257 results on '"Weyergang A"'
Search Results
52. Like muligheter til god leseforståelse? 20 år med lesing i PISA
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Jostein Andresen Ryen, Camilla G. Magnusson, Andreas Pettersen, Fredrik Jensen, Astrid Roe, Cecilie Weyergang, Jonas Bakken, Tove Stjern Frønes, Julius Kristjan Björnsson, and Marit Kjærnsli
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media_common.quotation_subject ,Reading (process) ,Theology ,Psychology ,Literacy ,media_common - Abstract
Like muligheter til god leseforståelse? 20 år med lesing i PISA presenterer forskning basert på PISA-undersøkelsen 2018. Hovedresultatene fra undersøkelsen ble presentert i en kortrapport i desember 2019, og denne antologien består av primær- og sekundæranalyser av norske resultater i lesing siden PISA 2000. Ulike tematiske felt innenfor leseforskningen har fått egne kapitler, som lesestrategier, kritisk lesing, lesevaner og å lese mellom linjene. Vi utdyper resultatene blant annet ved å sette dem i sammenheng med annen aktuell forskning og andre skoleundersøkelser, og vi ser lesing i PISA-undersøkelsen i lys av revisjonen av læreplanen, LK20. Kapitlene undersøker også om variasjon i elevenes lesing ser ut til å gjenspeile systematiske forskjeller mellom elevgrupper, og besvarer antologiens tittel Like muligheter til god leseforståelse?. Bokas midtdel har en didaktisk profil som vil komme lærere, lærerstudenter, skoleledere og andre til nytte.
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- 2020
53. Light-enhanced VEGF121/rGel: A tumor targeted modality with vascular and immune-mediated efficacy
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Johannes Waltenberger, Michael G. Rosenblum, Lawrence H. Cheung, Marius S. Eng, Ellen Skarpen, Qian Peng, Khalid A. Mohamedali, Kristian Berg, Ane Sofie Viset Fremstedal, and Anette Weyergang
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0301 basic medicine ,Drug ,Stromal cell ,business.industry ,media_common.quotation_subject ,Pharmaceutical Science ,Cancer ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Stroma ,Fusion Toxin ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,business ,Adverse effect ,media_common - Abstract
Interactions between stromal cells and tumor cells pay a major role in cancer growth and progression. This is reflected in the composition of anticancer drugs which includes compounds directed towards the immune system and tumor-vasculature in addition to drugs aimed at the cancer cells themselves. Drug-based treatment regimens are currently designed to include compounds targeting the tumor stroma in addition to the cancer cells. Treatment limiting adverse effects remains, however, one of the major challenges for drug-based therapy and novel tolerable treatment modalities with diverse high efficacy on both tumor cells and stroma is therefore of high interest. It was hypothesized that the vascular targeted fusion toxin VEGF121/rGel in combination with the intracellular drug delivery technology photochemical internalization (PCI) stimulate direct cancer parenchymal cell death in addition to inhibition of tumor perfusion, and that an immune mediated response is relevant for treatment outcome. The aim of the present study was therefore to elucidate the anticancer mechanisms of VEGF121/rGel-PCI. In contrast to VEGF121/rGel monotherapy, VEGF121/rGel-PCI was found to mediate its effect through VEGFR1 and VEGFR2, and a targeted treatment effect was shown on two VEGFR1 expressing cancer cell lines. A cancer parenchymal treatment effect was further indicated on H&E stains of CT26-CL25 and 4 T1 tumors. VEGF121/rGel-PCI was shown, by dynamic contrast enhanced MRI, to induce a sustained inhibition of tumor perfusion in both tumor models. A 50% complete remission (CR) of CT26.CL25 colon carcinoma allografts was found in immunocompetent mice while no CR was detected in CT26.CL25 bearing athymic mice. In conclusion, the present report indicate VEGF121/rGel –PCI as a treatment modality with multimodal tumor targeted efficacy that should be further developed towards clinical utilization.
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- 2018
54. Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins
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Gunhild Mari Mælandsmo, Michael G. Rosenblum, Lina Prasmickaite, Pål Kristian Selbo, Ellen Skarpen, Soldano Ferrone, J. Kaur, A. Høgset, M. S. Eng, Birgit Engesæter, Kristian Berg, and Anette Weyergang
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0301 basic medicine ,Light ,Saporin ,Cell Survival ,medicine.medical_treatment ,Antineoplastic Agents ,Triple Negative Breast Neoplasms ,Article ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,Immunotoxin ,Tumor Cells, Cultured ,Animals ,Humans ,Medicine ,Physical and Theoretical Chemistry ,Amelanotic melanoma ,Melanoma ,Cell Proliferation ,Dose-Response Relationship, Drug ,biology ,business.industry ,Immunotoxins ,Membrane Proteins ,Photochemical Processes ,medicine.disease ,Radiation therapy ,030104 developmental biology ,Chondroitin Sulfate Proteoglycans ,CSPG4 ,030220 oncology & carcinogenesis ,Conventional PCI ,Cancer research ,biology.protein ,Triple-Negative Breast Carcinoma ,Drug Screening Assays, Antitumor ,business - Abstract
Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS(2a) (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS(2a) + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.
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- 2018
55. Inhibiting autophagy increases the efficacy of low-dose photodynamic therapy
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Ieva Ailte, Andreas Brech, Pål Kristian Selbo, Maja Radulovic, Sabine Weisheit, Catherine S. Wegner, and Anette Weyergang
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Pharmacology ,Programmed cell death ,Photosensitizing Agents ,Cell Survival ,Chemistry ,Endosome ,Vesicle ,Autophagy ,Cell ,RNA-Binding Proteins ,Biochemistry ,Cell biology ,Cytosol ,Treatment Outcome ,medicine.anatomical_structure ,Endocytic vesicle ,Photochemotherapy ,Cell Line, Tumor ,Cancer cell ,medicine ,Humans - Abstract
Rupture and permeabilization of endocytic vesicles can be triggered by various causes, such as pathogenic invasions, amyloid proteins, and silica crystals leading to cell death and degeneration. A cellular quality control process, called lysophagy was recently described to target damaged lysosomes for autophagic sequestration within isolation membranes in order to protect the cell from the consequences of lysosomal leakage. This protective process, however, might interfere with treatment conditions, such as photodynamic therapy (PDT) and the intracellular drug delivery method photochemical internalization (PCI). PCI-induced permeabilization of endosomes and lysosomes is purposely triggered to release drugs that are sequestered in these organelles into the cytosol in order to synergistically kill cancer cells. Here, we show that photochemical treatment with the PCI-photosensitizer TPCS2a/fimaporfin results in both induction of autophagy and inhibition of the autophagic flux. The autophagic response is accompanied by recruitment of ubiquitin (Ubq), p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3) to damaged vesicles, marked by Galectin 3 (Gal3). Furthermore, ultrastructural analysis revealed a homogenously thick p62-positive layer surrounding these permeabilized vesicles. Although p62 seems to be important during the selective autophagic sequestration, we show that its presence is not essential for the effective removal of damaged vesicles or the recovery of the lysosomal content. An active autophagic response and the presence of p62, however, is important for cancer cells to survive low-dose TPCS2a-PDT. Thus, targeting both p62 and autophagy together and independently, in a light-controlled/PCI based delivery of cancer therapeutics could increase the effectiveness of the treatment regime.
