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Kreftfondet Ved St Photodynamic Therapy (PDT) Research Group Norwegian University of Science and Technology (NTNU) Projects and Abstracts *** Ruthenium porphyrin-induced photodamage in bladder cancer cells Vanya Bogoevaa, , , Monica Siksjøb, Kristin G. Sæterbøb, Thor Bernt Meløb, Astrid Bjørkøyb, Mikael Lindgrenb, c, Odrun A. Gederaasd a Department Molecular Biology of Cell Cycle, Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. “G. Bonchev” Str., Bl. 21, Sofia 1113, Bulgaria b Department of Physics, Norwegian University of Science and Technology, N-7491 Trondheim, Norway c Department of Physics, Chemistry and Biology, Linköping University, SE- 58183 Linköping, Sweden d Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7491 Trondheim, Norway Received 19 August 2015, Revised 27 January 2016, Accepted 29 January 2016, Available online 1 February 2016 Show less doi:10.1016/j.pdpdt.2016.01.012 Get rights and content 1 Highlights • Photophysical properties of ruthenium (II) porphyrin, verified that the photosensitizer is capable of activating singlet oxygen. • In vitro experiments on bladder cancer cells, indicated that RuP, irradiated with blue light, induced cellular phototoxicity of 93% • The present investigation of RuP-PDT showed that the dominating mode of cell death is necrosis. Abstract Photodynamic therapy (PDT) is a noninvasive treatment for solid malignant and flat tumors. Light activated sensitizers catalyze photochemical reactions that produce reactive oxygen species which can cause cancer cell death. In this work we investigated the photophysical properties of the photosensitizer ruthenium (II) porphyrin (RuP), along with its PDT efficiency onto rat bladder cancer cells (AY27). Optical spectroscopy verified that RuP is capable to activate singlet oxygen via blue and red absorption bands and inter system crossing (ISC) to the triplet state. In vitro experiments on AY27 indicated increased photo-toxicity of RuP (20 μM, 18 h incubation) after cell illumination (at 435 nm), as a function of blue light exposure. Cell survival fraction was significantly reduced to 14% after illumination of 20 μM RuP with 15.6 J/cm2, whereas the “dark toxicity” of 20 μM RuP was 17%. Structural and morphological changes of cells were observed, due to RuP accumulation, as well as light-dependent cell death was recorded by confocal microscopy. Flow cytometry verified that PDT-RuP (50 μM) triggered significant photo-induced cellular destruction with a photoxicity of (93% ± 0.9%). Interestingly, the present investigation of RuP-PDT showed that the dominating mode of cell death is necrosis. RuP “dark toxicity” compared to the conventional chemotherapeutic drug cisplatin was higher, both evaluated by the MTT assay (24 h). In conclusion, the present investigation shows that RuP with or without photoactivation induces cell death of bladder cancer cells. Keywords Photodynamic therapy; PDT; Ruthenium porphyrin; photophysical characterization; singlet oxygen; bladder cancer Download full text in PDF Opens in a new window. Article suggestions will be shown in a dialog on return to ScienceDirect. *** 2 Photochemical internalization of bleomycine and temozolomide – in vitro studies on glioma cell line F98 Odrun A. Gederaas1, Anette Hauge1,2, Pål Ellingsen2,3, Kristian Berg4, Dag Altin5, Tora Bardal6, Anders Høgset7 and Mikael Lindgren2 1) Department of Cancer Research and Molecular Medicine, University of Science and Technology, N-7489 Trondheim, Norway 2) Department of Physics, N-7491 Trondheim, Norway. 3) Department of Artic Geophysics, The university Centre in Svalbard, N-9171 Longyearbyen, Norway 4) Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway 5) Altin BioTrix, Finn Bergs Veg 3, N-7022 Trondheim, Norway 5) Department of Biology, N-7491 Trondheim, Norway 6) PCI Biotech ASA, Strandvegen 55, 1366 Lysaker, Oslo, Norway Photodynamic therapy (PDT) is an effective treatment for malignant1 and non- malignant diseases, and testing of novel photosensitizers is important prior to in vivo experiments and clinical trials. During PDT experiments the activated photosensitizer 1 transfers energy to nearby oxygen molecules, generating singlet oxygen ( O2) resulting in oxidative stress in cells, which further elicit cell death by necrosis and apoptosis. In the present study we review the use of the photosensitizer meso- tetraphenyl chlorin disulphonate (TPCS2a - Amphinex®) in rat glioma cancer cells in combination with the novel photochemical internalization (PCI) technique2. The tested anticancer drugs were Bleomycin (BLM) and Temozolomide (TMZ). Glioma o cells were incubated with TPCS2a (0.2ug/ml, 18h, 37 C) before BLM or TMZ stimulation (4 h) prior to red light illumination (Quanta System, 652 nm, 50 mW/cm2). The demonstration of structural and morphological changes within glioma cells upon the PCI technique, shown that BLM-PCI is an effective method for killing of F98 glioma cells, but smaller effects were observed using TMZ. The cell survival after BLM-PCI, quantified by the MTT assay, was reduced about 25% after 24 h relative to controls, and 31% after TMZ-PCI. The supplementing quantification by clonogenic assays, using BLM (0.1uM), indicated a long–term cytotoxic effect. The surviving fraction of clonogenic cells was reduced to 5% after light exposure (80s) with PCI compared to 70% in the case of PDT. The present study demonstrates that PCI of BLM is an effective method for killing of F98 glioma cells, but smaller effects was observed using TMZ following the “light after” strategy. The results are the basis for further in vivo studies on our rat glioma cancer model using PDT and PCI. *** Studies of the photosensitizer disulfonated meso-tetraphenyl chlorin in an orthotopic rat bladder tumor model. Baglo Y, Peng Q, Hagen L, Berg K, Høgset A, Drabløs F, Gederaas OA. 3 Photodiagnosis Photodyn Ther. 2015 Mar; 12(1):58-66. doi: 10.1016/j.pdpdt.2014.12.005. Epub 2015 Jan 6. 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. Copyright © 2014 Elsevier B.V. All rights reserved. 4 Figure 2: Fluorescence emission spectra of TPCS2a in bladder tumor tissues. Data were obtained from JETI PDT fluorometer at calibrated integration time of 200 ms. Fluorescence of TPCS2a was excited at 405 nm by JETI equipped laser. TPCS2a fluorescence was detected ex vivo only from TPCS2a-treated bladder tumor tissue, not the controls. Figure 3: Uptake and retention of TPCS2a in bladder tumor tissues. (A) Relative florescence intensity (RFI) of TPCS2a measured 72 h after intravesical instillation at concentration of 1, 2, 3, and 5 mg/ml respectively (protocol A); (B) RFI of TPCS2a with an originally instilled concentration of 3 mg/ml measured at retention time of 4, 24, 48, and 72 h respectively (protocol B). Data were obtained from a JETI PDT fluorometer at calibrated integration time of 200 ms. Mean RFI of each group is shown as a horizontal line. Please observe the difference in vertical scale between A and B. *** Transl Oncol. 2014 Dec;7(6):812-23. doi: 10.1016/j.tranon.2014.10.005. Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide. Gederaas OA1, Søgaard CD1, Viset T2, Bachke S1, Bruheim P3, Arum CJ4, Otterlei M5. 5 Abstract Non-muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell's DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication
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