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Sample records for 5-aminolevulinic acid-mediated photodynamic

  1. 5-aminolevulinic acid-mediated photodynamic therapy on Hep-2 and MCF-7c3 cells.

    PubMed

    Alvarez, María Gabriela; Lacelli, M S; Rivarola, Viviana; Batlle, Alcira; Fukuda, Haydée

    2007-01-01

    The cytotoxic effect of 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PPIX) on two human carcinoma cell lines, MCF-7c3 cells and Hep 2 cells, was studied. In both cell lines, PPIX content depends on the ALA concentration and incubation time. The maximal PPIX content was higher in the MCF-7c3 cells, reaching a value of 8 microg/10(6) cells, compared to the Hep-2 cells, which accumulated 3.2 microg/10(6) cells. Treatment of cells with the iron chelator desferrioxamine prior to ALA exposure enhances the amount of PPIX, consequently diminishing enzymatic activity of ferroquelatase. Photo sensitization of the cells was in correlation with the PPIX content; therefore, conditions leading to 80% cell death in the MCF-7c3 cells provoke a 50% cell death in the Hep 2 cells. Using fluorescence microscopy, cell morphology was analyzed after incubation with 1 mM ALA during 5 hr and irradiation with 54 Jcm(-2); 24 hr post-PDT, MCF-7c3 cells revealed the typical morphological changes of necrosis. Under the same conditions, Hep-2 cells produced chromatine fragmentation characteristic of apoptosis. PPIX accumulation was observed to occur in a perinuclear region in the MCF-7c3 cells; while in Hep-2 cells, it was localized in lysosomes. Different mechanisms of cell death were observed in both cell lines, depending on the different intracellular localization of PPIX.

  2. Her2 oncogene transformation enhances 5-aminolevulinic acid-mediated protoporphyrin IX production and photodynamic therapy response

    PubMed Central

    Yang, Xue; Palasuberniam, Pratheeba; Myers, Kenneth A.; Wang, Chenguang; Chen, Bin

    2016-01-01

    Enhanced protoporphyrin IX (PpIX) production in tumors derived from the administration of 5-aminolevulinic acid (ALA) enables the use of ALA as a prodrug for photodynamic therapy (PDT) and fluorescence-guided tumor resection. Although ALA has been successfully used in the clinic, the mechanism underlying enhanced ALA-induced PpIX production in tumors is not well understood. Human epidermal growth receptor 2 (Her2, Neu, ErbB2) is a driver oncogene in human cancers, particularly breast cancers. Here we showed that, in addition to activating Her2/Neu cell signaling, inducing epithelial-mesenchymal transition and upregulating glycolytic enzymes, transfection of NeuT (a mutated Her2/Neu) oncogene in MCF10A human breast epithelial cells significantly enhanced ALA-induced PpIX fluorescence by elevating some enzymes involved in PpIX biosynthesis. Furthermore, NeuT-transformed and vector control cells exhibited drastic differences in the intracellular localization of PpIX, either produced endogenously from ALA or applied exogenously. In vector control cells, PpIX displayed a cell contact-dependent membrane localization at high cell densities and increased mitochondrial localization at low cell densities. In contrast, no predominant membrane localization of PpIX was observed in NeuT cells and ALA-induced PpIX showed a consistent mitochondrial localization regardless of cell density. PDT with ALA caused significantly more decrease in cell viability in NeuT cells than in vector cells. Our data demonstrate that NeuT oncogene transformation enhanced ALA-induced PpIX production and altered PpIX intracellular localization, rendering NeuT-transformed cells increased response to ALA-mediated PDT. These results support the use of ALA for imaging and photodynamic targeting Her2/Neu-positive tumors. PMID:27527860

  3. 5-aminolevulinic acid-mediated photodynamic therapy and its strain-dependent combined effect with antibiotics on Staphylococcus aureus biofilm

    PubMed Central

    Li, Xian-Hui; Yang, Chen; Guo, Li-Min; Liu, Chun-Hong; Qu, Di; Zheng, Chun-Quan

    2017-01-01

    Staphylococcus aureus (S. aureus) is hard to be eradicated, not only due to the emergence of antibiotic resistant strains but also because of its ability to form biofilm. Antibiotics are the major approach to treating biofilm infections, but their effects are unsatisfactory. One of the potential alternative treatments for controlling biofilm infections is photodynamic therapy (PDT), which requires the administration of photosensitizer, followed by light activation. 5-aminolevulinic acid (ALA), a natural photosensitizer prodrug, presents favorable characteristics, such as easy penetration and rapid clearance. These advantages enable ALA-based PDT (ALA-PDT) to be well-tolerated by patients and it can be repeatedly applied without cumulative toxicity or serious side effects. ALA-PDT has been proven to be an effective treatment for multidrug resistant pathogens; however, the study of its effect on S. aureus biofilm is limited. Here, we established our PDT system based on the utilization of ALA and a light-emitting diode, and we tested the effect of ALA-PDT on S. aureus biofilm as well as the combined effect of ALA-PDT and antibiotics on S. aureus biofilm. Our results showed that ALA-PDT has a strong antibacterial effect on S. aureus biofilm, which was confirmed by the confocal laser scanning microscope. We also found that lethal photosensitization occurred predominantly in the upper layer of the biofilm, while the residual live bacteria were located in the lower layer of the biofilm. In addition, the improved bactericidal effect was observed in the combined treatment group but in a strain-dependent manner. Our results suggest that ALA-PDT is a potential alternative approach for future clinical use to treat S. aureus biofilm-associated infections, and some patients may benefit from the combined treatment of ALA-PDT and antibiotics, but drug sensitivity testing should be performed in advance. PMID:28358851

  4. 5-aminolevulinic acid-mediated photodynamic therapy and its strain-dependent combined effect with antibiotics on Staphylococcus aureus biofilm.

    PubMed

    Zhang, Qing-Zhao; Zhao, Ke-Qing; Wu, Yang; Li, Xian-Hui; Yang, Chen; Guo, Li-Min; Liu, Chun-Hong; Qu, Di; Zheng, Chun-Quan

    2017-01-01

    Staphylococcus aureus (S. aureus) is hard to be eradicated, not only due to the emergence of antibiotic resistant strains but also because of its ability to form biofilm. Antibiotics are the major approach to treating biofilm infections, but their effects are unsatisfactory. One of the potential alternative treatments for controlling biofilm infections is photodynamic therapy (PDT), which requires the administration of photosensitizer, followed by light activation. 5-aminolevulinic acid (ALA), a natural photosensitizer prodrug, presents favorable characteristics, such as easy penetration and rapid clearance. These advantages enable ALA-based PDT (ALA-PDT) to be well-tolerated by patients and it can be repeatedly applied without cumulative toxicity or serious side effects. ALA-PDT has been proven to be an effective treatment for multidrug resistant pathogens; however, the study of its effect on S. aureus biofilm is limited. Here, we established our PDT system based on the utilization of ALA and a light-emitting diode, and we tested the effect of ALA-PDT on S. aureus biofilm as well as the combined effect of ALA-PDT and antibiotics on S. aureus biofilm. Our results showed that ALA-PDT has a strong antibacterial effect on S. aureus biofilm, which was confirmed by the confocal laser scanning microscope. We also found that lethal photosensitization occurred predominantly in the upper layer of the biofilm, while the residual live bacteria were located in the lower layer of the biofilm. In addition, the improved bactericidal effect was observed in the combined treatment group but in a strain-dependent manner. Our results suggest that ALA-PDT is a potential alternative approach for future clinical use to treat S. aureus biofilm-associated infections, and some patients may benefit from the combined treatment of ALA-PDT and antibiotics, but drug sensitivity testing should be performed in advance.

  5. 5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix--a new experimental approach.

    PubMed

    Wierrani, F; Kubin, A; Jindra, R; Henry, M; Gharehbaghi, K; Grin, W; Söltz-Szötz, J; Alth, G; Grünberger, W

    1999-01-01

    The aim of this study was to treat patients for ectocervical dysplasia [cervical intraepithelial neoplasia (CIN) grades 1 and 2] and associated human papilloma virus (HPV) infections with photodynamic therapy (PDT). In 20 patients, 5-aminolevulinic acid (5-ALA, 12% w/v) was applied topically with a cervical cap 8 h prior to illumination. A thermal light source (150 W halogen lamp) emitting a broadband red light (total energy: 100 J/cm2, fluence rate: 90 mW/cm2) was used for superficial illumination of the portio. In addition, an Nd:YAG pumped dye laser (652 nm) was used to illuminate the cervical canal (total energy: 50 J/cm2, fluence rate: 300 mW/cm2). Preliminary results of follow-ups at 1, 3, 6, and 9 months posttherapy showed a cytological improvement in the grading of the PAP smears in 19 patients and the eradication of cervical HPV in 80%. These results demonstrate that ectocervical dysplasia and associated HPV infections can be treated by PDT.

  6. Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA)

    PubMed Central

    Yonemura, Yutaka; Endo, Yoshio; Canbay, Emel; Liu, Yang; Ishibashi, Haruaki; Mizumoto, Akiyoshi; Hirano, Masamitu; Imazato, Yuuki; Takao, Nobuyuki; Ichinose, Masumi; Noguchi, Kousuke; Li, Yan; Wakama, Satoshi; Yamada, Kazuhiro; Hatano, Koutarou; Shintani, Hiroshi; Yoshitake, Hiroyuki; Ogura, Shun-ichiro

    2017-01-01

    In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM. PMID:28257041

  7. Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA).

    PubMed

    Yonemura, Yutaka; Endo, Yoshio; Canbay, Emel; Liu, Yang; Ishibashi, Haruaki; Mizumoto, Akiyoshi; Hirano, Masamitu; Imazato, Yuuki; Takao, Nobuyuki; Ichinose, Masumi; Noguchi, Kousuke; Li, Yan; Wakama, Satoshi; Yamada, Kazuhiro; Hatano, Koutarou; Shintani, Hiroshi; Yoshitake, Hiroyuki; Ogura, Shun-Ichiro

    2017-03-01

    In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM.

  8. Therapeutic effects of topical 5-aminolevulinic acid photodynamic therapy

    PubMed Central

    Hu, Yin-E; Dai, Shu-Fang; Wang, Bin; Qu, Wei; Gao, Jun-Ling

    2016-01-01

    Objective: To evaluate the therapeutic effects of combined 5-aminolevulinic acid (ALA) and photodynamic therapy (PDT) on genital warts and the safety. Methods: One hundred ten patients with genital warts who were treated in our hospital from June 2013 to October 2014 were selected. The warts and affected parts were disinfected with benzalkonium bromide solution, and the warts were covered with absorbent cotton that had already been added freshly prepared 20% ALA solution, packaged and fixed. Then they were wet-dressed in dark, into which ALA solution was added according to the proportion of 5:3:2 every 30 minutes for three consecutive hours. Afterwards, the warts were illuminated by using photodynamic laser apparatus. The clinical outcomes, adverse reactions and recurrence rates were observed. Results: Genital warts were relieved in 107 out of the 110 cases (cure rate: 97.3%). Male patients had significantly better treatment outcomes at the urethral orifice than those in other affected parts. In the 107 patients, the cure rate of male patients was 98.8%, and they were cured after being treated four times. In contrast, female patients, who were cured after 5 times of treatment, had the cure rate of 91.7%. Their cure rates were similar (χ2=0, P>0.05), but the males were cured after significantly fewer times of treatment than the females (t=-7.432, P<0.05). Five patients suffered from mild tingling or burning sensation upon dressing at the urethral orifice, and the others were all free from systemic adverse reactions. After illumination, a small portion of the patients had mildly red, swelling, painful affected parts, with mild edema that almost disappeared within three days. Three patients relapsed at the urethral orifice and were then cured after further treatment. Conclusion: ALA-PDT can treat genital warts safely with high cure rate and low recurrence rate, particularly working for those of males at the urethral orifice. PMID:27648048

  9. 5-aminolevulinic acid in photodynamic diagnosis and therapy of urological malignancies

    NASA Astrophysics Data System (ADS)

    Nelius, Thomas; de Riese, Werner T. W.