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- 2021
56. Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance
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Pål Kristian Selbo, Andreas Brech, Anders Høgset, Sabine Weisheit, Kristian Berg, Cathrine Elisabeth Olsen, Anette Weyergang, and Victoria Tudor Edwards
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Chlorophyll ,0301 basic medicine ,Porphyrins ,Cell Survival ,medicine.medical_treatment ,Photodynamic therapy ,Biology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,polycyclic compounds ,medicine ,Humans ,Photosensitizer ,Doxorubicin ,Cytotoxicity ,Pharmacology ,Photosensitizing Agents ,eye diseases ,030104 developmental biology ,Photochemotherapy ,chemistry ,Drug Resistance, Neoplasm ,Cell culture ,Apoptosis ,Pheophorbide A ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,MCF-7 Cells ,Cancer research ,Female ,therapeutics ,medicine.drug - Abstract
Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS2a) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS2a-PDT-resistance was neither found to correspond with lower TPCS2a-accumulation nor reduced generation of reactive oxygen species (ROS). Cross-resistance to chemotherapy (doxorubicin) or radiotherapy was not observed. TPCS2a-PDT-resistant cells acquired a higher proliferation capacity and an enhanced expression of EGFR and ERK1/2. p38 MAPK was found to be a death-signalling pathway in the MA11 cells post TPCS2a-PDT, contrasting the MA11/TR cells in which PDT generated a sustained phosphorylation of p38 that had lost its death-mediated signalling, and an abrogated activation of its downstream effector MAPKAPK2. No difference in apoptosis, necrosis or autophagy responses was found between the treated cell lines. Development of TPCS2a-PDT resistance in the MDA-MB-231 cell line was also established, however, p38 MAPK did not play a role in the PDT-resistance. MCF-7 cells did not develop TPCS2a-PDT-resistance. Photochemical internalisation (PCI) of 1 pM of EGF-saporin induced equal strong cytotoxicity in both MA11 and MA11/TR cells. In conclusion, loss of p38 MAPK-inducing death signalling is the main mechanism of resistance to TPCS2a-PDT in the MA11/TR cell line. This work provides mechanistic knowledge of intrinsic and acquired PDT-resistance which is dependent on choice of photosensitizer, and suggests PCI as a rational therapeutic intervention for the elimination of PDT-resistant cells.
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- 2017
57. The Potential of Photochemical Internalization (PCI) for the Cytosolic Delivery of Nanomedicines
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Berg, Kristian, primary, Weyergang, Anette, additional, Høgset, Anders, additional, and Selbo, Pål Kristian, additional
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- 2010
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58. Photochemical Internalization (PCI): A Technology for Drug Delivery
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Berg, Kristian, primary, Weyergang, Anette, additional, Prasmickaite, Lina, additional, Bonsted, Anette, additional, Høgset, Anders, additional, Strand, Marie-Therese R., additional, Wagner, Ernst, additional, and Selbo, Pål K., additional
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- 2010
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59. Photochemical internalization (PCI): A novel technology for activation of endocytosed therapeutic agents
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Berg, Kristian, Høgset, Anders, Prasmickaite, Lina, Weyergang, Anette, Bonsted, Anette, Dietze, Andreas, Lou, Pei-Jen, Bown, Stephen, Norum, Ole-Jacob, Møllergård, Hanne Mali Thesen, and Selbo, Pål Kristian
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- 2006
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60. Hva er relevant lesekompetanse i dagens samfunn, og hvordan måleslesing i PISA 2018?
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Weyergang, Cecilie, primary and Magnusson, Camilla G., additional
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- 2020
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61. Å lese kritisk: Elevers vurderinger av teksters troverdighetog pålitelighet
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Weyergang, Cecilie, primary and Frønes, Tove Stjern, additional
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- 2020
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62. Production of Recombinant Gelonin Using an Automated Liquid Chromatography System
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Berstad, Maria E. B., primary, Cheung, Lawrence H., additional, and Weyergang, Anette, additional
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- 2020
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63. Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy
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Wong, Judith Jing Wen, primary, Berstad, Maria Brandal, additional, Fremstedal, Ane Sofie Viset, additional, Berg, Kristian, additional, Patzke, Sebastian, additional, Sørensen, Vigdis, additional, Peng, Qian, additional, Selbo, Pål Kristian, additional, and Weyergang, Anette, additional
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- 2020
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64. Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization
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Olsen, Cathrine Elisabeth, primary, Cheung, Lawrence H., additional, Weyergang, Anette, additional, Berg, Kristian, additional, Vallera, Daniel A., additional, Rosenblum, Michael G., additional, and Selbo, Pål Kristian, additional
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- 2019
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65. Y1068 phosphorylation is the most sensitive target of disulfonated tetraphenylporphyrin-based photodynamic therapy on epidermal growth factor receptor
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Weyergang, Anette, Selbo, Pål Kristian, and Berg, Kristian
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- 2007
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66. Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin
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Weyergang, Anette, Selbo, Pål Kristian, and Berg, Kristian
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- 2006
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67. Porphyrin-related photosensitizers for cancer imaging and therapeutic applications
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BERG, K., SELBO, P. K., WEYERGANG, A., DIETZE, A., PRASMICKAITE, L., BONSTED, A., ENGESAETER, B. Ø., ANGELL-PETERSEN, E., WARLOE, T., FRANDSEN, N., and HØGSET, A.
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- 2005
68. Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization
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Michael G. Rosenblum, Pål Kristian Selbo, Cathrine Elisabeth Olsen, Kristian Berg, Lawrence H. Cheung, Daniel A. Vallera, and Anette Weyergang
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cancer stem cells ,lcsh:Medicine ,Article ,ribosome-inactivating proteins ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immunotoxin ,Cytotoxic T cell ,Medicine ,MTT assay ,CD133 ,Gelonin ,Cytotoxicity ,neoplasms ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,photochemical internalization ,lcsh:R ,General Medicine ,Molecular biology ,carbohydrates (lipids) ,immunotoxins ,photodynamic therapy ,030220 oncology & carcinogenesis ,embryonic structures ,drug delivery ,Conventional PCI ,Cancer cell ,prominin-1 ,business - Abstract
The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated and glycosylated forms of both human and murine CD133/prominin-1 to a gene encoding the ribosome-inactivating protein (RIP) gelonin (rGelonin). RIP-activity was assessed in a cell-free translation assay. Selective binding and intracellular accumulation of scFvCD133/rGelonin was evaluated by flow cytometry and fluorescence microscopy. PCI of scFvCD133/rGelonin was explored in CD133high and CD133low cell lines and a CD133neg cell line, where cytotoxicity was evaluated by the MTT assay. scFvCD133/rGelonin exhibited superior binding to and a higher accumulation in CD133high cells compared to CD133low cells. No cytotoxic responses were detected in either CD133high or CD133low cells after 72 h incubation with <, 100 nM scFvCD133/rGelonin. Despite a severe loss in RIP-activity of scFvCD133/rGelonin compared to free rGelonin, PCI of scFvCD133/rGelonin induced log-fold reduction of viability compared to PCI of rGelonin. Strikingly, PCI of scFvCD133/rGelonin exceeded the cytotoxicity of PCI of rGelonin also in CD133low cells. In conclusion, PCI promotes strong cytotoxic activity of the per se non-toxic scFvCD133/rGelonin in both CD133high and CD133low cancer cells.
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- 2019
69. Photochemical internalization (PCI) of bleomycin induces T-cell activation of importance for curative effect and systemic anti-tumor immunity (Conference Presentation)
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Berg, Kristian, primary, Fremstedal, Ane Sofie, additional, Weyergang, Anette, additional, Golab, Jakub, additional, and Norum, Ole-Jacob, additional
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- 2019
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70. Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics
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Kristian Berg, Anders Høgset, Cathrine Elisabeth Olsen, Pål Kristian Selbo, Monica Bostad, Victoria Tudor Edwards, and Anette Weyergang
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Photosensitizing Agents ,Abcg2 ,biology ,CD44 ,Cancer ,Endosomes ,medicine.disease ,Photochemistry ,Drug Delivery Systems ,Endocytic vesicle ,Photochemotherapy ,Cancer stem cell ,Drug delivery ,Cancer cell ,Neoplastic Stem Cells ,biology.protein ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Stem cell ,Reactive Oxygen Species - Abstract
Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.
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- 2015
71. Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer
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Kristian Berg, Michael G. Rosenblum, Ane Sofie Viset Fremstedal, Maria E B Berstad, Ellen Skarpen, Yu Cao, Bente Bull-Hansen, Anette Weyergang, and Qian Peng
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photodynamic ,Receptor, ErbB-2 ,Recombinant Fusion Proteins ,Blotting, Western ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Mice ,Drug Delivery Systems ,Trastuzumab ,Fusion Toxin ,Immunotoxin ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Ovarian Neoplasms ,Photosensitizing Agents ,business.industry ,Immunotoxins ,photochemical internalization ,medicine.disease ,Xenograft Model Antitumor Assays ,immunotoxin ,ovarian cancer ,Endocytic vesicle ,Oncology ,Cell culture ,HER2/neu/ErbB2 ,Immunology ,Conventional PCI ,Drug delivery ,Cancer research ,Female ,Ovarian cancer ,business ,Single-Chain Antibodies ,Research Paper ,medicine.drug - Abstract
HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.
