3 bladder cancer cells, it induces high cytotoxicity after a single dose of light irradiation. In HT-1376 bladder cancer cells resistant to therapy, a second light irradiation treatment enhanced in vitro and in vivo photodynamic efficacy. The enhanced phototoxicity in HT-1376 cancer cells seems to be due to the ability of ChlGal₈ to accumulate in the mitochondria, via facilitative glucose transporter 1 (GLUT1), in the period between single and repeated irradiation. A photodynamic therapy (PDT) regimen using an extra dose of light irradiation and ChlGal₈ as PS represents a promising strategy in treating resistant cancers in a clinical setting.