    2003-06-01

    Completeness and certainty of tumor detection are very important issues in clinical oncology. Recent technological developments in ultrasound, radiologic and magnetic resonance imaging diagnostics are very promising, but could not improve the detection rate of early stage malignancies. One of the most promising new approaches is the use of 5-aminolevulinic acid, a potent photosensitizer, in photodynamic diagnosis and therapy. 5-aminolevulinic acid is meanwhile a well-established tool in the photodynamic diagnosis of bladder cancer. It has been shown to improve the sensitivity of detection of superficial tumors and carcinoma in situ, which enables to reduce the risk of tumor recurrence related to undetected lesions or incomplete transurethral resection of the primary lesions. The use of 5-aminolevulinic acid is steadily expanding in diagnostics of urological malignancies. First clinical results are now reported in detection of urethral and ureteral lesions as well as in urine fluorescence cytology. Furthermore, due to the selective accumulation in transitional cell carcinoma of the bladder, 5-aminolevulinic acid may be an ideal candidate for photodynamic therapy in superficial bladder cancer. Summarizing the data of multiple clinical trials, 5-aminolevulinic acid is a promising agent in photodynamic diagnostics and treatment of superficial bladder cancer.

  10. Photodynamic inactivation of Klebsiella pneumoniae biofilms and planktonic cells by 5-aminolevulinic acid and 5-aminolevulinic acid methyl ester.

    PubMed

    Liu, Chengcheng; Zhou, Yingli; Wang, Li; Han, Lei; Lei, Jin'e; Ishaq, Hafiz Muhammad; Nair, Sean P; Xu, Jiru

    2016-04-01

    The treatment of Klebsiella pneumoniae, particularly extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae, is currently a great challenge. Photodynamic antimicrobial chemotherapy is a promising approach for killing antibiotic-resistant bacteria. The aim of this study was to evaluate the capacity of 5-aminolevulinic acid (5-ALA) and its derivative 5-ALA methyl ester (MAL) in the presence of white light to cause photodynamic inactivation (PDI) of K. pneumoniae planktonic and biofilm cells. In the presence of white light, 5-ALA and MAL inactivated planktonic cells in a concentration-dependent manner. Biofilms were also sensitive to 5-ALA and MAL-mediated PDI. The mechanisms by which 5-ALA and MAL caused PDI of ESBL-producing K. pneumonia were also investigated. Exposure of K. pneumonia to light in the presence of either 5-ALA or MAL induced cleavage of genomic DNA and the rapid release of intracellular biopolymers. Intensely denatured cytoplasmic contents and aggregated ribosomes were also detected by transmission electron microscopy. Scanning electron microscopy showed that PDI of biofilms caused aggregated bacteria to detach and that the bacterial cell envelope was damaged. This study provides insights into 5-ALA and MAL-mediated PDI of ESBL-producing K. pneumoniae.

  11. Photodynamic therapy with 5-aminolevulinic acid: basic principles and applications

    NASA Astrophysics Data System (ADS)

    Pottier, Roy H.; Kennedy, James C.

    1996-01-01

    Numerous photosensitizing pigments that absorb visible light and are selectively retained in neoplastic tissue are being investigated as potential photochemotherapeutic agents. While much emphasis is being placed on the synthesis of new, far-red absorbing photosensitizers, an alternative approach has been to stimulate the human body to produce its own natural photosensitizer, namely protoporphyrin IX (PpIX). Exogenous 5-aminolevulinic acid (ALA) is rapidly bioconverted into PP by mitochondria, the process being particularly efficient in tumor cells. Since PpIX has a natural and rapid clearing mechanism (via the capture of iron in the process of being converted into heme), ALA-PDT does not suffer from lingering skin phototoxicity. ALA may be introduced orally, intravenously, or topically, and ALA-PDT has been shown to be effective in the treatment of both malignant and non-malignant lesions.

  12. Repetitive 5-aminolevulinic acid mediated photodynamic therapy of rat glioma

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Madsen, Steen J.; Angell-Petersen, Even; Peng, Qian; Sioud, Mouldy; Sun, Chung-Ho; Sorensen, Dag R.

    2004-07-01

    The probability of achieving local control with current single-shot, intraoperative PDT treatments of intracerebral gliomas seems improbable due to the length of time required to deliver adequate light fluences to depths of 1 - 2 cm in the resection margin. The results of in vitro experiments indicated that PDT, repeated at weekly intervals, was substantially more effective at inhibiting glioma spheriod growth than single treatment regimes. This prompted the initiation of in vivo studies of repetitive PDT in a rat glioma model. BT4C cell line tumors were established in the brains of inbred BD-IX rats. Three days following tumor induction, the animals were injected with 250 mg/kg ALA i.p. and four hours later, after the introduction of an optical fiber, light treatment at various radiant energies was given over a 10- to 30-minute interval. Two additional treatments were given at weekly intervals. In vitro experiments verified that spheroids derived from the cell line were sensitive to ALA PDT. Microfluorometry of frozen tissue sections showed that PpIX is produced with a 10 - 20:1 tumor to normal tissue selectivity ratio four hours after 250 mg/kg ALA i.p. Toxic radiant energy levels for ALA PDT have been determined.

  13. Recent advances in photodynamic diagnosis of gastric cancer using 5-aminolevulinic acid

    PubMed Central

    Koizumi, Noriaki; Harada, Yoshinori; Minamikawa, Takeo; Tanaka, Hideo; Otsuji, Eigo; Takamatsu, Tetsuro

    2016-01-01

    Photodynamic diagnosis based on 5-aminolevulinic acid-induced protoporphyrin IX has been clinically applied in many fields based upon its evidenced efficacy and adequate safety. In order to establish a personalized medicine approach for treating gastric cancer patients, rapid intraoperative detection of malignant lesions has become important. Feasibility of photodynamic diagnosis using 5-aminolevulinic acid for gastric cancer patients has been investigated, especially for the detection of peritoneal dissemination and lymph node metastasis. This method enables intraoperative real-time fluorescence detection of peritoneal dissemination, exhibiting higher sensitivity than white light observation without histopathological examination. The method also enables detection of metastatic foci within excised lymph nodes, exhibiting a diagnostic accuracy comparable to that of a current molecular diagnostics technique. Although several complicating issues still need to be resolved, such as the effect of tissue autofluorescence and the insufficient depth penetration of excitation light, this simple and rapid method has the potential to become a useful diagnostic tool for gastric cancer, as well as urinary bladder cancer and glioma. PMID:26811665

  14. Recent advances in photodynamic diagnosis of gastric cancer using 5-aminolevulinic acid.

    PubMed

    Koizumi, Noriaki; Harada, Yoshinori; Minamikawa, Takeo; Tanaka, Hideo; Otsuji, Eigo; Takamatsu, Tetsuro

    2016-01-21

    Photodynamic diagnosis based on 5-aminolevulinic acid-induced protoporphyrin IX has been clinically applied in many fields based upon its evidenced efficacy and adequate safety. In order to establish a personalized medicine approach for treating gastric cancer patients, rapid intraoperative detection of malignant lesions has become important. Feasibility of photodynamic diagnosis using 5-aminolevulinic acid for gastric cancer patients has been investigated, especially for the detection of peritoneal dissemination and lymph node metastasis. This method enables intraoperative real-time fluorescence detection of peritoneal dissemination, exhibiting higher sensitivity than white light observation without histopathological examination. The method also enables detection of metastatic foci within excised lymph nodes, exhibiting a diagnostic accuracy comparable to that of a current molecular diagnostics technique. Although several complicating issues still need to be resolved, such as the effect of tissue autofluorescence and the insufficient depth penetration of excitation light, this simple and rapid method has the potential to become a useful diagnostic tool for gastric cancer, as well as urinary bladder cancer and glioma.

  15. Comparison of 5-Aminolevulinic Acid Photodynamic Therapy and Clobetasol Propionate in Treatment of Vulvar Lichen Sclerosus.

    PubMed

    Shi, Lei; Miao, Fei; Zhang, Ling-Lin; Zhang, Guo-Long; Wang, Pei-Ru; Ji, Jie; Wang, Xiao-Jie; Huang, Zheng; Wang, Hong-Wei; Wang, Xiu-Li

    2016-06-15

    The aim of this study was to evaluate the effectiveness of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for the treatment of vulvar lichen sclerosus (VLS) and compare its effectiveness with that of clobetasol propionate. Four sessions of topical photodynamic therapy (PDT) were administered at 2-week intervals (n = 20). Clobetasol propionate (0.05%) was used daily for 8 weeks (n = 20). The rate of complete response in the PDT group (14/20) was double that of the clobetasol propionate group (7/20) (p < 0.05, 2 = 4.912). Horizontal visual analogue scores indicated that PDT was more effective than clobetasol propionate. Pain intensity numeric rating scale values for PDT were between 3.05 and 4.45. One month after the final session of PDT, only one patient relapsed and all 7 patients in clobetasol propionate group relapsed. ALA-PDT is a well-tolerated and effective option for the treatment of VLS.

  16. Responses to hexyl 5-aminolevulinate-induced photodynamic treatment in rat bladder cancer model

    NASA Astrophysics Data System (ADS)

    Arum, Carl-Jørgen; Gederas, Odrun; Larsen, Eivind; Randeberg, Lise; Zhao, Chun-Mei

    2010-02-01

    OBJECTIVES: In this study, we evaluated histologically the effects of hexyl 5-aminolevulinateinduced photodynamic treatment in the AY-27 tumor cell induced rat bladder cancer model. MATERIAL & METHODS: The animals (fischer-344 female rats) were divided into 2 groups, half of which were orthotopically implanted with 400,000 syngeniec AY-27 urothelia1 rat bladder cancer cells and half sham implanted. 14 days post implantation 6 rats from each group were treated with hexyl 5-aminolevulinate-induced photodynamic treatment (8mM HAL and light fluence of 20 J/cm2). Additional groups of animals were only given HAL instillation, only light treatment, or no treatment. All animals were sacrificed 7 days after the PDT/only HAL/only light or no treatment. Each bladder was removed, embedded in paraffin and stained with hematoxylin, eosin, and saferin for histological evaluation at high magnification for features of tissue damage by a pathologist blinded to the sample source. RESULTS: In all animals that were AY-27 implanted and not given complete PDT treatment, viable tumors were found in the bladder mucosa and wall. In the animals treated with complete HAL-PDT only 3 of 6 animals had viable tumor. In the 3 animals with viable tumor it was significantly reduced in volume compared to the untreated animals. It was also noted that in the PDT treated animals there was a significantly increased inflammatory response (lymphocytic and mononuclear cell infiltration) in the peri-tumor area compared to implanted animals without complete HAL-PDT. CONCLUSION: Our results suggest that hexyl 5-aminolevulinate-induced photodynamic treatment in a rat bladder cancer model involves both direct effects on cell death (necrosis and apoptosis) and indirect effects to evoke the host immune-response, together contributing to tumor eradication.