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- 2015
72. Svangerskap, fødsel og barseltid - mer enn bare overlevelse.
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SOLNES MILTENBURG, ANDREA, BAINS, SUKHJEET, STRØM-ROUM, ELLEN MARIE, VARTDAL, VEGARD WEYERGANG, SØRBYE, INGVIL KRARUP, ALNÆS-KATJAVIVI, PATJI, SUNDBY, JOHANNE, and NYFLØT, LILL TRINE
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- 2023
73. Photochemical delivery of bleomycin induces T-cell activation of importance for curative effect and systemic anti-tumor immunity
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Ole Jacob Norum, Ane Sofie Viset Fremstedal, Anette Weyergang, Jakub Golab, and Kristian Berg
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0301 basic medicine ,Indoles ,T cell ,T-Lymphocytes ,Pharmaceutical Science ,Mice, Nude ,Spleen ,Chromosomal translocation ,Photochemistry ,Bleomycin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Delivery Systems ,Immunity ,Cell Line, Tumor ,Neoplasms ,Carcinoma ,medicine ,Organometallic Compounds ,Animals ,Photosensitizer ,Mice, Inbred BALB C ,Antibiotics, Antineoplastic ,Photosensitizing Agents ,Chemistry ,medicine.disease ,3. Good health ,Tumor Burden ,Cytosol ,030104 developmental biology ,medicine.anatomical_structure ,Photochemotherapy ,030220 oncology & carcinogenesis ,Female - Abstract
Photochemical internalization (PCI) is a technology to enhance intracellular drug delivery by light-induced translocation of endocytosed therapeutics into the cytosol. The aim of this study was to explore the efficacy of PCI-based delivery of bleomycin and the impact on systemic anti-tumor immunity. Mouse colon carcinoma cells (CT26.CL25), stably expressing the bacterial β-galactosidase, were inoculated into the legs of athymic or immuno-competent BALB/c mice strains. The mice were injected with the photosensitizer AlPcS2a and bleomycin (BLM) prior to tumor light exposure from a 670nm diode laser. Photochemical activation of BLM was found to induce synergistic inhibition of tumor growth as compared to the sum of the individual treatments. However, a curative effect was not observed in the athymic mice exposed to 30J/cm2 of light while >90% of the thymic mice were cured after exposure to only 15J/cm2 light. Cured thymic mice, re-challenged with CT26.CL25 tumor cells on the contralateral leg, rejected 57-100% of the tumor cells inoculated immediately and up to 2months after the photochemical treatment. T-cells from the spleen of PCI-treated mice were found to inhibit the growth of CT26.CL25 cells in naive thymic mice with a 60% rejection rate. The results show that treatment of CT26.CL25 tumors in thymic mice by PCI of BLM induces a systemic anti-tumor immunity.
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- 2017
74. Photochemical activation of the recombinant HER2-targeted fusion toxin MH3-B1/rGel; Impact of HER2 expression on treatment outcome
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Michael G. Rosenblum, Anette Weyergang, Kristian Berg, Ellen Skarpen, Bente Bull-Hansen, and Yu Cao
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Porphyrins ,Light ,Cell Survival ,Receptor, ErbB-2 ,medicine.drug_class ,Recombinant Fusion Proteins ,Pharmaceutical Science ,Monoclonal antibody ,Photochemistry ,Antibodies ,Flow cytometry ,Immunotoxin ,Fusion Toxin ,Cell Line, Tumor ,medicine ,Humans ,Gelonin ,skin and connective tissue diseases ,Photosensitizing Agents ,medicine.diagnostic_test ,Chemistry ,Immunotoxins ,Photochemical Processes ,Cell culture ,Conventional PCI ,Ribosome Inactivating Proteins, Type 1 ,Intracellular - Abstract
HER2 is overexpressed in 20-30% of breast tumors and is associated with aggressiveness and increased risk of recurrence and death. The HER2 protein is internalized as a part of its activity, and may therefore be utilized as a target for the specific intracellular delivery of drugs. Photochemical internalization (PCI) is a novel technology now undergoing clinical evaluation for its ability to improve the release into the cytosol of drugs entrapped in the endo/lysosomal compartment. PCI employs an amphiphilic photosensitizer which localizes in the membranes of endo/lysosomes. Subsequent light exposure (visible light) causes destabilization of the endo/lysosomal membranes. PCI has been proven highly effective for improving the cytosolic delivery of targeted toxins based on type I ribosome inactivating protein toxins such as gelonin. We examined the impact of the level of target antigen expression on PCI efficacy. Four human breast cancer cell lines (MDA-MB-231, BT-20, Zr-75-1 and SK-BR-3) covering a wide range of HER2 expression were included in the present study. PCI of the HER2-targeted fusion toxin MH3-B1/rGel was found to be highly effective in all four cell lines. The increase in PCI-mediated efficacy was not directly correlated with the cellular levels of HER2 as assessed by western blots, the overall uptake of MH3-B1/rGel as measured by flow cytometry, the amount of MH3-B1/rGel localized to endo/lysosomes assessed by confocal microscopy or the cell sensitivity to the photochemical treatment itself (photosensitizer and light without MH3-B1/rGel). However, correcting the PCI efficacy for the baseline cellular sensitivity to rGel revealed a linear correlation (R(2)=0.80) with HER2 expression. The present report therefore concludes the cellular sensitivity to the toxin as an important parameter for PCI efficacy and also indicates PCI of a HER2-targeted fusion toxin as an attractive treatment alternative for breast cancer patients with both HER2-low and -high expression.
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- 2014
75. Circumvention of resistance to photodynamic therapy in doxorubicin-resistant sarcoma by photochemical internalization of gelonin
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Pål Kristian Selbo, Anette Weyergang, Cathrine Elisabeth Olsen, and Kristian Berg
- Subjects
GPX1 ,animal structures ,Cell Survival ,Pyridines ,medicine.medical_treatment ,Poly ADP ribose polymerase ,p38 mitogen-activated protein kinases ,Poly (ADP-Ribose) Polymerase-1 ,Apoptosis ,Photodynamic therapy ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Glutathione Peroxidase GPX1 ,Cell Line, Tumor ,Physiology (medical) ,medicine ,Humans ,Doxorubicin ,Enzyme Inhibitors ,Phosphorylation ,Gelonin ,chemistry.chemical_classification ,Glutathione Peroxidase ,Reactive oxygen species ,Caspase 3 ,Chemistry ,Imidazoles ,Sarcoma ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Photochemotherapy ,Drug Resistance, Neoplasm ,Cell culture ,Ribosome Inactivating Proteins, Type 1 ,Cancer research ,Poly(ADP-ribose) Polymerases ,Reactive Oxygen Species ,therapeutics ,medicine.drug - Abstract
A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line. ROS-induced p38 activation was, in addition, shown to be reduced to one-third of the signal of the parental MES-SA cells 2h after PDT, and addition of the p38 inhibitor SB203580 confirmed p38 activation as a death signal after PDT in the MES-SA cells. The MES-SA/Dx5 cells were also cross-resistant to ionizing radiation in agreement with the increased GPx1 and GPx4 expression. Surprisingly, PDT-induced endo/lysosomal release of the ribosome-inactivating protein gelonin (photochemical internalization (PCI)) was more effective in the PDT-resistant MES-SA/Dx5 cells, as measured by synergy calculations in both cell lines. Analysis of death-inducing signaling indicated a low activation of caspase-3 and a strong PARP I cleavage after PDT and PCI in both cell lines. The PARP I activation was, however, stronger after PCI than after PDT in the MES-SA cells, but not in the MES-SA/Dx5 cells, and therefore cannot explain the strong PCI effect in the MES-SA/Dx5 cells. In conclusion PCI of recombinant gelonin circumvents ROS resistance in an apoptosis-independent manner.
