Yan Baglo1, Qian Peng2, Lars Hagen3, Kristian Berg4, Anders Høgset5, Finn Drabløs3, Odrun A Gederaas3. 1. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7491 Trondheim, Norway. Electronic address: yan.baglo@ntnu.no. 2. Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway. 3. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7491 Trondheim, Norway. 4. Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway. 5. PCI Biotech AS, Strandveien 55, N-1366 Lysaker, Norway.
Abstract
BACKGROUND: Photochemical internalization (PCI) is a novel technology for the release of a therapeutic molecule from endocytic vesicles into the cytosol of a cell. The release of molecules occurs after activation of an endocytic membrane-embedded photosensitizer by light. In this study uptake and localization of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) were explored to optimize a PCI protocol in an orthotopic rat bladder tumor model. METHODS: Female Fischer F344 rats were intravesically instilled with 0.4×10(6) AY-27 transitional carcinoma cells before allowing tumor growth for 14 days. The photosensitizer TPCS2a was intravesically instilled at different concentrations, and bladders were excised after different time intervals. The retention, penetration, and localization of intratumoral TPCS2a were explored ex vivo using fluorescence spectroscopy and fluorescence microscopy to determine an optimal PCI protocol. These results were compared to histological analysis of necrotic areas after activation of intratumoral TPCS2a by red light (652nm, 0.5J/cm(2)). RESULTS: A superficial distribution pattern of the photosensitizer TPCS2a was seen in bladder tumor tissue, and TPCS2a was almost cleared from the tumors after 72h. The highest retention of TPCS2a was found at 24h after instillation when using a concentration of 3mg/ml. CONCLUSION: An optimal PCI protocol was defined for the tumor model, including a 24-h TPCS2a-to-light interval and a dose of 3mg/ml TPCS2a. This protocol will be utilized for the study of PCI-enhanced therapeutic effects on non-muscle invasive bladder cancer, using a potent chemotherapeutic under an optimal light dose.
BACKGROUND: Photochemical internalization (PCI) is a novel technology for the release of a therapeutic molecule from endocytic vesicles into the cytosol of a cell. The release of molecules occurs after activation of an endocytic membrane-embedded photosensitizer by light. In this study uptake and localization of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) were explored to optimize a PCI protocol in an orthotopic ratbladder tumor model. METHODS: Female Fischer F344 rats were intravesically instilled with 0.4×10(6) AY-27 transitional carcinoma cells before allowing tumor growth for 14 days. The photosensitizer TPCS2a was intravesically instilled at different concentrations, and bladders were excised after different time intervals. The retention, penetration, and localization of intratumoral TPCS2a were explored ex vivo using fluorescence spectroscopy and fluorescence microscopy to determine an optimal PCI protocol. These results were compared to histological analysis of necrotic areas after activation of intratumoral TPCS2a by red light (652nm, 0.5J/cm(2)). RESULTS: A superficial distribution pattern of the photosensitizer TPCS2a was seen in bladder tumor tissue, and TPCS2a was almost cleared from the tumors after 72h. The highest retention of TPCS2a was found at 24h after instillation when using a concentration of 3mg/ml. CONCLUSION: An optimal PCI protocol was defined for the tumor model, including a 24-h TPCS2a-to-light interval and a dose of 3mg/ml TPCS2a. This protocol will be utilized for the study of PCI-enhanced therapeutic effects on non-muscle invasive bladder cancer, using a potent chemotherapeutic under an optimal light dose.
Authors: Alejandra Martinez de Pinillos Bayona; Caroline M Moore; Marilena Loizidou; Alexander J MacRobert; Josephine H Woodhams Journal: Int J Cancer Date: 2015-03-23 Impact factor: 7.396
Authors: Alejandra Martinez de Pinillos Bayona; Josephine H Woodhams; Hayley Pye; Rifat A Hamoudi; Caroline M Moore; Alexander J MacRobert Journal: Cancer Lett Date: 2017-02-20 Impact factor: 8.679