  17. Enhanced 5-aminolevulinic acid-gold nanoparticle conjugate-based photodynamic therapy using pulse laser

    NASA Astrophysics Data System (ADS)

    Xu, Hao; Yao, Cuiping; Wang, Jing; Chang, Zhennan; Zhang, Zhenxi

    2016-02-01

    The low bioavailability is a crucial limitation for the application of 5-aminolevulinic acid (ALA) in theranostics. In this research, 5-aminolevulinic acid and gold nanoparticle conjugates (ALA-GNPs) were synthesized to improve the bioavailability of ALA and to investigate the impact of ALA photodynamic therapy (ALA-PDT) in Hela cells. A 532 nm pulse laser and light-emitting diode (central wavelengths 502 nm) were jointly used as light sources in PDT research. The results show a 532 nm pulse laser can control ALA release from ALA-GNPs by adjusting the pulse laser dose. This laser control release may be attributed to the heat generation from GNPs under pulse laser irradiation, which indicates accurately adjusting the pulse laser dose to control the drug release in the cell interior can be considered as a new cellular surgery modality. Furthermore, the PDT results in Hela cells indicate the enhancement of ALA release by pulse laser before PDT can promote the efficacy of cell eradication in the light-emitting diode PDT (LED-PDT). This laser mediated drug release system can provide a new online therapy approach in PDT and it can be utilized in the optical monitor technologies based individual theranostics.

  18. Utilization of 5-aminolevulinic acid in the photodynamic therapy of tumors: biochemical and photobiological aspects

    NASA Astrophysics Data System (ADS)

    Pottier, Roy H.; Kennedy, James C.

    1994-03-01

    Inherent in both plants and animals is the natural porphyrin, Protoporphyrin IX (Pp). Although Pp does not appear to have any intrinsic biological activity, it is a potent natural photosensitizer. When activated with ultraviolet or visible light, this photosensitizer can induce significant photodynamic effects on tissues, cells, subcellular elements, and macromolecules via the production of singlet oxygen. The biosynthesis of endogenous Pp is under strict enzymatic control. It is possible to bypass a rate controlling step and induce large, transient concentrations of Pp by the addition of exogenous 5-aminolevulinic acid (ALA). ALA may be administered systemically or topically. Much larger amounts of Pp are produced in certain types of tumor tissue than in adjacent normal tissue. Topically applied ALA can be used to treat a variety of skin lesions, including actinic keratosis, basal cell carcinomas and psoriasis.

  19. Optical spectroscopy by 5-aminolevulinic acid hexylester induced photodynamic treatment in rat bladder cancer

    NASA Astrophysics Data System (ADS)

    Larsen, Eivind L. P.; Randeberg, Lise L.; Gederaas, Odrun A.; Arum, Carl-Jørgen; Krokan, Hans E.; Hjelme, Dag R.; Svaasand, Lars O.

    2006-02-01

    Photodynamic therapy (PDT) is a treatment modality which has been shown to be effective for both malignant and non-malignant diseases. New photosensitizers such as 5-aminolevulinic acid hexylester (hALA) may increase the efficiency of PDT. Monitoring of the tissue response provides important information for optimizing factors such as drug and light dose for this treatment modality. Optical spectroscopy may be suited for this task. To test the efficacy of hALA induced PDT, a study on rats with a superficial bladder cancer model, in which a bladder cancer cell line (AY-27) is instilled, will be performed. Preliminary studies have included a PDT feasibility study on rats, fluorescence spectroscopy on AY-27 cell suspensions, and optical reflection and fluorescence spectroscopy in rat bladders in vivo. The results from the preliminary studies are promising, and the study on hALA induced PDT treatment of bladder cancer will be continued.

  20. Review of dermatology use of 5-aminolevulinic acid photodynamic therapy in China from 1997 to 2013

    NASA Astrophysics Data System (ADS)

    Wang, Peiru; Zhang, Guolong; Wang, Xiuli

    2015-07-01

    The prodrug 5-aminolevulinic acid (ALA) and its ester derivatives have been used in photodynamic therapy (PDT) in dermatology worldwide. In China, ALA-PDT was first used to treat urethral condylomata acuminata and non-melanoma skin cancers in 1997. A powder formulation of ALA hydrochloride was approved by the Chinese Food and Drug Administration for the treatment of condylomata acuminata in 2007. Large successful experience of treating condylomatas was accumulated compared with Western countries. Meanwhile, numerous clinical studies as well as off-label use of ALAPDT have been carried out in China. To reflect the progress of ALA-PDT in China, several major Chinese and English databases were searched and published data were reviewed in this article.

  1. Treatment of actinic cheilitis by photodynamic therapy with 5-aminolevulinic acid and blue light activation.

    PubMed

    Zaiac, Martin; Clement, Annabelle

    2011-11-01

    Actinic cheilitis (AC), a common disorder of the lower lip, should be treated early to prevent progression to invasive squamous cell carcinoma. This study evaluated the safety and efficacy of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) activated by blue light for the treatment of AC. Fifteen patients with clinically evident or biopsy-proven AC received two treatments with ALA PDT with blue light activation. Treatments were spaced three to five weeks apart. Most patients achieved 65% to 75% clearance three to five weeks after the first treatment and all achieved more than 75% clearance one month after the second treatment. Three patients achieved complete clearance. Pain and burning during irradiation were absent or mild. All patients said they would repeat the procedure. ALA PDT with 417 nm blue light is a promising option for the treatment of AC of the lower lip.

  2. Effectiveness of 5-aminolevulinic acid photodynamic therapy in the treatment of hidradenitis suppurativa: a report of 5 cases.

    PubMed

    Andino Navarrete, R; Hasson Nisis, A; Parra Cares, J

    2014-01-01

    Hidradenitis suppurativa has been described as a chronic, recurrent, and disabling inflammatory disease involving the entire hair follicle. Several treatments, including photodynamic therapy, have been used, but the results have been inconsistent and recurrence is high. In this prospective study, we evaluated disease severity, quality of life, and treatment tolerance in 5 patients with moderate to severe hidradenitis suppurativa treated with photodynamic therapy using 5-aminolevulinic acid and a 635-nm light source. Treatment effectiveness was evaluated using the Sartorius severity score, the Dermatology Life Quality Index, and a visual analog scale for pain and disease activity. Significant improvements were observed with all 3 instruments and the effects remained visible at 8 weeks. Our results suggest that photodynamic therapy with 5-aminolevulinic acid and a light wavelength of 635 nm could reduce disease severity and improve quality of life in patients with difficult-to-treat hidradenitis suppurativa.

  3. 5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Inhibits RIPK1/RIPK3-Dependent Necroptosis in THP-1-Derived Foam Cells

    PubMed Central

    Tian, Fang; Yao, Jianting; Yan, Meng; Sun, Xin; Wang, Wei; Gao, Weiwei; Tian, Zhen; Guo, Shuyuan; Dong, Zengxiang; Li, Bicheng; Gao, Tielei; Shan, Peng; Liu, Bing; Wang, Haiyang; Cheng, Jiali; Gao, Qianping; Zhang, Zhiguo; Cao, Wenwu; Tian, Ye

    2016-01-01

    Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived foam cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in foam cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis. PMID:26911899

  4. Comparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapy.

    PubMed

    Fang, Yi-Ping; Tsai, Yi-Hung; Wu, Pao-Chu; Huang, Yaw-Bin

    2008-05-22

    Topical photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for many non-melanoma skin cancers. The major limitation of this therapy, however, is the low permeability of ALA through the stratum corneum (SC) of the skin. The objective of the present work was to characterize ethosomes containing ALA and to enhance the skin production of protoporphyrin IX (PpIX), compared to traditional liposomes. Results showed that the average particle sizes of the ethosomes were less than those of liposomes. Moreover, the entrapment efficiency of ALA in the ethosome formulations was 8-66% depending on the surfactant added. The particle size of the ethosomes was still approximately <200 nm after 32 days of storage. An in vivo animal study observed the presence of PpIX in the skin by confocal laser scanning microscopy (CLSM). The results indicated that the penetration ability of ethosomes was greater than that of liposomes. The enhancements of all the formulations were ranging from 11- to 15-fold in contrast to that of control (ALA in an aqueous solution) in terms of PpIX intensity. In addition, colorimetry detected no erythema in the irradiated skin. The results demonstrated that the enhancement ratio of ethosome formulations did not significantly differ between the non-irradiated and irradiated groups except for PE/CH/SS, which may have been due to a photobleaching effect of the PDT-irradiation process.

  5. Off-label photodynamic therapy for recalcitrant facial flat warts using topical 5-aminolevulinic acid.

    PubMed

    Yang, Ya-Li; Sang, Junjun; Liao, Ning-Xin; Wei, Fang; Liao, Wanqin; Chen, Jiang-Han

    2016-07-01

    The facial flat wart (verruca plana) is one of the most common reasons for dermatology and primary care visits. Although there are many therapeutic modalities, no single therapy has been proven to be completely curative. Case reports and uncontrolled studies suggested that photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) can effectively treat recalcitrant facial flat warts. A total of 12 patients with recalcitrant facial flat warts were enrolled in the study. ALA gel (10 %) was applied topically to lesions and incubated for 3 h. The lesions were irradiated by an LED light of 630 ± 10 nm at dose levels of 60-100 mW/cm. Clinical assessment was conducted before and after every treatment for up to 24 weeks. Among the ten patients completing three sessions of ALA-PDT, five had complete lesions clearance, and the other five patients were significantly improved. At the 24-week follow-up, the average effective rate was 88.8 %, with no recurrences. No significant side effects were reported. A low-dose topical ALA-PDT regimen using 10 % ALA, 3 h incubation, and a red light source for three treatment sessions are suggested as the optimal scheme for the treatment of recalcitrant flat warts on the face in Chinese patients. Superior efficacy is found in elevated or active period lesions with mild side effects.

  6. Role of 5-aminolevulinic acid-conjugated gold nanoparticles for photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Zhang, Zhenxi; Wang, Sijia; Xu, Hao; Wang, Bo; Yao, Cuiping

    2015-05-01

    There are three possible mechanisms for 5-aminolevulinic acid (5-ALA) conjugated gold nanoparticles (GNPs) through electrostatic bonding for photodynamic therapy (PDT) of cancer: GNPs delivery function, singlet oxygen generation (SOG) by GNPs irradiated by light, and surface resonance enhancement (SRE) of SOG. Figuring out the exact mechanism is important for further clinical treatment. 5-ALA-GNPs and human chronic myeloid leukemia K562 cells were used to study delivery function and SOG by GNPs. The SRE of SOG enabled by GNPs was explored by protoporphyrin IX (PpIX)-GNPs conjugate through electrostatic bonding. Cell experiments show that the GNPs can improve the efficiency of PDT, which is due to the vehicle effect of GNPs. PpIX-GNPs conjugate experiments demonstrated that SOG can be improved about 2.5 times over PpIX alone. The experiments and theoretical results show that the local field enhancement (LFE) via localized surface plasmon resonance (LSPR) of GNPs is the major role; the LFE was dependent on the irradiation wavelength and the GNP's size. The LFE increased with an increase of the GNP size (2R ≤50 nm). However, the LSPR function of the GNPs was not found in cell experiments. Our study shows that in 5-ALA-conjugated GNPs PDT, the delivery function of GNPs is the major role.