- Published
- 2013
76. Sustained EKR inhibition by EGFR targeting therapies is a predictive factor for synergistic cytotoxicity with PDT as neoadjuvant therapy
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Pål Kristian Selbo, Anette Weyergang, and Kristian Berg
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Porphyrins ,Cell Survival ,medicine.medical_treatment ,Biophysics ,Cetuximab ,Antineoplastic Agents ,Cell Count ,Photodynamic therapy ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Erlotinib Hydrochloride ,Cell Line, Tumor ,medicine ,Adjuvant therapy ,Humans ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,Neoadjuvant therapy ,Photosensitizing Agents ,biology ,business.industry ,Drug Synergism ,Tyrphostins ,Neoadjuvant Therapy ,ErbB Receptors ,Gene Expression Regulation ,Photochemotherapy ,Monoclonal ,Quinazolines ,biology.protein ,Erlotinib ,business ,Signal Transduction ,medicine.drug - Abstract
Background Tyrosin kinase inhibitors (TKIs) and monoclonal antibodies aimed to target epidermal growth factor receptor (EGFR) have shown limited effect as monotherapies and drug resistance is a major limitation for therapeutic success. Adjuvant therapies to EGFR targeting therapeutics are therefore of high clinical relevance. Methods Three EGFR targeting drugs, Cetuximab, Erlotinib and Tyrphostin AG1478 were used in combination with photodynamic therapy (PDT) in two EGFR positive cell lines, A-431 epidermoid skin carcinoma and WiDr colorectal adenocarcinoma cells. The amphiphilic meso-tetraphenylporphine with 2 sulphonate groups on adjacent phenyl rings (TPPS2a) was utilized as a photosensitizer for PDT. The cytotoxic outcome of the combined treatments was evaluated by cell counting and MTT. Cellular signalling was explored by Western blotting. Results PDT as neoadjuvant to Tyrphostin in A-431 cells as well as to Tyrphostin or Erlotinib in WiDr cells revealed synergistic cytotoxicity. In contrast, Erlotinib or Cetuximab combined with neoadjuvant PDT induced an antagonistic effect on cell survival of A-431 cells. Neoadjuvant PDT and EGFR targeting therapies induced a synergistic inhibition of ERK as well as synergistic cytotoxicity only when the EGFR targeting monotherapies caused a prolonged ERK inhibition. There were no correlation between EGFR inhibition by the EGFR targeting monotherapies or the combined therapies and the cytotoxic outcome combination-therapies. Conclusions The results suggest that sustained ERK inhibition by EGFR targeting monotherapies is a predictive factor for synergistic cytotoxicity when combined with neoadjuvant PDT. General significance The present study provides a rationale for selecting anticancer drugs which may benefit from PDT as adjuvant therapy.
- Published
- 2013
77. Photochemical internalization (PCI) of HER2-targeted toxins
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Kristian Berg, Anette Weyergang, and Maria E B Berstad
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chemistry.chemical_classification ,Reactive oxygen species ,Chemistry ,medicine.medical_treatment ,Biophysics ,Photodynamic therapy ,Endocytosis ,Biochemistry ,Endocytic vesicle ,Immunotoxin ,Conventional PCI ,medicine ,Photosensitizer ,skin and connective tissue diseases ,Cytotoxicity ,neoplasms ,Molecular Biology - Abstract
Background Photochemical internalization (PCI) is a modality for cytosolic release of drugs trapped in endocytic vesicles. The method is based upon photosensitizers localized in the membranes of endocytic vesicles which create membrane rupture upon light exposure by generating reactive oxygen species (ROS), predominantly singlet oxygen ( 1 O 2 ). Methods The human epidermal growth factor receptor 2 (HER2)-targeted immunotoxin (IT), trastuzumab–saporin, was evaluated in combination with PCI using TPCS 2a (Amphinex®), a new photosensitizer approved for clinical use. Results PCI synergistically enhanced the cytotoxicity of trastuzumab–saporin on trastuzumab-resistant HER2 + Zr-75-1 cells. The PCI effect was only observed when the IT was administered prior to the photochemical treatment (“light after” strategy), while administration of a non-targeted drug may equally well be performed after light exposure. Mechanistic studies showed reduced ligand-induced HER2 phosphorylation and receptor-mediated endocytosis after TPCS 2a -PDT. Photochemical disruption of the cytoplasmic domain of HER2 was found to be induced by 1 O 2 generated both by photosensitizer located in the endocytic vesicles and in the outer leaflet of the plasma membrane. Conclusions Administration of the HER2-targeted toxin prior to light exposure is a prerequisite for successful PCI-mediated delivery of HER2-targeted toxins. General significance PCI of HER2-targeted toxins is demonstrated as a highly effective treatment modality which may overcome trastuzumab resistance. The mechanistic studies of the lack of PCI effect of the “light first” procedure is of outermost importance when designing a clinical PCI treatment protocol for delivery of HER2-targeted therapies.
- Published
- 2012
78. CHAPTER 9. Photochemical Internalization-Enhanced Targeting of Vasculature and Cancer Stem Cells—Present and Future Perspectives
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Anette Weyergang, Kristian Berg, and Pål Kristian Selbo
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Drug ,Endosome ,media_common.quotation_subject ,medicine.medical_treatment ,Vesicle ,Photodynamic therapy ,Pharmacology ,Biology ,Cell biology ,Endocytic vesicle ,Cancer stem cell ,Conventional PCI ,medicine ,Photosensitizer ,media_common - Abstract
In this review, we present recent developments in photochemical internalization (PCI) technology as a rational strategy for the specific and efficient targeting of vasculature and cancer stem cells. The PCI method is based on the same principles as photodynamic therapy; however, the major difference is the coadministration of a drug that co-localizes with the PCI photosensitizer in endocytic vesicles (endosomes and lysosomes). In addition, the photosensitizer needs to be primarily located in the membranes of the endocytic vesicles and the drug to be activated by PCI has to be trapped inside the endocytic vesicles. Photochemical-induced disruption of the membranes of these vesicles induces endosomal release of the drug of interest, thereby strongly enhancing its biological effect. Recently, we have demonstrated in various publications that the PCI method can be used for the targeting and rapid shutdown of the tumor vasculature, eradication of cancer stem cells and to enhance vaccines. Future PCI will be dependent on collaboration with academic or industry laboratories that have potent drugs that require improved endosomal escape. Currently, we are developing recombinant toxin-based therapeutics for better tumor cell and vasculature targeting.
