Photodynamic therapy with focus on bladder cancer
The monitoring of hexyl 5-aminolevulinate-induced photodynamic therapy by optical spectroscopy, using a rat bladder cancer model, has continued. The interdisiplinary collaborations at NTNU (in vitro and in vivo) together with St. Olavs Hospital (see Larsen et al., J. Biomed. Optics. 2008, 13(4), 044031, have resulted so long in 2 PhD (Eivind Larsen, IET, NTNU, (2010) and Carl-Jørgen Arum, IKM, NTNU (2011)). The treatment efficacy of other sensitizers, in combination with chemotherapy, have also been studied using the same animal model.
The treatment of different cancers could be substantially improved to develop therapies that specifically and effectively attacked the cancer cells, without harming the normal cells. Photodynamic therapy (PDT) is an approved treatment for both malignant and non-malignant diseases, based on photochemical reactions utilizing a photosensitizer and light to produce reactive oxygen species, further leading to cell death. The PCI technology, which is based on similar photochemical principles as PDT, allows for a photochemically induced release of endocytosed drug molecules into the cytosol in functionally active form.
In this projects, PCI with the photosensitising compound Amphinex will be employed for the treatment of bladder and glioma cancer by delivering therapeutic agents into respectively cancer cells including cytotoxic drugs (such as Bleomycin. Research in Photodynamic Therapy (PDT) and Photochemical Internalization (PCI) represents and involves scientists from different and interdisciplinary fields, and is quite necessary for development of new industrial technology; technology connected to cancer treatment and technology with high innovation potential.(An example is PCI Biotech AS, Oslo, who got the “Innovation prize for 2011).
Photodynamic therapy with focus on bladder cancer
Photodynamic therapy (PDT) is an effective treatment involving light and a photosensitizer used in conjugation with molecular oxygen to elicit cell death. The purpose of some of this study is to find the optimal treatment and search for changes, also in protein expression; both in vitro (cell lines) and in vivo (animal studies).
The interdisciplinary field PDT is being developed at NTNU by a PDT research group at IKM (led by researcher scientist Gederaas), and the work with 5 departments at NTNU/St. Olav’s Hospital has for instance described PDT efficacy using a rat bladder model (Larsen et al. J. Biomedical Optics, 13(4), 2008). A further development of PDT is photochemical internalisation (PCI), a novel technology for light-directed drug delivery. Using the specific photosensitizer Amphinex ® (PCI Biotech ASA, Oslo), photochemical reactions were triggered in tumorous endosomal membrane leading to the release of endocytosed drug molecules into cytosol. In this project, PCI with Amphinex will be employed by delivering therapeutic agents into target cells (rat bladder cancer cells). These agents will include small molecule drugs (e.g. cytotoxic agent Bleomycin) and nucleic acids (e.g. siRNA) using our model. The research work will be based on collaborations, both nationally (UIO, NTNU, The Norwegian Radiumhospital, SINTEF, Photocure ASA and PCI Biotech ASA (financial support) and internationally (Univ. Salzburg, Univ. of Munchen and Univ. College Hospital, London).
Objectives: Principle objective is to develop Amphinex-mediated PCI delivery technology for the treatment of bladder cancer in collaboration with PCI Biotech ASA, and sub-objectives consist of:
1) investigation of optimal incubation time with photosensitizer Amphinex in rat bladder;
2) investigation of optimal illumination time for photochemical treatment in rat bladder tumors;
3) establishment of optimal illumination for delivery of cytotoxic drugs into bladder tumours;
4) establishment of PCI for delivery of nucleic acids both in vivo and in vitro; and
5) development of PCI-mediated gene therapy based on results from earlier phases of the project.
Relevance: Treatment of bladder cancer depends on the stage of the disease, cancer type, patient’s age and general health condition. So far, treatment options consist of surgery, endoscopic resection, chemotherapy and immunotherapy. Interestingly, PCI technique is possible to reduce the often serious side effects in the conventional therapies and preserve patients’ bladder. In the first PCI clinical study performed at University College Hospital (London) this year, 14 patients were given a single Amphinex-PCI with Bleomycine treatment and the results were very promising that all treated tumours in the patients disappeared a few weeks after treatment without drug-related serious adverse events (VG, 4th Feb. 2010). At present, several important drug molecules have been investigated on human cells showing enhanced delivery and biological effects after PCI treatment.
Photodynamic Therapy with focus on bladder cancer.