  7. Photodynamic therapy of urethral condylomata acuminata using topically 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Wang, Xiuli; Wang, Hongwei; Wang, Haishan; Xu, Shizheng; Liao, Kanghuang; Hillemanns, Peter

    2005-07-01

    Background Electrocoagulation and laser evaporation for urethral condylomata acuminata have high recurrence rates and can be associated with urethral malformations. Objective To investigate the effect of photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) on urethral condylomata acuminata and to examine the histological changes in lesions of condylomata acuminata after ALA-PDT. Methods One hundred and sixty-four urethral condylomata patients were given topical ALA followed by intraurethral PDT through a cylindrical fiber. Among the cases, 16 penile and vulval condylomatous lesions in 11 patients were treated with topical ALA-PDT at same time. After the treatment, biopsy specimens were collected from the 16 penile and vulval lesions. The histological changes were then evaluated by light microscope and electron microscope. Results The complete response rate for urethral condylomata by topical ALA-PDT was 95.12% and the recurrence rate was 5.13% after 6 to 24 months follow-up. Keratinocytes in middle and upper layers of the epidermis with marked vacuolation and some necrocytosis were detected one and three hours after PDT. Necrosis in all layers of the epidermis was noted five hours after PDT by microscopy. In electron microscopy of kerationcytes, distinct ultrastructural abnormalities of mitochondrion, endoplasmic reticulum and membrane damage were observed. Apoptotic bodies were detected three hours after PDT and a large number of the keratinocytes exhibited necrosis five hours after PDT by electron microscope. Conclusions Results suggests that topical ALA-PDT is a simple, effective, relatively safe, less recurrent and comparatively well tolerated treatment for urethral condylomata acuminata. The mechanisms might be that ALA-PDT could trigger apoptotic process and necrosis in the HPV infected keratinocytes. Key words:

  8. Hydrokolloid occlusive dressings for photodynamic therapy (PDT) of cutaneous lesions with endogenous porphyrins induced by 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Gahlen, Johannes; Stern, Josef; Herfarth, Christian

    1995-03-01

    Protoporphyrin (Pp IX) is the final intermediate product before haem and can be stimulated to a phototoxic reaction with light. The presence of 5-aminolevulinic acid can increase the intracellular biosynthesis of Pp IX in certain types of tumor cells. The photosensitizing concentrations of Pp IX make laser light induced fluorescence diagnostics (LIFD) and photodynamic therapy possible. A topical application of a 5-aminolevulinic acid solution requires a waterproof occlusive dressing for several hours. We developed a simple technique for a practical preparation for PDT using a hydrocolloid dressing. The normal surrounding skin can be spared. We present our first therapeutic experience with a case of cutaneous breast cancer in a 65-year-old female patient. Six hours after topical application of 10% isotonic 5- aminolevulinic acid under the hydrocolloid dressing PDT was performed (Ar-Dye Laser, 630 nm wavelength). Twenty four hours after PDT a superficial tumor necrosis could be observed with a maximum depth of tumor necrosis of 2 - 3 mm. The surrounding normal skin was without any inflammation.

  9. Photodynamic therapy using systemic administration of 5-aminolevulinic acid and a 410-nm wavelength light-emitting diode for methicillin-resistant Staphylococcus aureus-infected ulcers in mice.

    PubMed

    Morimoto, Kuniyuki; Ozawa, Toshiyuki; Awazu, Kunio; Ito, Nobuhisa; Honda, Norihiro; Matsumoto, Sohkichi; Tsuruta, Daisuke

    2014-01-01

    Bacterial resistance to antibiotics has become a worldwide problem. One potential alternative for bacterial control is photodynamic therapy. 5-aminolevulinic acid is a natural precursor of the photosensitizer protoporphyrin IX. Relatively little is known about the antibacterial efficacy of photodynamic therapy using the systemic administration of 5-aminolevulinic acid; a few reports have shown that 5-aminolevulinic acid exerts photodynamic effects on methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In this study, we evaluated the effectiveness of photodynamic therapy using 5-aminolevulinic acid and a 410-nm wavelength light-emitting diode in vitro and in vivo for the treatment of MRSA. We found that 5-aminolevulinic acid photodynamic therapy with the light-emitting diode had an in-vitro bactericidal effect on MRSA. In vivo, protoporphyrin IX successfully accumulated in MRSA on ulcer surfaces after intraperitoneal administration of 5-aminolevulinic acid to mice. Furthermore, 5-aminolevulinic acid photodynamic therapy accelerated wound healing and decreased bacterial counts on ulcer surfaces; in contrast, vancomycin treatment did not accelerate wound healing. Our findings indicate that 5-aminolevulinic acid photodynamic therapy may be a new treatment option for MRSA-infected wounds.

  10. Pyogenic granuloma in a patient with psoriasis successfully treated by 5-aminolevulinic acid photodynamic therapy: A case report.

    PubMed

    Liu, Juan; Zhou, Bing-Rong; Yi, Fei; Wu, Hong-Jin; Zhang, Jia-An; Luo, Dan

    2016-01-01

    Pyogenic granuloma (PG) is an acquired benign vascular tumor of unknown etiology. In the present case report, PG was detected in a 49-year-old Chinese male patient with chronic plaque psoriasis. The psoriasis lesions on the finger where the granuloma had developed had been scratched excessively, as declared by the patient. No retinoid therapeutic agents were used during treatment. The patient responded poorly to cryotherapy and surgical curettage. However, following one session of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), signs of improvement were demonstrated 1 week after the treatment, and 1 month following treatment, there were no signs of reoccurrence. Although a report demonstrating treatment success in one patient may be inadequate to estimate the true efficiency of ALA-PDT, dermatologists may consider ALA-PDT as an alternative therapy for stubborn PG.

  11. Pyogenic granuloma in a patient with psoriasis successfully treated by 5-aminolevulinic acid photodynamic therapy: A case report

    PubMed Central

    LIU, JUAN; ZHOU, BING-RONG; YI, FEI; WU, HONG-JIN; ZHANG, JIA-AN; LUO, DAN

    2016-01-01

    Pyogenic granuloma (PG) is an acquired benign vascular tumor of unknown etiology. In the present case report, PG was detected in a 49-year-old Chinese male patient with chronic plaque psoriasis. The psoriasis lesions on the finger where the granuloma had developed had been scratched excessively, as declared by the patient. No retinoid therapeutic agents were used during treatment. The patient responded poorly to cryotherapy and surgical curettage. However, following one session of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), signs of improvement were demonstrated 1 week after the treatment, and 1 month following treatment, there were no signs of reoccurrence. Although a report demonstrating treatment success in one patient may be inadequate to estimate the true efficiency of ALA-PDT, dermatologists may consider ALA-PDT as an alternative therapy for stubborn PG. PMID:26889266

  12. Cystic acne improved by photodynamic therapy with short-contact 5-aminolevulinic acid and sequential combination of intense pulsed light and blue light activation.

    PubMed

    Melnick, Stuart

    2005-01-01

    Photodynamic therapy with short-contact 5-aminolevulinic acid (Levulan Kerastick, Dusa Pharmaceuticals, Inc.) and activation by intense pulsed light in an initial treatment and blue light in 3 subsequent treatments has resulted in significant improvement in severity of acne, reduction in the number of lesions, improvement in skin texture, and smoothing of scar edges in an Asian patient with severe (class 4) facial cystic acne and scarring.

  13. Increased brain edema following 5-aminolevulinic acid mediated photodynamic in normal and tumor bearing rats

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Angell-Petersen, Even; Spetalen, Signe; Mathews, Marlon; Madsen, Steen J.

    2007-02-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to both tumor cells as well as cerebral blood vessels leading to degradation of the blood brain barrier with subsequent increase of brain edema. The increase in brain edema following ALA-PDT was evaluated in terms of animal survival, histopatological changes in normal brain and tumor tissue and MRI scanning. The effect of steroid treatment, to reduce post-treatment PDT induced edema, was also examined. Methods:Tumors were established in the brains of inbred BD-IX and Fisher rats. At various times following tumor induction the animals were injected with ALA ip. and four hours later light treatment at escalating fluences and fluence rates were given. Nontumor bearing control animals were also exposed to ALA-PDT in a similar manner to evaluate damage to normal brain and degree of blood brain barrier (BBB) disruption. Results: Despite a very low level of PpIX production in normal brain, with a 200:1 tumor to normal tissue selectivity ratio measured at a distance of 2 mm from the tumor border, many animals succumbed shortly after treatment. A total radiant energy of 54 J to non-tumor bearing animals resulted in 50% mortality within 5 days of treatment. Treatment of tumor bearing animals with moderate fluence levels produced similar brain edema compared to higher fluence levels. ALA PDT in nontumor bearing animals produced edema that was light dose dependent. PDT appeared to open the BBB for a period of 24-48 hrs after which it was restored. The addition of post operative steroid treatment reduced the incident of post treatment morbidity and mortality. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and non-evasive modality in following the development of the edema reaction and the degree and time course of BBB dysfunction thus allowing the use of fewer animals.

  14. Photosensitizer fluorescence and singlet oxygen luminescence as dosimetric predictors of topical 5-aminolevulinic acid photodynamic therapy induced clinical erythema.

    PubMed

    Mallidi, Srivalleesha; Anbil, Sriram; Lee, Seonkyung; Manstein, Dieter; Elrington, Stefan; Kositratna, Garuna; Schoenfeld, David; Pogue, Brian; Davis, Steven J; Hasan, Tayyaba

    2014-02-01

    The need for patient-specific photodynamic therapy (PDT) in dermatologic and oncologic applications has triggered several studies that explore the utility of surrogate parameters as predictive reporters of treatment outcome. Although photosensitizer (PS) fluorescence, a widely used parameter, can be viewed as emission from several fluorescent states of the PS (e.g., minimally aggregated and monomeric), we suggest that singlet oxygen luminescence (SOL) indicates only the active PS component responsible for the PDT. Here, the ability of discrete PS fluorescence-based metrics (absolute and percent PS photobleaching and PS re-accumulation post-PDT) to predict the clinical phototoxic response (erythema) resulting from 5-aminolevulinic acid PDT was compared with discrete SOL (DSOL)-based metrics (DSOL counts pre-PDT and change in DSOL counts pre/post-PDT) in healthy human skin. Receiver operating characteristic curve (ROC) analyses demonstrated that absolute fluorescence photobleaching metric (AFPM) exhibited the highest area under the curve (AUC) of all tested parameters, including DSOL based metrics. The combination of dose-metrics did not yield better AUC than AFPM alone. Although sophisticated real-time SOL measurements may improve the clinical utility of SOL-based dosimetry, discrete PS fluorescence-based metrics are easy to implement, and our results suggest that AFPM may sufficiently predict the PDT outcomes and identify treatment nonresponders with high specificity in clinical contexts.