- Published
- 2016
79. Strongly amphiphilic photosensitizers are not substrates of the cancer stem cell marker ABCG2 and provides specific and efficient light-triggered drug delivery of an EGFR-targeted cytotoxic drug
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Gunhild Mari Mælandsmo, Anette Weyergang, Pål Kristian Selbo, Marius Strombo Eng, Monica Bostad, Anders Høgset, and Kristian Berg
- Subjects
Porphyrins ,Light ,Cell Survival ,medicine.medical_treatment ,Pharmaceutical Science ,Photodynamic therapy ,Pharmacology ,Biology ,Substrate Specificity ,Surface-Active Agents ,chemistry.chemical_compound ,Side population ,Cancer stem cell ,Cell Line, Tumor ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Humans ,Photosensitizer ,Cytotoxicity ,Drug Carriers ,Photosensitizing Agents ,Molecular Structure ,Flow Cytometry ,Drug Resistance, Multiple ,Endocytosis ,Neoplasm Proteins ,ErbB Receptors ,Microscopy, Fluorescence ,chemistry ,Drug Resistance, Neoplasm ,Pheophorbide A ,Drug delivery ,ATP-Binding Cassette Transporters ,Drug carrier - Abstract
A wide range of anti-cancer drugs are substrates of the ATP-binding cassette transporter ABCG2/CD338/BCRP/MXR, which is thought to play an important role in multi-drug resistance (MDR) and protection of cancer stem cells (CSC) against chemotherapeutics and photodynamic therapy (PDT). Hence, it is of importance to develop drugs that are not substrates of ABCG2. The aim of this study was to elucidate if photosensitizers utilized for the endo-lysosomal release drug delivery method photochemical internalization (PCI) are substrates for ABCG2. The breast carcinoma cell line MA11, with a Hoechst 33342 side population of >50% was used as an ABCG2high model. The photosensitizer Pheophorbide A (PhA) and Hoechst 33342 were used as positive control substrates of ABCG2. ABCG2-inhibition by fumitremorgin C (FTC) did neither induce an increased accumulation of three different PCI-photosensitizers (di-sulfonated meso-tetraphenylporphine (TPPS(2a)), di-sulfonated meso-tetraphenylchlorin (TPCS(2a)) and di-sulfonated aluminium phtalocyanine (AlPcS(2a))) nor enhanced the photosensitization (P=0.65 for TPCS(2a)-PDT) of these PCI-based photosensitizers in the MA11 cells. The same results were also obtained with TPPS(2a) in the malignant glioma cell line U87 having a SP of ~0.1%. In contrast, both uptake and PDT-induced cytotoxicity was strongly enhanced for PhA when combined with FTC (P
- Published
- 2012
80. Photodynamic Therapy Targets the mTOR Signaling Network in Vitro and in Vivo
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Olav Kaalhus, Anette Weyergang, Pål Kristian Selbo, Kristian Berg, and Qian Peng
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medicine.medical_treatment ,Mice, Nude ,Pharmaceutical Science ,Photodynamic therapy ,Mice ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Phosphorylation ,Cytotoxicity ,PI3K/AKT/mTOR pathway ,Sirolimus ,Mice, Inbred BALB C ,Cell growth ,Chemistry ,TOR Serine-Threonine Kinases ,Cancer ,Drug Synergism ,medicine.disease ,Photochemotherapy ,Cancer research ,Molecular Medicine ,Female ,Protein Kinases ,Signal Transduction - Abstract
Mammalian target of rapamycin (mTOR) is a regulator of cell growth and proliferation and its activity is altered in many human cancers. The main objective of this study was to evaluate in vitro and in vivo targeting of mTOR by photodynamic therapy (PDT), a treatment modality for cancer. The amphiphilic endolysosomal localizing photosensitizer AlPcS(2a) and the p53 mutated rapamycin-resistant colon adenocarcinoma cell line WiDr were used as models. AlPcS(2a)-PDT downregulated the levels of Ser(2448) phosphorylated mTOR (p-mTOR), total mTOR and phosphorylation of ribosomal S6 (p-S6) immediately after light exposure in a dose-dependent manner, indicating a direct targeting of the mTOR signaling network. Low-dose PDT attenuated the level of p-mTOR in a transient manner; approximately 35% reduction of p-mTOR was obtained 5 min after a LD(35) PDT dose, but returned to the basal level 24 h later. Treatment with the mTOR inhibitor rapamycin reduced the p-mTOR level by 25% after 4-24 h of incubation. Combination treatment of rapamycin and PDT in vitro resulted in synergistic cytotoxic effects when rapamycin was administered after PDT. However, antagonistic effects were obtained when rapamycin was incubated both before and after PDT. In vivo, activated mTOR in the WiDr-xenografts was downregulated by 35 and 75% 5 min and 24 h post PDT respectively as measured by immunoblotting. In contrast to untreated tumors where p-mTOR expression was found throughout the tumors, immunohistochemical staining revealed only expression of p-mTOR in the rim of the tumor at 24 and 48 h post PDT. In conclusion, AlPcS(2a)-PDT is a novel mTOR-targeted cancer therapy. Rapamycin synergistically enhances the cytotoxicity of PDT only when administered post light exposure.
- Published
- 2008
81. Photochemical activation of drugs for the treatment of therapy-resistant cancers
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Kristian Berg, Cathrine Elisabeth Olsen, Maria E B Berstad, Anette Weyergang, Pål Kristian Selbo, and Bente Bull-Hansen
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Drug ,Chemotherapy ,Photosensitizing Agents ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Photodynamic therapy ,Drug resistance ,Pharmacology ,Targeted therapy ,Multiple drug resistance ,Radiation therapy ,Photochemotherapy ,Drug Resistance, Neoplasm ,Neoplasms ,Conventional PCI ,medicine ,Cancer research ,Humans ,Physical and Theoretical Chemistry ,business ,media_common - Abstract
Resistance to chemotherapy, molecular targeted therapy as well as radiation therapy is a major obstacle for cancer treatment. Cancer resistance may be exerted through multiple different mechanisms which may be orchestrated as observed in multidrug resistance (MDR). Cancer resistance may be intrinsic or acquired and often leaves patients without any treatment options. Strategies for alternative treatment modalities for resistant cancer are therefore highly warranted. Photochemical internalization (PCI) is a technology for cytosolic delivery of macromolecular therapeutics based on the principles of photodynamic therapy (PDT). The present report reviews the current knowledge of PCI of therapy-resistant cancers. In summary, PCI may be able to circumvent several of the major mechanisms associated with resistance towards chemotherapeutics including increased expression of drug efflux pumps, altered intracellular drug distribution and increased ROS scavenging. Current data also suggest PCI of targeted toxins as highly effective in cancers resistant to clinically available targeted therapy such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). PCI may therefore, in general, represent a future treatment option for cancers resistant to other therapies.
- Published
- 2015
82. Photochemical internalization (PCI): A novel technology for activation of endocytosed therapeutic agents
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Lina Prasmickaite, Andreas Dietze, Ole Jacob Norum, Kristian Berg, Stephen G. Bown, Anette Bonsted, Hanne Mali Thesen Møllergård, Pei-Jen Lou, Pål Kristian Selbo, Anette Weyergang, and Anders Høgset
- Subjects
Cytosol ,Endocytic vesicle ,Immunotoxin ,Epidermal growth factor ,Drug delivery ,Surgery ,Dermatology ,Biology ,Endocytosis ,Cytotoxicity ,Molecular biology ,Intracellular ,Cell biology - Abstract
The utilization of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve the targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In most cases the targets of macromolecular therapeutics are intracellular. However, degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. Photochemical internalization (PCI) is a novel technology for the release of endocytosed macromolecules into the cytosol. The technology is based on the activation by light of photosensitizers located in endocytic vesicles to induce the release of macromolecules from the endocytic vesicles. Thereby endocytosed molecules can be released to reach their target of action before being degraded in lysosomes. PCI has been shown to stimulate intracellular delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), RIP-based immunotoxins, DNA delivered as gene-encoding plasmids or by means of adenoviruses or adeno-associated viruses, peptide–nucleic acids and chemotherapeutic agents such as bleomycin. The efficacy and specificity of PCI of macromolecular therapeutic agents have been improved by combining the macromolecules with targeting moieties, such as the epidermal growth factor. Several animal models have been used for in vivo documentation of the PCI principle. Recent results also indicate that PCI may reverse doxorubicin resistance or be utilized to circumvent multidrug resistance. In general, PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that it may have a variety of useful applications for site-specific drug delivery, as for example in gene therapy, vaccination and cancer treatment.
- Published
- 2006
83. Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin
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Kristian Berg, Pål Kristian Selbo, and Anette Weyergang
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Time Factors ,Saporin ,Cell Survival ,Biotin ,Pharmaceutical Science ,Pharmacology ,medicine.disease_cause ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Cytotoxicity ,Protein Synthesis Inhibitors ,Dose-Response Relationship, Drug ,Epidermal Growth Factor ,biology ,Chemistry ,Toxin ,Immunotoxins ,Drug Synergism ,ErbB Receptors ,Microscopy, Fluorescence ,Targeted drug delivery ,Cell culture ,Drug delivery ,biology.protein ,Streptavidin ,Antibody ,Ribosomes - Abstract
Epidermal growth factor receptor (EGFR) targeting has become a major field in both cancer research and therapy. In the present study an EGF–saporin affinity toxin has been established and evaluated in two EGFR overexpressing cancer cell lines. The binding of saporin to EGF did not influence the ribosome-inactivating activity of saporin as measured by a luminescence based reticulocyte lysate assay. Control experiments, using untargeted saporin, EGFR-negative cell lines and competition with EGF and anti-EGFR antibody were used to document selective uptake of the affinity toxin. One limitation in administration of macromolecular-drugs is lysosomal degradation. Photochemical internalization (PCI) is a modality for cytosolic release of macromolecules based on photochemical rupture of endocytic membranes and subsequent drug release. It was shown that PCI increases the toxicity of EGF–saporin significantly in EGFR-positive cells. EGF binding to saporin enhanced the PCI-induced cytotoxicity in NuTu-19 cells about 1000-fold when the photochemical treatment alone killed 50% of the cells. In conclusion, PCI of EGF–saporin is a promising method for increasing the efficiency of protein toxin-based cancer therapies. PCI of targeting toxins also exert a triple tumour-selectivity; utilization of an affinity toxin, preferential accumulation of the photosensitizer in neoplastic lesions, and site-directed light activation.