Celler i kroppen produserer lysømfindtlige porfyriner. Ved å stimulere cellene kan cellene danne mer av dette, og ved deretter å belyse dem vil kun kreftcellene drepes.
Prosjektets hovedmål og delmål.
As for most cancers the treatment of bladder cancer would be substantially improved if one were able to develop therapies that specifically attack the cancer cells, without harming normal cells, and that is the main objective of this project. Such treatments could substantially reduce the often very serious side effects seen with conventional chemotherapeutic treatments. Furthermore, if efficient enough, they could also replace surgery or reduce the extent of surgery, making it possible to preserve important organs and functions in the patient, e.g. the bladder in the case of bladder cancer. Sub goals are detecting protein damage on cellular level during PDT and to use optical spectroscopy for useful information. The translations science, based on information from molecular level until clinic, is quite necessary in developing new industrial technology connected to cancer treatment.
The principal objective of this project is an improved investigation of the intracellular mechanisms after photodynamic therapy (PDT), and to achieve optimising of PDT in patients. In combination with photochemical internalisation (PCI), the goal is to use gene therapy principle in vitro and in vivo. The model will provide possibility of investigating carcinogenesis, tumour development and therapeutic effects in the native organ. This interdisiplinary project will further be analysed using the established FUGE platforms to reach the subgoals and detecting protein damage on cellular level during PDT/PCI. Further, the immune stimulatory and vaccinating effects have to be evaluated by challenging of the same tumour cell line in animals cured by PDT or PCI. Specificity will be evaluated by instillation of another bladder cancer tumour cell line.
Relevans for helseforetaket
Our translations science is based on information from molecular level until clinic, which is quite necessary developing new industrial technology connected to cancer treatment, and the research last years have results in models (Larsen et al., 2008) which are actual and important for collaborations with national and international research groups. NTNU/St. Olav’s Hospital and the Norwegian Radium Hospital are the only universities who have started science based on bladder cancer and photochemical internalisation (PCI). That treatment can substantially reduce the often very serious side effects seen with conventional chemotherapeutic treatments. Furthermore, if efficient enough, the technique could also replace surgery or reduce the extent of surgery, making it possible to preserve important organs and functions in the patient, e.g. the bladder in the case of bladder cancer. It is important for “Helseforetakene” to continue as one part of these experiments
Tissue responses to hexyl 5-aminolevulinate-induced photodynamic treatment in syngeneic orthotopic rat bladder cancer model: possible pathways of action.
J Biomed Opt 2011 Feb;16(2):028001.
Photo induced hexylaminolevulinate destruction of rat bladder cells AY-27.
Photochem Photobiol Sci 2011 Jun;10(6):1072-9. Epub 2011 mar 22
Photodynamic therapy with hexyl aminolevulinate induces carbonylation, posttranslational modifications and changed expression of proteins in cell survival and cell death pathways.
Photochem Photobiol Sci 2011 Jul;10(7):1137-45. Epub 2011 mar 30
Tissue respopnses to heeic orthotopic rat bladder cancer model:posxyl 5-aminolevulinate-induced photodynamic treatment in syngen
J. Biomed. Optics. 16 (2) 0000, Febr. 2011
Application of Amphinex-mediated Photochemical Internalization associated with Bleomycin in treatment of bladder cancer in rats
Forskningsrapport til PCI Biotech AS, Aug. 2010
Photo induced hexylaminolevulinate destruction of rat bladder cells AY-27
J. Photochem.Photobiol. Sci. Submitted Dec. 2010
Can dog smell lung cancer? First study using exhaled breath and urine scrteening in unselected patients suspected to have lung c
Submitted Dec. 2010
Photodynamic therapy with hexyl aminolevulinate induces carbonylation, posttranalational modifications and changes expression op
J. Photochem. Photobiol. Sci., in press, (Submitted Nov. 2010)
In vivo and in vitrodetection of PpIX after treatment with hexyl 5-aminolevulinate and light.
Euroepean Sosiety for Photobiology , Abstract book.
Effects of photodynamic therapy on protein expression in cells.
Congress of European Society for Photobiology, Abstract book.
Reactive oxygen species and cytotoxicity in rat bladder cancer cells (AY-27) after hexyl 5-aminolevulinate-induced photodynamic
european Aociety for Photobiology, Abstract book.
A study of urothelial carcinoma: Gene expression profiling, tumorigenesis and therapies in othotopic animal models
- januar 2011
- Duan Chen
Biomedical Applications of Diffuse Reflectance Spectroscopy and Hyperspectral Imaging
- desember 2010
- Lise Randeberg