  15. Photosensitizer fluorescence and singlet oxygen luminescence as dosimetric predictors of topical 5-aminolevulinic acid photodynamic therapy induced clinical erythema

    PubMed Central

    Mallidi, Srivalleesha; Anbil, Sriram; Lee, Seonkyung; Manstein, Dieter; Elrington, Stefan; Kositratna, Garuna; Schoenfeld, David; Pogue, Brian; Davis, Steven J.; Hasan, Tayyaba

    2014-01-01

    Abstract. The need for patient-specific photodynamic therapy (PDT) in dermatologic and oncologic applications has triggered several studies that explore the utility of surrogate parameters as predictive reporters of treatment outcome. Although photosensitizer (PS) fluorescence, a widely used parameter, can be viewed as emission from several fluorescent states of the PS (e.g., minimally aggregated and monomeric), we suggest that singlet oxygen luminescence (SOL) indicates only the active PS component responsible for the PDT. Here, the ability of discrete PS fluorescence-based metrics (absolute and percent PS photobleaching and PS re-accumulation post-PDT) to predict the clinical phototoxic response (erythema) resulting from 5-aminolevulinic acid PDT was compared with discrete SOL (DSOL)-based metrics (DSOL counts pre-PDT and change in DSOL counts pre/post-PDT) in healthy human skin. Receiver operating characteristic curve (ROC) analyses demonstrated that absolute fluorescence photobleaching metric (AFPM) exhibited the highest area under the curve (AUC) of all tested parameters, including DSOL based metrics. The combination of dose-metrics did not yield better AUC than AFPM alone. Although sophisticated real-time SOL measurements may improve the clinical utility of SOL-based dosimetry, discrete PS fluorescence-based metrics are easy to implement, and our results suggest that AFPM may sufficiently predict the PDT outcomes and identify treatment nonresponders with high specificity in clinical contexts. PMID:24503639

  16. Dormant cancer cells accumulate high protoporphyrin IX levels and are sensitive to 5-aminolevulinic acid-based photodynamic therapy

    PubMed Central

    Nakayama, Taku; Otsuka, Shimpei; Kobayashi, Tatsuya; Okajima, Hodaka; Matsumoto, Kentaro; Hagiya, Yuichiro; Inoue, Keiji; Shuin, Taro; Nakajima, Motowo; Tanaka, Tohru; Ogura, Shun-ichiro

    2016-01-01

    Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to drive the production of an intracellular photosensitizer, protoporphyrin IX (PpIX), are in common clinical use. However, the tendency to accumulate PpIX is not well understood. Patients with cancer can develop recurrent metastatic disease with latency periods. This pause can be explained by cancer dormancy. Here we created uniformly sized PC-3 prostate cancer spheroids using a 3D culture plate (EZSPHERE). We demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner not only in spheroids but also in 2D culture. Dormant cancer cells accumulated high PpIX levels and were sensitive to ALA-PDT. In dormant cancer cells, transporter expressions of PEPT1, ALA importer, and ABCB6, an intermediate porphyrin transporter, were upregulated and that of ABCG2, a PpIX exporter, was downregulated. PpIX accumulation and ALA-PDT cytotoxicity were enhanced by G0/G1-phase arrestors in non-dormant cancer cells. Our results demonstrate that ALA-PDT would be an effective approach for dormant cancer cells and can be enhanced by combining with a cell-growth inhibitor. PMID:27857072

  17. Rheological characterization and permeation behavior of poloxamer 407-based systems containing 5-aminolevulinic acid for potential application in photodynamic therapy.

    PubMed

    van Hemelrijck, Carlos; Müller-Goymann, Christel C

    2012-11-01

    Topical application of 5-aminolevulinic acid (ALA) in photodynamic therapy is of great interest because of avoiding systemic side effects with such an easy way of application. However, due to ALA's high polarity its dermal bioavailability is rather limited and thus, permeation enhancement of this active is of major interest in research. In a previous study, a semisolid poloxamer 407-based (POX), five-component system ("thermogel") was developed for permeation enhancement of ALA across isolated human stratum corneum. In the present study, five-component systems of systematically varied compositions were investigated both rheologically and in terms of permeation enhancement. The five-component systems contained water, a fixed combination of 1:1 of isopropyl alcohol (IPA) and dimethyl isosorbide (DMIS) and a fixed ratio of 4:1 of POX to propylene glycol dicaprylocaprate (MIG). Rheological characterization showed that complex viscosity depended on IPA/DMIS and POX/MIG content. The gelation temperature (GT) was strongly influenced by interactions between MIG, IPA and DMIS. Regarding permeation behavior, several systems showing better permeation fluxes than the original "thermogel" were identified. Surprisingly, permeation flux did not inversely correlate with the complex viscosity, showing that permeation behavior may depend on a variety of further physicochemical characteristics including individual composition and microstructure of the respective formulation.

  18. Diagnostic approach for cancer cells in urine sediments by 5-aminolevulinic acid-based photodynamic detection in bladder cancer.

    PubMed

    Miyake, Makito; Nakai, Yasushi; Anai, Satoshi; Tatsumi, Yoshihiro; Kuwada, Masaomi; Onishi, Sayuri; Chihara, Yoshitomo; Tanaka, Nobumichi; Hirao, Yoshihiko; Fujimoto, Kiyohide

    2014-05-01

    Bladder urothelial carcinoma is diagnosed and followed up after transurethral resection using a combination of cystoscopy, urine cytology and urine biomarkers at regular intervals. However, cystoscopy can overlook flat lesions like carcinoma in situ, and the sensitivity of urinary tests is poor in low-grade tumors. There is an emergent need for an objective and easy urinary diagnostic test for the management of bladder cancer. In this study, three different modalities for 5-aminolevulinic acid (ALA)-based photodynamic diagnostic tests were used. We developed a compact-size, desktop-type device quantifying red fluorescence in cell suspensions, named "Cellular Fluorescence Analysis Unit" (CFAU). Urine samples from 58 patients with bladder cancer were centrifuged, and urine sediments were then treated with ALA. ALA-treated sediments were subjected to three fluorescence detection assays, including the CFAU assay. The overall sensitivities of conventional cytology, BTA, NMP22, fluorescence cytology, fluorescent spectrophotometric assay and CFAU assay were 48%, 33%, 40%, 86%, 86% and 87%, respectively. Three different ALA-based assays showed high sensitivity and specificity. The ALA-based assay detected low-grade and low-stage bladder urothelial cells at shigher rate (68-80% sensitivity) than conventional urine cytology, BTA and NMP22 (8-20% sensitivity). Our findings demonstrate that the ALA-based fluorescence detection assay is promising tool for the management of bladder cancer. Development of a rapid and automated device for ALA-based photodynamic assay is necessary to avoid the variability induced by troublesome steps and low stability of specimens.

  19. Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: new photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy

    PubMed Central

    Johnson, Renjith P; Chung, Chung-Wook; Jeong, Young-Il; Kang, Dae Hwan; Suh, Hongsuk; Kim, Il

    2012-01-01

    Background 5-Aminolevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy. The main drawback associated with ALA-based photodynamic therapy (ALA-PDT) and ALA fluorescence diagnosis results from the hydrophilic nature of ALA and lack of selectivity for tumor versus nontumor cells. The application of certain triggers, such as pH, into conventional sensitizers for controllable 1O2 release is a promising strategy for tumor-targeted treatment. Methods A series of pH-sensitive ALA-poly(L-histidine) [p(L-His)n] prodrugs were synthesized via ring opening polymerization of 1-benzyl-N-carboxy-L-histidine anhydride initiated by the amine hydrochloride group of ALA itself. As an alternative to ALA for PDT, the synthesized prodrugs were used to treat a cultured human colon cancer HCT116 cell line under different pH conditions. The effect of ALA-p(L-His)n derivatives was evaluated by monitoring the fluorescence intensity of protoporphyrin IX, and measuring the cell survival rate after suitable light irradiation. Results The cytotoxicity and dark toxicity of ALA and synthesized ALA-p(L-His) derivatives in HEK293T and HCT116 cells in the absence of light at pH 7.4 and 6.8 shows that the cell viability was relatively higher than 100%. ALA-p(L-His)n showed high phototoxicity and selectivity in different pH conditions compared with ALA alone. Because the length of the histidine chain increases in the ALA-p(L-His)n prodrugs, the PDT effect was found to be more powerful. In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)15, compared with treatment using ALA alone. Conclusion The newly synthesized ALA-p(L-His)n derivatives are an effective alternative to ALA for enhancing protoporphyrin IX production and the selectivity of the phototoxic effect in tumor cells. PMID:22679363

  20. A Clinical Trial Using Attrition Combined with 5-Aminolevulinic Acids Based Photodynamic Therapy in Treating Squamous Cell Carcinoma

    PubMed Central

    Peng, Jianzhong; Feng, Weiguo; Luo, Xianyan; Wang, Tao; Xiang, Wenzhong; Dai, Yeqin; Zhu, Jingyu; Zheng, Junhui

    2017-01-01

    Background Squamous cell carcinoma (SCC) is the second most common type of skin cancer, for which non- or mini-invasive treatment is of critical importance. 5-aminolevulinic acids based photodynamic therapy (ALA-PDT) is a mini-invasive approach that causes focal tumor cell injury, apoptosis, and necrosis through light sensitivity. The efficacy of combining ALA-PDT and surgery in treating SCC, however, has not been demonstrated. Material/Methods A total of 60 SCC patients were randomly assigned into attrition plus ALA-PDT group (experimental group) and single ALA-PDT treatment group (control group). Clinical efficacy, recurrence rate, and adverse effects were analyzed in conjunction with H&E staining and immunohistochemistry (IHC) staining for p53 expression. Results The overall effective rate of the experimental group was 73.3%, which was significantly higher than that of the control group (46.7%). The experimental group also had a lower recurrence rate (16.6% versus 30.0%, p<0.05). Similar rates of adverse effects existed between the two groups. After treatment, abnormal cells disappeared, while the p53 positive rate after treatment was elevated in the two groups (p<0.05 comparison of before and after treatment). The experimental group had a higher p53 positive rate compared to the control group (p<0.05). Conclusions Combined therapy of attrition with ALA-PDT significantly elevated the effective treatment rate and can decrease the recurrence rate with reliable safety in treating SCC, thus ALA-PDT can be used as an optimal plan for SCC treatment. PMID:28314866

  1. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen.

    PubMed

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-03

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, Fv/Fm, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H2O2 production and greater increases in H2O2-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage.

  2. Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy: the influence of light color and irradiance on the treatment outcome in vitro.

    PubMed

    Helander, Linda; Krokan, Hans E; Johnsson, Anders; Gederaas, Odrun A; Plaetzer, Kristjan

    2014-08-01

    Hexyl 5-aminolevulinate (HAL) is a lipophilic derivative of 5-aminolevulinate, a key intermediate in biosynthesis of the photosensitizer protoporphyrin IX (PpIX). The photodynamic efficacy and cell death mode after red versus blue light illumination of HAL-induced PpIX have been examined and compared using five different cancer cell lines. LED arrays emitting at 410 and 624 nm served as homogenous and adjustable light sources. Our results show that the response after HAL-PDT is cell line specific, both regarding the shape of the dose-survival curve, the overall dose required for efficient cell killing, and the relative amount of apoptosis. The ratio between 410 and 624 nm in absorption coefficient correlates well with the difference in cell killing at the same wavelengths. In general, the PDT efficacy was several folds higher for blue light as compared with red light, as expected. However, HAL-PDT₆₂₄ induced more apoptosis than HAL-PDT₄₁₀ and illumination with low irradiance resulted in more apoptosis than high irradiance at the same lethal dose. This indicates differences in death modes after low and high irradiance after similar total light doses. From a treatment perspective, these differences may be important.

  3. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen

    SciTech Connect

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-03

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, F{sub v}/F{sub m}, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H{sub 2}O{sub 2} production and greater increases in H{sub 2}O{sub 2}-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. - Highlights: • We employ two different types of photodynamic stress, white and brown necrosis. • We examine molecular mechanisms of antioxidative and detoxification systems. • ALA and OF develop differential actions of antioxidant and detoxification systems. • Coordinated mechanism of antioxidants and detoxification works against toxic ROS. • Detoxification system plays critical roles in protection against photodynamic stress.