- Published
- 2006
84. Design of an EGFR-targeting toxin for photochemical delivery: in vitro and in vivo selectivity and efficacy
- Author
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Maria E B Berstad, Sebastian Patzke, Ane Sofie Viset Fremstedal, Qian Peng, Lawrence H. Cheung, Kristian Berg, Anette Weyergang, and Michael G. Rosenblum
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Cancer Research ,Photochemistry ,Recombinant Fusion Proteins ,Cetuximab ,Mice, Nude ,Apoptosis ,Antibodies, Monoclonal, Humanized ,Mice ,Drug Delivery Systems ,In vivo ,Epidermal growth factor ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Gelonin ,Molecular Biology ,Toxins, Biological ,biology ,Epidermal Growth Factor ,Squamous Cell Carcinoma of Head and Neck ,medicine.disease ,Head and neck squamous-cell carcinoma ,ErbB Receptors ,Head and Neck Neoplasms ,Monoclonal ,Immunology ,Cancer research ,biology.protein ,Carcinoma, Squamous Cell ,Ribosome Inactivating Proteins, Type 1 ,Female ,Tyrosine kinase ,medicine.drug - Abstract
The number of epidermal growth factor receptor (EGFR)-targeting drugs in the development for cancer treatment is continuously increasing. Currently used EGFR-targeted monoclonal antibodies and tyrosine kinase inhibitors have specific limitations related to toxicity and development of resistance, and there is a need for alternative treatment strategies to maximize the clinical potential of EGFR as a molecular target. This study describes the design and production of a novel EGFR-targeted fusion protein, rGel/EGF, composed of the recombinant plant toxin gelonin and EGF. rGel/EGF was custom-made for administration by photochemical internalization (PCI), a clinically tested modality for cytosolic release of macromolecular therapeutics. rGel/EGF lacks efficient mechanisms for endosomal escape and is therefore minimally toxic as monotherapy. However, PCI induces selective and efficient cytosolic release of rGel/EGF in EGFR-expressing target cells by light-directed activation of photosensitizers accumulated selectively in tumor tissue. PCI of rGel/EGF was shown to be highly effective against EGFR-expressing cell lines, including head and neck squamous cell carcinoma (HNSCC) cell lines resistant to cetuximab (Erbitux). Apoptosis, necrosis and autophagy were identified as mechanisms of action following PCI of rGel/EGF in vitro. PCI of rGel/EGF was further shown as a highly tumor-specific and potent modality in vivo, with growth inhibitory effects demonstrated on A-431 squamous cell carcinoma (SCC) xenografts and reduction of tumor perfusion and necrosis induction in SCC-026 HNSCC tumors. Considering the small amount of rGel/EGF injected per animal (0.1 mg/kg), the presented in vivo results are highly promising and warrant optimization and production of rGel/EGF for further preclinical evaluation with PCI.
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- 2014
85. Porphyrin-related photosensitizers for cancer imaging and therapeutic applications
- Author
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Andreas Dietze, Kristian Berg, Lina Prasmickaite, A. Høgset, Trond Warloe, Pål Kristian Selbo, Birgit Engesæter, Even Angell-Petersen, N. Frandsen, Anette Weyergang, and Anette Bonsted
- Subjects
Porphyrins ,Histology ,Macromolecular Substances ,medicine.medical_treatment ,Photodynamic therapy ,Bleomycin ,Fluorescence ,Pathology and Forensic Medicine ,Mice ,chemistry.chemical_compound ,Neoplasms ,medicine ,Animals ,Humans ,Photosensitizer ,chemistry.chemical_classification ,Reactive oxygen species ,Photosensitizing Agents ,Chemistry ,Singlet oxygen ,Biological activity ,Porphyrin ,Endocytic vesicle ,Photochemotherapy ,Biochemistry ,Biophysics - Abstract
A photosensitizer is defined as a chemical entity, which upon absorption of light induces a chemical or physical alteration of another chemical entity. Some photosensitizers are utilized therapeutically such as in photodynamic therapy (PDT) and for diagnosis of cancer (fluorescence diagnosis, FD). PDT is approved for several cancer indications and FD has recently been approved for diagnosis of bladder cancer. The photosensitizers used are in most cases based on the porphyrin structure. These photosensitizers generally accumulate in cancer tissues to a higher extent than in the surrounding tissues and their fluorescing properties may be utilized for cancer detection. The photosensitizers may be chemically synthesized or induced endogenously by an intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) or 5-ALA esters. The therapeutic effect is based on the formation of reactive oxygen species (ROS) upon activation of the photosensitizer by light. Singlet oxygen is assumed to be the most important ROS for the therapeutic outcome. The fluorescing properties of the photosensitizers can be used to evaluate their intracellular localization and treatment effects. Some photosensitizers localize intracellularly in endocytic vesicles and upon light exposure induce a release of the contents of these vesicles, including externally added macromolecules, into the cytosol. This is the basis for a novel method for macromolecule activation, named photochemical internalization (PCI). PCI has been shown to potentiate the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins, immunotoxins, gene-encoding plasmids, adenovirus, peptide-nucleic acids and the chemotherapeutic drug bleomycin. The background and present status of PDT, FD and PCI are reviewed.
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- 2005
86. Re: Omskjæring av gutter
- Author
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Vegard Weyergang Vartdal
- Subjects
03 medical and health sciences ,0302 clinical medicine ,business.industry ,Medicine ,030212 general & internal medicine ,General Medicine ,030204 cardiovascular system & hematology ,business - Published
- 2016
87. Light-triggered, efficient cytosolic release of IM7-saporin targeting the putative cancer stem cell marker CD44 by photochemical internalization
- Author
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Pål Kristian Selbo, Monica Bostad, Marianne Kausberg, Anette Weyergang, Kristian Berg, Cathrine Elisabeth Olsen, and Anders Høgset
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Time Factors ,Saporin ,Light ,Endosome ,Pharmaceutical Science ,Biotin ,Endosomes ,Sensitivity and Specificity ,Cytosol ,Immunotoxin ,Cancer stem cell ,Cell Line, Tumor ,Drug Discovery ,Humans ,Drug Carriers ,Photosensitizing Agents ,biology ,Ribosome-inactivating protein ,Immunotoxins ,CD44 ,Colocalization ,Antibodies, Monoclonal ,Flow Cytometry ,Molecular biology ,Saporins ,Hyaluronan Receptors ,Photochemotherapy ,biology.protein ,Neoplastic Stem Cells ,Ribosome Inactivating Proteins, Type 1 ,Molecular Medicine ,Streptavidin ,Lysosomes ,Reactive Oxygen Species - Abstract
We have used the site specific and light-depended drug delivery method photochemical internalization (PCI) to release an immunotoxin (IT), targeting the CD44 receptor, into the cytosol of target cells. The IT consisted of a pan CD44 mAb (clone IM7) bound to the ribosome inactivating protein (RIP) saporin by a biotin-streptavidin linker named IM7-saporin. PCI is based upon photosensitizing compounds localized in the membrane of endosomes and lysosomes causing membrane rupture upon illumination followed by release of the IT into the cytosol. In this in vitro study, we have used 7 different human cancer cell lines of various origins to investigate the cytotoxic effect of PCI-based targeting of the cancer stem cell (CSC) marker CD44. Epi-fluorescence microscopy shows both specific binding and uptake of the IM7-Alexa488, after 30 min and 18 h of incubation, and colocalization with the PCI-photosensitizer TPCS2a prior to light-triggered cytosolic release of the CD44-targeting IT. PCI of IM7-saporin resulted in efficient and specific cytotoxicity in CD44-expressing but not in CD44-negative cancer cells. A higher level of reactive oxygen species (ROS) was found in untreated and photodynamic therapy (PDT)-treated LNCaP (CD44(neg)) compared to that of DU145 (CD44(pos)) prostate cancer (PC) cells. This may explain the PDT-resistance observed in the DU145 cells. PCI-based targeting of CD44-expressing cancer cells gives very potent and specific cytotoxic effects and may represent a rational strategy for achieving site-selective elimination of CSCs in aggressive androgen-independent and treatment-resistant PC cells preventing cytotoxic effects on distant normal stem cells.
