What is photodynamic death

Effects of photodynamic therapy with the photosensitizer mTHPC (Foscan®) on large blood vessels, nerves and muscle tissue in the rabbit animal model.


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https://refubium.fu-berlin.de/handle/fub188/803
http://dx.doi.org/10.17169/refubium-5005
Title page and table of contents Introduction Bibliography Own research Results Discussion Summary Summary Bibliography Appendix Acknowledgments, curriculum vitae
dc. description. abstract
Photodynamic therapy (PDT) represents a new, promising treatment concept in tumor treatment. A photosensitizer is applied intravenously, which is increasingly concentrated in tumor cells and activated by light of specific wavelengths (laser light). Under the influence of oxygen, singlet oxygen and free radicals are formed, which damage various cell components and lead to cell death. This treatment is already being used successfully in various areas of oncology. For example, squamous cell carcinomas of the skin or oral mucous membranes, adenocarcinomas of the breast tissue and tumors in the urogenital tract can be destroyed. The intraoperative use of photodynamic therapy in addition to surgical tumor resection is intended to destroy remaining microscopic tumor residues and minimize the risk of locoregional recurrences. Particularly in the head and neck area with its complex anatomical situation, however, there is a risk of attacking vital structures such as large blood vessels and nerves and causing functional damage. mTHPC is the most commonly used photosensitizer for tumors in the head and neck area, but so far there are no detailed histological studies on the effects of intraoperative PDT on non-neoplastic vital structures. In this work, the effects of intraoperative PDT with the photosensitizer mTHPC on large blood vessels and nerves as well as the surrounding tissues and the smaller vessels located therein in the neck and femoral region of clinically healthy rabbits were investigated. In order to find the treatment parameters that cause maximum tissue damage, light intensities (10 or 20 J / cm²) and treatment intervals (3 minutes, 6, 24, 48, 72 and 96 hours) were varied. The mTHPC dose was continuously 0.3 mg / kg. The vessels (A. carotis V. jugularis int. Or A. and V. femoralis) and nerves (N. vagus or N. femoralis) were surgically exposed and the irradiation took place directly in the open surgical site. The effects of photodynamic therapy on these vessels, nerves, the microcirculation and the surrounding tissues were histologically examined and evaluated. In addition, fluorescence microscopic examinations were carried out to show the localization of the photosensitizer in the tissue 6 minutes as well as 24 and 72 hours after the injection. With the present work, we were able to show that the vital structures in the irradiation area of ​​photodynamic therapy are subject to considerable histopathological changes, depending on the parameters. As already described in the literature for other structures, higher light intensities (20 J / cm²) and shorter treatment intervals (24 hours versus 96 hours) produce the stronger reactions. The very short treatment interval (3 minutes), on the other hand, resulted in only minimal damage. The photodynamic effects on the examined arteries (aa. Carotis or femoralis) were hyperplasia of the endothelial cells up to obliteration of the vessel, formation of cobblestone endothelium, detachment of the endothelium in the venous vessels (veins jugularis or femoralis) and thrombus formation. An occlusion of the large vessels by thrombosis or cell proliferation was found in seven cases out of 148, but none of these animals showed corresponding symptoms of the disease. The photodynamic therapy also led to a demyelination of the Nv. vagi resp. femoralis. Here, too, no lameness could be diagnosed even in cases of almost complete demyelination. The irradiated skeletal muscles as well as the surrounding connective and fatty tissue were subject to pronounced necrosis. No systemic side effects attributable to PDT alone were observed. Four of the total of 42 animals suffered postoperatively, some peracute, from severe respiratory symptoms that did not improve despite treatment. One of these animals therefore had to be euthanized before the examinations were completed, the other 3 animals died. These four animals were all subject to the PDT with the most severe treatment conditions, but the deaths are not directly related to it. The disease, which was presumably already latent before, has apparently passed into an acute stage due to surgical stress and / or PDT. In several cases, wound healing disorders occurred, partly with abscesses, but these are probably not a direct consequence of PDT but are among the normal postoperative complications in rabbits. The results from the histological examinations contrasted with the fluorescence of the photosensitizer in the tissue. The strongest fluorescence was independent of the time in the lumen of the vessels, partly at the level of the endothelial cells, perivascular and perimysial. Shortly after the injection (6 minutes) the absolute fluorescence was greatest. Already 24 hours after the injection it was significantly lower overall and after 72 hours fluorescence could hardly be perceived. In accordance with the objective of the present work, special attention was paid to the effects of intraoperative PDT on the vital structures of the main vessels and nerves. From the results of this work it can be concluded that intraoperative PDT with mTHPC leads, depending on the treatment parameters, to sometimes massive local histological damage to the large vessels and nerves. Serious clinical or vital complications, especially related to the vessels (rupture) and nerves (lameness), however, did not occur. Accordingly, photodynamic therapy with the photo sensitizer mTHPC seems to be a very promising and safe form of therapy that could significantly increase the survival rate of tumor patients.