  4. Tissue responses to hexyl 5-aminolevulinate-induced photodynamic treatment in syngeneic orthotopic rat bladder cancer model: possible pathways of action

    NASA Astrophysics Data System (ADS)

    Arum, Carl-Jørgen; Gederaas, Odrun A.; Larsen, Eivind L. P.; Randeberg, Lise L.; Hjelde, Astrid; Krokan, Hans E.; Svaasand, Lars O.; Chen, Duan; Zhao, Chun-Mei

    2011-02-01

    Orthotopic bladder cancer model in rats mimics human bladder cancer with respect to urothelial tumorigenesis and progression. Utilizing this model at pT1 (superficial stage), we analyze the tissue responses to hexyl 5-aminolevulinate-induced photodynamic therapy (HAL-PDT). In comparison to untreated rats, HAL-PDT causes little change in tumor-free rat bladder but induces inflammatory changes with increased lymphocytes and mononuclear cell infiltration in rat bladders with tumor. Immunohistochemistry reveals that HAL-PDT is without effect on proliferating cell nuclear antigen expression within the tumor and increases caspase-3 expression in both normal urothelium and the tumor. Transmission electron microscopy reveals severe mitochondrial damage, formations of apoptotic bodies, vacuoles, and lipofuscin bodies, but no microvillus-formed niches in HAL-PDT-treated bladder cancer rats. Bioinformatics analysis of the gene expression profile indicates an activation of T-cell receptor signaling pathway in bladder cancer rats without PDT. HAL-PDT increases the expression of CD3 and CD45RA in the tumor (determined by immunohistochemistry). We suggest that pathways of action of HAL-PDT may include, at least, activations of mitochondrial apoptosis and autophagy, breakdown of cancer stem cell niches, and importantly, enhancement of T-cell activation.

  5. Wavelength-dependent in-vitro and in-vivo photodynamic effects after sensitization with 5-aminolevulinic acid induced protoporphyrin IX

    NASA Astrophysics Data System (ADS)

    Szeimies, Rolf-Markus; Abels, Christoph; Fritsch, Clemens; Steinbach, Pia; Baeumler, Wolfgang; Messmann, Helmut; Goetz, Alwin E.; Goerz, Guenter; Landthaler, Michael

    1996-01-01

    Photodynamic therapy (PDT) with topically applied 5-aminolevulinic acid (ALA) is of growing interest, in particular in dermatology. Due to the fact that PDT with intravenously administered Photofrin is the only clinically approved sensitizer so far and is performed at a wavelength of 630 nm, this wavelength is also used in most experimental and clinical trials with ALA. In this study influence of irradiation with coherent light from a tunable dye laser at different wavelengths ranging from 625 to 649 nm was investigated. In in vitro experiments HaCaT immortalized human keratinocytes were sensitized with 30 (mu) g/ml ALA for 24 hrs. By determination of cell viability with the MTT test, best cell-killing effects were observed following irradiation at 635 nm. In an in vivo setting using an amelanotic melanoma (A-Mel-3) grown subcutaneously in Syrian Golden hamsters, these results were confirmed: tumor growth determined by measuring tumor volume increase after 28 days was less pronounced in animals treated with 100 mg/kg ALA i.v. and irradiated 2.5 hrs. later at 635 nm, as compared to animals receiving an equal dose and irradiated at 630 nm. This observation in vitro is probably due to large amounts of photosensitizing protoporphyrin IX (PP) localized in cell membranes which is visualized by confocal laser scanning microscopy (CLSM) and determined by HPLC analysis. These results suggest that in ALA-PDT when a coherent light source is used probably better results are achieved irradiating at 635 nm.

  6. eEF1A1 binds and enriches protoporphyrin IX in cancer cells in 5-aminolevulinic acid based photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fan, Zhichao; Cui, Xiaojun; Wei, Dan; Liu, Wei; Li, Buhong; He, Hao; Ye, Huamao; Zhu, Naishuo; Wei, Xunbin

    2016-05-01

    Photodynamic therapy (PDT) with protoporphyrin IX (PpIX), which is endogenously derived from 5-aminolevulinic acid (5-ALA) or its derivatives, is a promising modality for the treatment of both pre-malignant and malignant lesions. However, the mechanisms of how ALA-induced PpIX selectively accumulated in the tumors are not fully elucidated. Here we discovered that eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) interacted with PpIX (with an affinity constant of 2.96 × 106 M‑1). Microscopy imaging showed that ALA-induced PpIX was co-localized with eEF1A1 in cancer cells. eEF1A1 was found to enrich ALA-induced PpIX in cells by competitively blocking the downstream bioavailability of PpIX. Taken together, our study discovered eEF1A1 as a novel photosensitizer binding protein, which may play an essential role in the enrichment of ALA-induced PpIX in cancer cells during PDT. These suggested eEF1A1 as a molecular marker to predict the selectivity and efficiency of 5-ALA based PDT in cancer therapy.

  7. Inhibition of VDAC1 prevents Ca²⁺-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages.

    PubMed

    Chen, Haibo; Gao, Weiwei; Yang, Yang; Guo, Shuyuan; Wang, Huan; Wang, Wei; Zhang, Shuisheng; Zhou, Qi; Xu, Haobo; Yao, Jianting; Tian, Zhen; Li, Bicheng; Cao, Wenwu; Zhang, Zhiguo; Tian, Ye

    2014-12-01

    Ultrasound combined with endogenous protoporphyrin IX derived from 5-aminolevulinic acid (ALA-SDT) is known to induce apoptosis in multiple cancer cells and macrophages. Persistent retention of macrophages in the plaque has been implicated in the pathophysiology and progression of atherosclerosis. Here we investigated the effects of inhibition of voltage-dependent anion channel 1 (VDAC1) on ALA-SDT-induced THP-1 macrophages apoptosis. Cells were pre-treated with VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) disodium salt for 1 h or downregulated VDAC1 expression by small interfering RNA and exposed to ultrasound. Cell viability was assessed by MTT assay, and cell apoptosis along with necrosis was evaluated by Hoechst 33342/propidium iodide staining and flow cytometry. Levels of cytochrome c release was assessed by confocal microscope and Western blot. The levels of full length caspases, caspase activation, and VDAC isoforms were analyzed by Western blot. Intracellular reactive oxygen species generation, mitochondrial membrane permeability, and intracellular Ca(2+) [Ca(2+)]i levels were measured with fluorescent probes. We confirmed that the pharmacological inhibition of VDAC1 by DIDS notably prevented ALA-SDT-induced cell apoptosis in THP-1 macrophages. Additionally, DIDS significantly inhibited intracellular ROS generation and apoptotic biochemical changes such as inner mitochondrial membrane permeabilization, loss of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 and caspase-9. Moreover, ALA-SDT elevated the [Ca(2+)]i levels and it was also notably reduced by DIDS. Furthermore, both of intracellular ROS generation and cell apoptosis were predominately inhibited by Ca(2+) chelating reagent BAPTA-AM. Intriguingly, ALA-treatment markedly augmented VDAC1 protein levels exclusively, and the downregulation of VDAC1 expression by specific siRNA also significantly abolished cell apoptosis. Altogether, these

  8. Interstitial photodynamic therapy of canine prostate with meso-tetra-(m-hydroxyphenyl) chlorin and 5-aminolevulinic acid: a preliminary study

    NASA Astrophysics Data System (ADS)

    Chang, Shi-Chung; Buonaccorsi, Giovanni A.; MacRobert, Alexander J.; Bown, Stephen G.

    1996-01-01

    Photodynamic therapy (PDT) is proved to have potential for managing various malignancies. We investigated tissue biodistribution and photodynamic effects on a canine model in vivo using second generation photosensitizers, meso-tetra(m-hydroxyphenyl)chlorin (mTHPC) and 5-aminolaevulinic acid (ALA) to evaluate the feasibility and possible future application of PDT on the prostate. Using fluorescence microscopy, the optimal sensitization time of the prostate was between 24 - 72 hours with mTHPC and, 3 hours with ALA. After optimum time of sensitization, prostates of mature beagle were treated with laser at various sites by placing fiber interstitially under the guidance of transrectal ultrasound. The light dose for each treatment site was 100 J (100 mW for 1,000 seconds at the wavelength of 650 and 630 nm, respectively). With mTHPC, single laser fiber was able to induce organ confined PDT lesion as large as 20 by 18 by 18 mm in size. However, the PDT lesion with ALA was negligible 3 days after treatment. Physical distress manifested as urinary retention, poor appetite and body weigh loss, was more prominent with increasing number of treatment sites as a result of extensive prostatic swelling and urethral damages. However, these problems usually alleviated spontaneously 7 to 10 days after PDT. The characteristic histological changes were hemorrhagic necrosis and glandular destruction with preservation of interlobular collagen fibers. Urethral damage seen at the early stage healed by regeneration of urothelium in 4 weeks. We conclude that interstitial PDT with mTHPC is technically possible to produce extensive glandular necrosis in the normal prostate which heals safely and does not change the prostatic architecture. ALA, although it seems promising for bladder tumors, is much less effective than mTHPC on the prostate. With mTHPC, it might have the potential for treating prostate cancers localized in the periphery of the gland.

  9. In vitro study of cell death with 5-aminolevulinic acid based photodynamic therapy to improve the efficiency of cancer treatment

    NASA Astrophysics Data System (ADS)

    Firdous, S.; Nawaz, M.; Ikram, M.; Ahmed, M.

    2012-03-01

    Photodynamic therapy (PDT) is a kind of photochemo therapeutic treatment that exerts its effect mainly through the induction of cell death. Distinct types of cell death may be elicited by different PDT regimes. In this study, efforts are underway to optimize PDT protocols for improved efficacy and combination of all three PDT mechanisms involved in the different human carcinomas cell narcosis. Our in vitro cell culture experiments with 5-aminolevulanic acid (ALA) a clinically approved photiosensitizer (PS) and 635 nm laser light have yielded promising results, as follow: (1) (human cervical cancer (HeLa) cell line incubated, for 18 h, with 30 μg/ml of 5-ALA, treated with laser light dose of 50 J/cm2 can produce 85% of cell killing (2) human larynx carcinoma (Hep2c) cell line incubated, for 7 h, with 55 μg/ml of 5-ALA, treated with laser light dose of 85 J/cm2 can produce 75% of cell killing (3) human liver cancer (HepG2) cell line incubated, for 22-48 h, with 262 μg/ml of 5-ALA, treated with laser light dose of 120 J/cm2 can produce 95% of cell killing (4) human muscle cancer (RD) cell line incubated, for 47 h, with 250 μg/ml of 5-ALA, treated with laser light dose of 80 J/cm2 can produce 76% of cell killing (5) Human embryonic kidney (HEK293T) cell line incu-bated, for 18 h, with 400 μg/ml of 5-ALA, treated with laser light dose of 40 J/cm2 can produce 82% of cell killing confirming the efficacy of photodynamic therapy.

  10. Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): current clinical and development status

    NASA Astrophysics Data System (ADS)

    Marcus, Stuart L.; Sobel, Russel S.; Golub, Allyn L.; Carroll, Ronald L.; Lundahl, Scott L.; Shulman, D. Geoffrey

    1996-04-01

    Exogenous provision of ALA to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX, (PpIX), to produce a photodynamic effect. Therefore, ALA may be considered the only current PDT agent in clinical development which is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous T-cell lymphoma, superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses, and is also being examined for treatment of acne and hirsutism. PpIX induced by ALA application also may serve as a fluorescence detection marker for photodiagnosis (PD) of malignant and pre- malignant conditions of the urinary bladder and other organs. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and is beginning to be examined in human clinical studies. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This brief paper reviews the current clinical and development status of ALA PDT.