- Published
- 2014
88. Photochemical Internalization: A Novel Technology for Targeted Macromolecule Therapy
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Anette Weyergang, Pål Kristian Selbo, Kristian Berg, Marie Vikdal, and Ole Jacob Norum
- Subjects
Materials science ,Oligonucleotide ,Genetic enhancement ,Compartmentalization (psychology) ,Bleomycin ,Cytosol ,chemistry.chemical_compound ,surgical procedures, operative ,Endocytic vesicle ,chemistry ,Biochemistry ,Conventional PCI ,Drug delivery ,Biophysics ,cardiovascular diseases ,therapeutics - Abstract
Photochemical internalization (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides, and the chemotherapeuticum bleomycin. PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. The results show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that PCI may have a variety of useful applications for site-specific drug delivery, e.g., in gene therapy, vaccination, and cancer treatment. Our studies also indicate that PCI of bleomycin is superior to PDT in targeting the tumor periphery and that this is partly the cause of the improved treatment effect of PCI as compared to PDT.
- Published
- 2014
89. Photochemical internalization augments tumor vascular cytotoxicity and specificity of VEGF(121)/rGel fusion toxin
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Johannes Waltenberger, Michael G. Rosenblum, Kristian Berg, Qian Peng, Khalid A. Mohamedali, Lawrence H. Cheung, and Anette Weyergang
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CD31 ,Vascular Endothelial Growth Factor A ,Porphyrins ,Colon ,Swine ,Recombinant Fusion Proteins ,Pharmaceutical Science ,Antineoplastic Agents ,Pharmacology ,Bleomycin ,Cell Line ,chemistry.chemical_compound ,Mice ,Drug Delivery Systems ,Fusion Toxin ,Cell Line, Tumor ,Medicine ,Animals ,cardiovascular diseases ,Cytotoxicity ,Mice, Inbred BALB C ,Photosensitizing Agents ,business.industry ,Cancer ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,surgical procedures, operative ,chemistry ,Drug delivery ,Toxicity ,Conventional PCI ,Colonic Neoplasms ,Female ,business ,therapeutics - Abstract
Vascular targeting for cancer is increasingly recognized as a therapeutic strategy although the lack of objective responses and the development of resistance are major limitations for clinically-available drugs. Endothelial targeted toxins exert increased toxicity compared to antiangiogenic drugs and may therefore overcome these limitations. The specificity and toxicity of targeted toxins may be increased by utilization of a drug delivery system which provides selective release of the targeted toxins in the target cells. Photochemical internalization (PCI) is a non-invasive modality which causes translocation into the cytosol of agents that are trapped in endosomes. This study describes the first use of PCI in combination with a recombinant fusion toxin targeting tumor vasculature. Endothelial cells bearing VEGFR2 treated with VEGF121/rGel showed dramatic enhancement of toxicity after PCI utilizing the photosensitizer TPCS2a (Amphinex®). We compared the PCI of VEGF121/rGel to that of bleomycin which is currently under clinical evaluation. The VEGFR2 specificity of VEGF121/rGel was shown to be preserved by the PCI treatment. PCI of VEGF121/rGel was further shown to induce vascular collapse and edema in the invasive areas of CT26.CL25 colon carcinoma tumors as shown by CD31 IHC. Antitumor effects, as assessed by tumor growth delay were found for PCI of VEGF121/rGel and PCI of bleomycin with cure rates of 40% and 33% respectively. PCI of VEGF121/rGel was, however, better tolerated compared to PCI of bleomycin. Thus, PCI of vascular targeted toxins provides higher specificity and increased tolerability compared to PCI of bleomycin and may represent an interesting clinical future for the PCI technology.
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- 2013
90. Re: Omskjæring av gutter
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Vartdal, Vegard Weyergang, primary
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- 2016
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91. Photochemical Internalization: From Bench to Bedside with a Novel Technology for Targeted Macromolecule Therapy
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Kristian Berg, Pål Kristian Selbo, Anders Høgset, and Anette Weyergang
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Photochemical internalization ,business.industry ,Medicine ,Nanotechnology ,business ,Bench to bedside ,Macromolecule - Published
- 2013
92. Vascular endothelial cells as targets for photochemical internalization (PCI)
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Kristian Berg, Marie Vikdal, Anette Weyergang, and Pål Kristian Selbo
- Subjects
Saporin ,medicine.medical_treatment ,Photodynamic therapy ,Biochemistry ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Humans ,cardiovascular diseases ,Physical and Theoretical Chemistry ,Cells, Cultured ,biology ,business.industry ,General Medicine ,Saporins ,surgical procedures, operative ,Cell killing ,Photochemotherapy ,Cancer cell ,Immunology ,Conventional PCI ,Cancer research ,biology.protein ,Ribosome Inactivating Proteins, Type 1 ,Human umbilical vein endothelial cell ,HT1080 ,Endothelium, Vascular ,business - Abstract
Cancer treatment can be exerted by targeting both cancer cells and the vasculature supplying solid tumors. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, but recent data on contrast-enhanced MRI have indicated that the method also reduces blood perfusion in HT1080 fibrosarcoma xenografts. The present report aims to investigate if PCI may exert direct cytotoxic effects on endothelial cells. PCI of saporin was performed on endothelial human umbilical vein endothelial cell (HUVEC) and fibrosarcoma cells (HT1080) using two PCI-relevant photosensitizers, TPPS2a and AlPcS2a. A 22- and 13-fold higher photosensitizer uptake was detected in the endothelial cells compared with the HT1080 cells for AlPcS2a and TPPS2a, respectively. PCI of saporin was, however, found more effective in HT1080 cells. For HT1080 cells, PCI with saporin increased cell killing 1.9-fold over photodynamic therapy alone, but under the same conditions, only increased HUVEC cell killing by 1.6- and 1.3-fold with AlPcS2a and TPPS2a , respectively. Saporin uptake was higher in HUVECs than in the HT1080 cells, hence did not reflect the cell line differences in PCI efficacy. This is the first report on PCI-mediated kill of endothelial cells and lays the foundation for further preclinical evaluation of the PCI technology as an antivascular strategy to ablate tumors.
- Published
- 2013
93. Photochemical internalization (PCI) of HER2-targeted toxins: synergy is dependent on the treatment sequence
- Author
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Maria Brandal, Berstad, Anette, Weyergang, and Kristian, Berg
- Subjects
Photosensitizing Agents ,Porphyrins ,Light ,Receptor, ErbB-2 ,Immunotoxins ,Blotting, Western ,Breast Neoplasms ,Drug Synergism ,Trastuzumab ,Antibodies, Monoclonal, Humanized ,Saporins ,Endocytosis ,Photochemotherapy ,Drug Resistance, Neoplasm ,Ribosome Inactivating Proteins, Type 1 ,Tumor Cells, Cultured ,Humans ,Female ,Phosphorylation - Abstract
Photochemical internalization (PCI) is a modality for cytosolic release of drugs trapped in endocytic vesicles. The method is based upon photosensitizers localized in the membranes of endocytic vesicles which create membrane rupture upon light exposure by generating reactive oxygen species (ROS), predominantly singlet oxygen ((1)O(2)).The human epidermal growth factor receptor 2 (HER2)-targeted immunotoxin (IT), trastuzumab-saporin, was evaluated in combination with PCI using TPCS(2a) (Amphinex®), a new photosensitizer approved for clinical use.PCI synergistically enhanced the cytotoxicity of trastuzumab-saporin on trastuzumab-resistant HER2(+) Zr-75-1 cells. The PCI effect was only observed when the IT was administered prior to the photochemical treatment ("light after" strategy), while administration of a non-targeted drug may equally well be performed after light exposure. Mechanistic studies showed reduced ligand-induced HER2 phosphorylation and receptor-mediated endocytosis after TPCS(2a)-PDT. Photochemical disruption of the cytoplasmic domain of HER2 was found to be induced by (1)O(2) generated both by photosensitizer located in the endocytic vesicles and in the outer leaflet of the plasma membrane.Administration of the HER2-targeted toxin prior to light exposure is a prerequisite for successful PCI-mediated delivery of HER2-targeted toxins.PCI of HER2-targeted toxins is demonstrated as a highly effective treatment modality which may overcome trastuzumab resistance. The mechanistic studies of the lack of PCI effect of the "light first" procedure is of outermost importance when designing a clinical PCI treatment protocol for delivery of HER2-targeted therapies.