dc. description. abstract
Photodynamic therapy (PDT) represents a new encouraging treatment concept in tumor treatment. This treatment modality is based on the intravenous application of a photosensitizing drug that is supposed to accumulate in tumor cells and is activated by light of specific wavelengths (laser light). Under oxygen influence singlet oxygen and free radicals develop which damage different cell components and lead to cell death. This treatment is already used successfully in different fields of oncology. For example, squamous cell carcinomas of the skin or oral cavity, adenocarcinomas of the chest and tumors of the bladder can be destroyed. Intraoperative photodynamic therapy in addition to surgical tumor resection has been proposed to clean the former tumor bed by destroying any remaining tumor cells in order to minimize the danger of local recurrences. Especially in the head and neck area with its complex anatomical situation there is a risk of damaging blood vessels and nerves that are exposed during the treatment which causes functional disorder of these vital structures. Meso (tetrahydroxyphenyl) chlorine (mTHPC) is the mainly used photosensitizer for head and neck cancer but so far there are no detailed investigations to the effect of intraoperative PDT on these vital structures. In this study large blood vessels and nerves at the neck and groin area as well as the surrounding striated muscletissue and the microcirculation of clinically healthy rabbits were treated by intraoperative PDT using the photosensitizer mTHPC. In order to find the treatment parameters, which cause maximum tissue destruction the light intensity (10 J / cm2, 20 J / cm2) and drug-light-interval (3 minutes, 6, 24, 48, 72 and 96 hours) were varied . The mTHPC dose stayed a constant 0.3 mg / kg which was assessed very well in other investigations. After surgical exposure of the large blood vessels (A. carotis, V. jugularis, A. femoralis as well as V. femoralis) and nerves (N. vagus and N. femoralis) the PDT took place directly in the open operation site. The effects of the photodynamic therapy on large blood vessels, nerves, microcirculation as well as the surrounding tissue were histologically examined and evaluated. Supplemantary fluorescence microscopic investigations were carried out to achieve additional information about the localization of the photosensitizer at different time intervals after injection. Our results have shown that mTHPC mediated intra-operative PDT led to partly significant histological impact onto the vital structures in the irridation area. As described in literature, the stronger tissue reactions were caused by a light dose of 20 J / cm2 as well as by using shorter treatment intervals (24 hours in relation to 96 hours). The consequence of the very short treatment interval (3 minutes) on the other hand was only minimal damage. The mainly observed photodynamic effects on the blood vessels were hyperplasia of the vessel wall cells up to obliteration, formation of cobblestone endothelium, separation of the endothelium of venous vessels as well as thrombosis, but this did not result in any clinical symptoms. In seven of altogether 148 cases the vessels showed thrombosis or obliteration. The photodynamic therapy further led to a decrease of the myelin sheaths of the nerves however without any paresis. The striated musculature as well as the other surrounding tissues is subject to a pronounced necrosis. There were no systemic side effects only due to PDT observed. Four of the however altogether 48 animals suffer from incurable respiratory symptoms. Three rabbits died of this, one had to be sacrificed. These four animals were subject to the strongest treatment conditions, 24 hours and 20 J / cm². Probably it was a matter of a subclinical disease which already exists before PDT, and the death of the animals is not due to the PDT. Some complications in wound healing like developing of abscesses are common in rabbits and are not to see as a consequence of the PDT. The results from the histological investigations stood contrary to the fluorescence localization of the photosensitizer in the tissue. The strongest fluorescence was present in the lumen of the blood vessels partially at the level of the endothelial cells, furthermore perivascular and perimysial. Briefly after the injection (6 minutes) absolute fluorescence was largest. 24 hours after the injection it was clearly smaller and after 72 hours fluorescence was hardly noticeable. Summarizing from these findings it can be tissues concluded that intraoperative PDT with mTHPC leads to substantial histological changes of the large blood vessels as well as the nerves and the surroundingues. The extent of damage the depended on treatment parameters, however clinical or vital complications were not observed. mTHPC mediated intraoperative PDT seems to be a promising and safe treatment option which could complement existing treatment modalities in order to improve total survival rate in tumor patients.
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
photodynamic therapy (PDT)
meso- (tetrahydroxyphenyl) chlorine
600 Technology, Medicine, Applied Sciences :: 630 Agriculture :: 630 Agriculture and Allied Areas
Effects of photodynamic therapy with the photosensitizer mTHPC (Foscan®) on large blood vessels, nerves and muscle tissue in the rabbit animal model.
dc. contributor. firstReferee
Univ.-Prof. Dr. Roland Rudolph
dc. contributor. furtherReferee
dc. contributor. furtherReferee
Univ.-Prof. Klaus-Dieter Budras
urn: nbn: de: kobv: 188-2005000672
Effects of intra-operative photodynamic therapy with the photosensitizer Mthpc on rabbit large blood vessels, nerves, microcirculation and muscle-tissues.
refubium. mycore. fudocsId
FUDISS_thesis_000000001628
refubium. mycore. transfer
http://www.diss.fu-berlin.de/2005/67/
refubium. mycore. derivateId
FUDISS_derivate_000000001628
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