  11. Low-Dose Topical 5-Aminolevulinic Acid Photodynamic Therapy in the Treatment of Different Severity of Acne Vulgaris.

    PubMed

    Tao, Shi-Qin; Li, Fei; Cao, Lei; Xia, Ru-Shan; Fan, Hua; Fan, Ying; Sun, Hui; Jing, Cheng; Yang, Li-Jia

    2015-12-01

    The objective of this article is to investigate the effectiveness and safety of photodynamic therapy (PDT) with 3.6 % topical aminolevulinic acid (ALA) and a short incubation time with red light in moderate to severe acne. One hundred and thirty-six patients with moderate to severe acne were treated with 3.6 % topical ALA-PDT for three sessions with an interval of 2 weeks. Patients were evaluated for efficacy and safety on week 2, 4, 6, 8, and 12 after the initial treatment. Most patients showed apparent clearance of acne lesions at the treated site after three sessions. The effective treatment rates were increased after the multiple therapies. The clinical outcomes are the best at 4 weeks after the final treatment. The total effectiveness rate and cure rate of the low-dose ALA-PDT procedure is 92.65 and 47.06 %, respectively. Thirty-one patients and nineteen patients showed apparent exacerbation of acne lesions before the 2nd and 3rd treatment, respectively, but all of them showed good or excellent improvement after a three-course treatment. A few patients showed mild relapse including papules and comedos at 8 weeks after the final treatment. No significant differences are found in the effects of different acne severity and different genders. Adverse reactions are mild and transient. A 3.6 % topical ALA-PDT with a short time incubation with red light is a simple and an effective treatment option for moderate to severe acne with mild side effects in Chinese people.

  12. Homology Modeling of Human γ-Butyric Acid Transporters and the Binding of Pro-Drugs 5-Aminolevulinic Acid and Methyl Aminolevulinic Acid Used in Photodynamic Therapy

    PubMed Central

    Baglo, Yan; Gabrielsen, Mari; Sylte, Ingebrigt; Gederaas, Odrun A.

    2013-01-01

    Photodynamic therapy (PDT) is a safe and effective method currently used in the treatment of skin cancer. In ALA-based PDT, 5-aminolevulinic acid (ALA), or ALA esters, are used as pro-drugs to induce the formation of the potent photosensitizer protoporphyrin IX (PpIX). Activation of PpIX by light causes the formation of reactive oxygen species (ROS) and toxic responses. Studies have indicated that ALA and its methyl ester (MAL) are taken up into the cells via γ-butyric acid (GABA) transporters (GATs). Uptake via GATs into peripheral sensory nerve endings may also account for one of the few adverse side effects of ALA-based PDT, namely pain. In the present study, homology models of the four human GAT subtypes were constructed using three x-ray crystal structures of the homologous leucine transporter (LeuT) as templates. Binding of the native substrate GABA and the possible substrates ALA and MAL was investigated by molecular docking of the ligands into the central putative substrate binding sites in the outward-occluded GAT models. Electrostatic potentials (ESPs) of the putative substrate translocation pathway of each subtype were calculated using the outward-open and inward-open homology models. Our results suggested that ALA is a substrate of all four GATs and that MAL is a substrate of GAT-2, GAT-3 and BGT-1. The ESP calculations indicated that differences likely exist in the entry pathway of the transporters (i.e. in outward-open conformations). Such differences may be exploited for development of inhibitors that selectively target specific GAT subtypes and the homology models may hence provide tools for design of therapeutic inhibitors that can be used to reduce ALA-induced pain. PMID:23762315

  13. Lack of selectivity of protoporphyrin IX fluorescence for basal cell carcinoma after topical application of 5-aminolevulinic acid: implications for photodynamic treatment.

    PubMed

    Martin, A; Tope, W D; Grevelink, J M; Starr, J C; Fewkes, J L; Flotte, T J; Deutsch, T F; Anderson, R R

    1995-01-01

    Clinical trials of topical ALA in photodynamic therapy (PDT) of basal cell carcinoma (BCC) show significant recurrence rates. Exogenous 5-aminolevulinic acid (ALA) is converted by intracellular enzymes to photoactive protoporphyrin IX (PpIX) in human tissues. PpIX generates cytotoxic singlet oxygen when irradiated with visible light in the 400-640 nm range. To evaluate variability and heterogeneity in PpIX production by tumors in such trials, and to assess the usefulness of PpIX for marking skin tumors, we measured PpIX fluorescence distribution in BCC after topical application of 20% ALA cream. ALA cream was applied under occlusion for periods ranging from 3 to 18 h (average 6.9 h, SD 4 h) to 16 BCCs. ALA conversion to PpIX in the BCCs was assessed by in vivo photography, ex vivo video fluorescence imaging, and fluorescence microscopy. External macroscopic PpIX fluorescence, as assessed by in vivo and ex vivo imaging, correlated with the clinical presence of BCC. Examination by a digital imaging fluorescence microscope revealed inter- and intratumor fluorescence variability and heterogeneity. PpIX fluorescence corresponding to full tomor thickness was found in six superficial and four nodular tumors, and partial-thickness fluorescence was observed in five nodular tumors, but no PpIX fluorescence was observed in some areas of superficial, nodular and infiltrating tumors. In a significant number of nodular and infiltrating BCCs, topical ALA appeared to provide little or no PpIX in deep tumor lobules. In addition, no selectivity for tumor tissue versus normal epidermis was seen. The grossly brighter external PpIX fluorescence over tumors may be due, therefore, to enhanced penetration through tumor-reactive stratum corneum and to the tumor thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Characterization of a pseudo ternary phase diagram of poloxamer 407 systems for potential application of 5-aminolevulinic acid in photodynamic therapy.

    PubMed

    van Hemelrijck, Carlos; Müller-Goymann, Christel C

    2011-11-28

    A poloxamer 407 (POX) gel containing dimethyl isosorbide (DMIS), isopropyl alcohol (IPA), propylene glycol dicaprylocaprate (MIG) and water has been suggested in a previous study for permeation enhancement of 5-aminolevulinic acid (ALA) across isolated human stratum corneum. The purpose of this study was to characterize other formulations coming from the same pseudo ternary phase diagram as the "Thermogel" in order to find out which of them show appropriate characteristics to be used as a vehicle for ALA since it could be shown that variation of the ingredients' content had an influence on the permeation rate. A pseudo ternary phase diagram was developed with water, a fixed combination of 1:1 of IPA and DMIS and a fixed ratio of 4:1 POX to MIG. The systems were categorized according to their consistencies and ringing gel characteristics with special emphasis on appropriate formulations for dermal application. Polarizing microscopy enabled a clear differentiation between isotropic and anisotropic systems. Wide angle X-ray diffraction analyzes confirmed that anisotropy was due to crystalline POX. Furthermore both methods showed that IPA/DMIS was an inferior solvent mixture for POX related to water.

  15. Photodynamic Therapy (PDT) using intratumoral injection of the 5- aminolevulinic acid (5-ALA) for the treatment of eye cancer in cattle

    NASA Astrophysics Data System (ADS)

    Hage, Raduan; Mancilha, Geraldo; Zângaro, Renato A.; Munin, Egberto; Plapler, Hélio

    2007-02-01

    A six-year old Holstein cow with an eye cancer (ocular squamous cell carcinoma) involving the third eyelid and conjunctiva was submitted to photodynamic therapy using intratumoral 20% aminolevulinic acid (5-ALA - Aldrich Chemical Company, Milwaukee, USA) and a light emitting diode (LED - VET LED - MMOptics (R)) with wavelength between 600 and 700 nm, 2 cm diameter circular light beam, power of 150 mW, light dose of 50 J/cm2 as a source of irradiation. Fifteen days after the experimental procedure we observed about 50% tumor reduction and complete remission after 3 months. Relapse was not observed up to 12 months after the treatment. Although the study only includes one animal not allowing definite conclusions, it indicates that PDT represents a safe and technically feasible approach in the treatment of eye cancer in cattle.

  16. In vitro study of 5-aminolevulinic acid-based photodynamic therapy for apoptosis in human cervical HeLa cell line

    NASA Astrophysics Data System (ADS)

    Atif, M.; Firdous, S.; Khurshid, A.; Noreen, L.; Zaidi, S. S. Z.; Ikram, M.

    2009-12-01

    5-aminolevulanic acid (ALA), belonging among the promising second generation of sensitizers, was evaluated as an inducer of photodamage on HeLa (human cervical adenocarcinoma) cell line. A diode laser (635 nm) was used as a source for initiation of the photodynamic effect. We studied the influence of different incubation times, various concentrations of sensitizer, different irradiation doses and various combinations of sensitizer and light doses on the photodamage of HeLa cells. Viability of cells was determined by means of neutral red assay. The quantitative cellular uptake of ALA sensitizer was done by spectrophotometric measurements. No prominent cytotoxic or phototoxic effects on HeLa were observed due to sensitizer or light doses when studied independently of each other. However phototoxicity evoked by laser irradiated sensitizer was detected in HeLa cell line.

  17. Photodynamic therapy of human skin tumors using topical application of 5-aminolevulinic acid, dimethylsulfoxide (DMSO), and edetic acid disodium salt (EDTA)

    NASA Astrophysics Data System (ADS)

    Orenstein, Arie; Kostenich, Gennady; Tsur, H.; Roitman, Leonid; Ehrenberg, Benjamin; Malik, Zvi

    1995-01-01

    The results of photodynamic therapy (PDT) in 48 patients bearing basal cell carcinoma (BCC) and 7 patients with squamous cell carcinoma (SCC) of the skin are described. Five- aminolevulinic acid (5-ALA) was applied topically in two formulations. The first formulation contained 20% of 5-ALA in a base cream, and the second formulation (5-ALA composite cream), contained an additional 2% of dimethylsulfoxide (DMSO) and 2% of edetic acid disodium salt (EDTA). The creams were left on the skin for 2 - 5 hours. Production of protoporphyrin (PP) was measured in situ by a laser-induced fluorescence (LIF) method. The results of fluorescence measurement clearly indicate that PP accumulation in tumors induced by the 5-ALA composite cream was markedly higher than that induced by the 5-ALA cream. The tumors were light-irradiated (600 - 720 nm) after 4 - 5 hours of cream applications, using the light delivery system Versa-Light by a light dose of 100 J/cm2. The clinically superficial BCC tumors were highly responsive to PDT; the overall result in BCC patients was an 85.4% complete response. Histological examination showed an initial edematous reaction, followed by necrosis and complete disappearance of the tumor. The superficial SCC tumors showed a 100% complete response after PDT. The ulcerated nodular SCC showed partial responses.

  18. Photofrin and 5-aminolevulinic acid permeation through oral mucosa in vitro

    NASA Astrophysics Data System (ADS)

    Flock, Stephen T.; Alleman, Anthony; Lehman, Paul; Blevins, Steve; Stone, Angie; Fink, Louis; Dinehart, Scott; Stern, Scott J.