- Published
- 2012
94. Photochemical internalization of tumor-targeted protein toxins
- Author
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Anette, Weyergang, Pål K, Selbo, Maria E B, Berstad, Monica, Bostad, and Kristian, Berg
- Subjects
Drug Delivery Systems ,Photosensitizing Agents ,Photochemotherapy ,Macromolecular Substances ,Immunotoxins ,Neoplasms ,Humans ,Antineoplastic Agents ,Endosomes ,Molecular Targeted Therapy ,Lysosomes - Abstract
Photochemical internalization (PCI) is a method for intracellular delivery of hydrophilic macromolecular drugs with intracellular targets as well as other drugs with limited ability to penetrate cellular membranes. Such drugs enter cells by means of endocytosis and are to a large extent degraded by hydrolytic enzymes in the lysosomes unless they possess a mechanism for cytosolic translocation. PCI is based on photodynamic therapy (PDT) specifically targeting the endosomes and lysosomes of the cells, so that the drugs in these vesicles can escape into the cytosol from where they can reach their targets. The preferential retention of the photosensitizer (PS) in tumor tissue in combination with controlled light delivery makes PCI relatively selective for cancer tissue. The tumor specificity of PCI can be further increased by delivery of drugs that selectively target the tumors. Indeed, this has been shown by PCI delivery of several targeted protein toxins. Targeted protein toxins may be regarded as ideal drugs for PCI delivery, and may represent the clinical future for the PCI technology.
- Published
- 2011
95. Photochemical internalization: a new tool for gene and oligonucleotide delivery
- Author
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Kristian, Berg, Maria, Berstad, Lina, Prasmickaite, Anette, Weyergang, Pål K, Selbo, Ida, Hedfors, and Anders, Høgset
- Subjects
Cytosol ,Photosensitizing Agents ,Oligonucleotides ,Photochemical Processes ,Transfection ,Endocytosis - Abstract
Photochemical internalization (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles. Upon activation by light such photosensitizers induce a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to increase the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins, immunotoxins, plasmids, adenovirus, various oligonucleotides, dendrimer-based delivery of chemotherapeutica and unconjugated chemotherapeutica such as bleomycin and doxorubicin. This review will present the basis for the PCI concept and the most recent significant developments.
- Published
- 2011
96. The Potential of Photochemical Internalization (PCI) for the Cytosolic Delivery of Nanomedicines
- Author
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Pål Kristian Selbo, Anders Høgset, Kristian Berg, and Anette Weyergang
- Subjects
medicine.anatomical_structure ,Oligonucleotide ,Chemistry ,Genetic enhancement ,Cell ,Drug delivery ,Extracellular ,medicine ,Gene silencing ,Pharmacology ,Intracellular ,Cell biology ,Viral vector - Abstract
Utilization of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents or DNA complexes for clinical applications. Macromolecules with therapeutic potential include proteins such as ribosome-inactivating protein toxins for treatment of cancer and other indications, antibodies and growth factors for cell surface targeting, peptides and mRNA for vaccination, DNA utilizing nonviral and viral vectors for gene therapy, and oligonucleotides (antisense oligonucleotides, ribozymes, peptide nucleic acids (PNAs), and siRNA for gene silencing) and nanoparticles for drug delivery [1]. There are many extracellular and intracellular barriers for these molecules to overcome before they can arrive at the target cells, enter the cell, and reach intracellular therapeutic targets. Degradation by serum enzymes and elimination by cells of the reticuloendothelial system (RES), penetration into the target tissues
- Published
- 2010
97. Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics
- Author
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Selbo, Pål Kristian, primary, Bostad, Monica, additional, Olsen, Cathrine Elisabeth, additional, Edwards, Victoria Tudor, additional, Høgset, Anders, additional, Weyergang, Anette, additional, and Berg, Kristian, additional
- Published
- 2015
- Full Text
- View/download PDF
98. Photochemical internalization (PCI): a technology for drug delivery
- Author
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Kristian, Berg, Anette, Weyergang, Lina, Prasmickaite, Anette, Bonsted, Anders, Høgset, Marie-Therese R, Strand, Ernst, Wagner, and Pål K, Selbo
- Subjects
Photosensitizing Agents ,Light ,Antibodies, Monoclonal ,Cetuximab ,Antibodies, Monoclonal, Humanized ,Photochemical Processes ,Saporins ,Endocytosis ,Cell Line ,ErbB Receptors ,Cytosol ,Drug Delivery Systems ,Ribosome Inactivating Proteins, Type 1 ,Polyethyleneimine ,Biotinylation ,Polylysine - Abstract
The utilization of macromolecules in therapy of cancer and other diseases is becoming increasingly relevant. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes, and other macromolecules for clinical applications. To achieve the expected biological effect of these macromolecules, in many cases, internalization to the cell cytosol is crucial. At an intracellular level, the most fundamental obstruction for cytosolic release of the therapeutic molecule is the membrane-barrier of the endocytic vesicles. Photochemical internalization (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to potentiate the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides, and the chemotherapeutic bleomycin. PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. The present protocol describes PCI of an epidermal growth factor receptor (EGFR)-targeted protein toxin (Cetuximab-saporin) linked via streptavidin-biotin for screening of targeted toxins as well as PCI of nonviral polyplex-based gene therapy. Although describing in detail PCI of targeted protein toxins and DNA polyplexes, the methodology presented in these protocols are also applicable for PCI of other gene therapy vectors (e.g., viral vectors), peptide nucleic acids (PNA), small interfering RNA (siRNA), polymers, nanoparticles, and some chemotherapeutic agents.
- Published
- 2010
99. Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer
- Author
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Bull-Hansen, Bente, primary, Berstad, Maria B., additional, Berg, Kristian, additional, Cao, Yu, additional, Skarpen, Ellen, additional, Fremstedal, Ane Sofie, additional, Rosenblum, Michael G., additional, Peng, Qian, additional, and Weyergang, Anette, additional
- Published
- 2015
- Full Text
- View/download PDF
100. Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules
- Author
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Anders Høgset, Ole Jacob Norum, Maria E B Berstad, Pål Kristian Selbo, Marie Vikdal, Kristian Berg, and Anette Weyergang
- Subjects
Endosome ,Cell Survival ,media_common.quotation_subject ,Pharmaceutical Science ,Nanotechnology ,Antineoplastic Agents ,Endosomes ,Gene delivery ,Endocytosis ,Mice ,Cell Line, Tumor ,Neoplasms ,Medicine ,Animals ,Internalization ,media_common ,Mice, Inbred BALB C ,Photosensitizing Agents ,business.industry ,Genetic transfer ,Photochemical Processes ,Xenograft Model Antitumor Assays ,Drug Resistance, Multiple ,Cell biology ,Endocytic vesicle ,Photochemotherapy ,Doxorubicin ,Delayed-Action Preparations ,Drug delivery ,business ,Drug carrier ,Lysosomes - Abstract
A successful cure of cancer by biopharmaceuticals with intracellular targets is dependent on both specific and sufficient delivery of the drug to the cytosol or nuclei of malignant cells. However, cytosolic delivery and efficacy of membrane-impermeable cancer therapeutics are often hampered by the sequestration and degradation of the drugs in the endolysosomal compartments. Hence, we developed photochemical internalization (PCI) as a site-specific drug delivery technology, which bursts the membrane of endocytic vesicles inducing release of entrapped drugs to the cytosol of light exposed cells. The principle of PCI has been demonstrated in >80 different cell lines and 10 different xenograft models of various cancers in different laboratories demonstrating its broad application potential. PCI-induced endosomal escape of protein- or nucleic acid-based therapeutics and some chemotherapeutics will be presented in this review. With a joint effort by life scientists the PCI technology is currently in a Phase I/II clinical trial with very promising initial results in the treatment of solid tumors.
- Published
- 2010
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