    1994-07-01

    Photofrin and 5-aminolevulinic acid are photosensitizers that show promise in the photodynamic treatment of cancer, port-wine stains, atherosclerosis and viral lesions. Photofrin is a mixture of porphyrins which, upon the absorption of light, become temporarily cytotoxic. One side-effect associated with the use of Photofrin is long-term cutaneous photosensitivity. It is possible that topical application of this photosensitizing dye will ameliorate such a side-effect. Another way to avoid the cutaneous photosensitivity in photodynamic therapy is to use 5- aminolevulinic acid, which is a porphyrin precursor that causes an increase in the synthesis and concentration of the photosensitizer protoporphyrin IX. 5-aminolevulinic acid is usually applied topically, and so minimizes cutaneous photosensitivity while maximizing the local protoporphyrin concentration. There are a host of disorders in oral mucosa that are potentially treatable by photodynamic therapy. However, since stratum corneum presents an impermeable barrier to many pharmaceuticals, it is not clear that topical application of the photosensitizer will result in a clinically relevant tissue concentration. We have therefore studied the permeation behavior of Photofrin and 5-aminolevulinic acid by applying them to the surface of ex vivo oral mucosa tissue positioned by a Franz diffusion cell. In order to increase the permeability of the photosensitizer across the stratum corneum, we studied the effects of four different drug carriers: phosphate buffered saline, dimethylsulfoxide, ethanol and Azone with isopropyl alcohol.

  19. Chemically triggered release of 5-aminolevulinic acid from liposomes*

    PubMed Central

    Plaunt, Adam J.; Harmatys, Kara M.; Hendrie, Kyle A.; Musso, Anthony J.

    2014-01-01

    5-Aminolevulinic acid (5-ALA), a prodrug of Protoporphyrin IX (PpIX), is used for photodynamic therapy of several medical conditions, and as an adjunct for fluorescence guided surgery. The clinical problem of patient photosensitivity after systemic administration could likely be ameliorated if the 5-ALA was delivered more selectivity to the treatment site. Liposomal formulations are inherently attractive as targeted delivery vehicles but it is hard to regulate the spatiotemporal release of aqueous contents from a liposome. Here, we demonstrate chemically triggered leakage of 5-ALA from stealth liposomes in the presence of cell culture. The chemical trigger is a zinc(II)-dipicolylamine (ZnBDPA) coordination complex that selectively targets liposome membranes containing a small amount of anionic phosphatidylserine. Systematic screening of several ZnBDPA complexes uncovered a compound with excellent performance in biological media. Cell culture studies showed triggered release of 5-ALA from stealth liposomes followed by uptake into neighboring mammalian cells and intracellular biosynthesis to form fluorescent PpIX. PMID:25414791

  20. Clearance of protoporphyrin IX induced by 5-aminolevulinic acid from WiDr human colon carcinoma cells

    NASA Astrophysics Data System (ADS)

    Juzeniene, Asta; Kaliszewski, Miron; Bugaj, Andrzej; Moan, Johan

    2009-06-01

    5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is the most widely practiced form of PDT in dermatology. One of the advantages of ALA-PDT is that undesirable photosensitization lasts only for 24-48 h. In order to optimize ALA-PDT it is necessary to understand the mechanisms controlling intracellular PpIX clearance (efflux and transformation into heme) in order to decrease protoporphyrin IX (PpIX) clearance rates in the early stages of its production. The aim of this study was to investigate the factors controlling the clearance of intracellular PpIX. Fluorescence spectroscopy was used to study PpIX kinetics in WiDr cells initially treated with ALA. The clearance rate of PpIX in WiDr cells was faster after application of a low concentration of ALA (0.1 mM) than after application of high concentration of ALA (1 mM). PpIX was cleared faster from cells which initially were seeded at low densities than cells seeded at higher densities. The presence of the iron chelator deferoxamine reduced the clearance rate of PpIX, while the presence of ferrous sulfate acted oppositely. The decay rate of PpIX in WiDr cells was faster at higher temperature than at lower. The ferrochelatase activity at pH 7.2 was significantly greater than that at pH 6.7. ALA concentration, application time, cell density, temperature, pH, intracellular iron content, intracellular amount and localization of PpIX are factors controlling PpIX clearance.

  1. Fractional radiofrequency combined with sonophoresis to facilitate skin penetration of 5-aminolevulinic acid.

    PubMed

    Park, Jong Min; Jeong, Ki-Heon; Bae, Myong Il; Lee, Sang-Jun; Kim, Nack-In; Shin, Min Kyung

    2016-01-01

    Ablative fractional technology has been used to improve transdermal drug delivery. However, there have been few previous in vivo investigations of the relative potency and methodology of fractional radiofrequency (RF) combined with sonophoresis. The purpose of this study was to investigate the effects of fractional RF combined with sonophoresis on 5-aminolevulinic acid (ALA) penetration of the skin. Three male domestic swine were used. The skin of the pigs was exposed to fractional RF and/or sonophoresis, followed by topical ALA application. Fluorescence intensity (FI) of porphyrin fluorescence was measured. In both the epidermis and the dermis, FI increased after fractional RF and increased additionally with the addition of sonophoresis. Fractional RF with sonophoresis effectively enhanced ALA skin penetration. Pre-fractional RF followed by posttreatment with sonophoresis can be used for ALA-photodynamic therapy to achieve higher ALA uptake.

  2. Treatment of oral leukoplakia by topical application of 5-aminolevulinic acid.

    PubMed

    Kübler, A; Haase, T; Rheinwald, M; Barth, T; Mühling, J

    1998-12-01

    A new therapy for the treatment of oral leukoplakia by 5-aminolevulinic acid (ALA) and photodynamic therapy (PDT) is presented. ALA, a precursor in the biosynthesis of haeme, induces the production of the endogenous photosensitizer protoporphyrin IX which can be used for PDT. Twelve patients, who had been suffering from leukoplakia of the oral mucosa for several years, were treated by ALA-mediated PDT. ALA was used as a topical photosensitizer and 20% ALA cream was applied to the leukoplakia lesion of the oral mucosa for two hours and then light activated at 630 nm, 100 mW/cm2 and 100 J/cm2. Five patients showed complete response to the treatment, four patients showed a partial response and in three patients treatment was unsuccessful. One patient with partial response was retreated, after which the lesion disappeared.

  3. Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity dependent on photoactivation

    NASA Astrophysics Data System (ADS)

    Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

    2009-06-01

    New approaches to PDT using multifunctional 5-aminolevulinic acid (ALA) based prodrugs activating mutual routes of toxicity are described. We investigated the mutual anti-cancer activity of ALA prodrugs which upon metabolic hydrolysis by unspecific esterases release ALA, formaldehyde or acetaldehye and the histone deacetylase inhibitor (HDACI) butyric acid. The most potent prodrug in this study was butyryloxyethyl 5-amino-4-oxopentanoate (AN-233) that stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells and generated an efficient photodynamic destruction. AN-233 induced a considerable high level of intracellular ROS in the cells following light irradiation, reduction of mitochondrial activity, dissipation of the mitochondrial membrane potential resulting in necrotic and apoptotic cell death. The main advantage of AN-233 over ALA stems from its ability to induce photodamage at a significantly lower dose than ALA.

  4. In vitro studies on the potential use of 5-aminolaevulinic acid-mediated photodynamic therapy for gynaecological tumours.

    PubMed Central

    Rossi, F. M.; Campbell, D. L.; Pottier, R. H.; Kennedy, J. C.; Dickson, E. F.

    1996-01-01

    Results are reported on the sensitivity of various gynaecological tumour cell lines to 5-aminolaevulinic acid-induced protoporphyrin IX-sensitised photodynamic therapy (ALA-PDT) in vitro. All cell lines tested accumulated ALA-induced protoporphyrin IX (PpIX) and demonstrated good sensitivity to ALA-PDT. Localisation of PpIX in the mitochondria was demonstrated by fluorescence microscopy. Subcellular damage following ALA-PDT was observed using transmission electron microscopy. This damage was localised initially to the mitochondria, with damage to membranes and the nucleus and complete loss of intracytoplasmic organisation being observed subsequently. There was no apparent difference in ALA-PDT response between a multidrug-resistant ovarian carcinoma cell line and its parent line. These results indicate that ALA-PDT has potential for application to therapy of gynaecological malignancies. Images Figure 5 Figure 6 Figure 7 PMID:8826853

  5. Reaction of acetaldehyde with 5-aminolevulinic acid via dihydropyrazine derivative.

    PubMed

    Suzuki, Toshinori; Yasuhara, Naoki; Ueda, Takashi; Inukai, Michiyo; Mio, Mitsunobu

    2015-01-01

    When a solution of 5-aminolevulinic acid (ALA) was incubated with acetaldehyde at neutral pH, a product was generated. This product was identified as 3-ethylpyrazine-2,5-dipropanoic acid (ETPY). ETPY was stable at neutral pH. It has been reported that ALA dimerizes at neutral pH generating 3,6-dihydropyrazine-2,5-dipropanoic acid (DHPY), and subsequently resulting in pyrazine-2,5-dipropanoic acid (PY) by autoxidation. In the present reaction, DHPY generated from ALA reacted with acetaldehyde, resulting in ETPY. Preadministration of ALA 3 min prior to acetaldehyde injection supressed the toxicity of acetaldehyde in male mice. These results suggest that ALA may be useful as a scavenger for acetaldehyde.

  6. Physicochemical characterisation of a novel thermogelling formulation for percutaneous penetration of 5-aminolevulinic acid.

    PubMed

    Grüning, Nadja; Müller-Goymann, Christel Charlotte

    2008-06-01

    The present contribution was dedicated to the development and characterisation of a semisolid formulation of 5-aminolevulinic acid (5-ALA), appropriate for the diagnosis and treatment of actinic keratosis in photodynamic therapy. To achieve sufficiently high concentrations of the polar substance within the living epithelium after topical application, the semisolid base was enriched with penetration enhancers. A semisolid liquid crystalline system for drug delivering was the formulation of choice. It was composed of isopropyl alcohol, dimethyl isosorbide, medium chain triglycerides, water, and Pluronic F 127 as a polyoxyethylene-polyoxypropylene surface-active block copolymer. Rheometrical investigations were performed in the oscillatory mode and showed a thermo reversible gelification behaviour of the formulation, which therefore was denoted Thermogel. Permeation studies through human stratum corneum revealed higher permeation coefficients for 5-ALA from the Thermogel than from different German Pharmacopoeia creams. For example a 7.5-fold increase in comparison with Basiscreme DAC, and a 19.5-fold increase compared to water containing hydrophilic ointment. With respect to Dolgit(R) Mikrogel, the permeation coefficient from the Thermogel was 6.4-fold higher. These results were in accordance with those of differential scanning calorimetry measurements. Thermogel disclosed the strongest interactions with stratum corneum lipids.

  7. Fluorescence photodetection of head and neck cancer following topical or systemic application of 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Leunig, Andreas; Rick, Kai; Stepp, Herbert G.; Gutmann, Ralph; Goetz, Alwin E.; Baumgartner, Reinhold; Feyh, Jens

    1996-12-01

    The aim of photodynamic diagnosis is the complete visualization of all neoplastic lesions in a tumorous organ after topical or systemic application of a tumor selective photosensitizer. In this investigation we performed quantitative fluorescence measurements following topical and systemic application of 5-aminolevulinic acid to head and neck tumors. We investigated 15 patients with neoplastic lesions of the oral cavity and 5 patients with carcinoma of the larynx after rinsing a 0.4 percent-5-ALA solution or inhalation 5 percent-5-ALA. One patient was given 5-ALA systemically p.o. in a concentration of 10mg/kg b.w. Time course and type of porphyrin accumulation were analyzed in neoplastic and surrounding normal tissue by measuring emission spectra of ALA-induced protoporphyrin IX fluorescence at regular intervals for up to 3 hours following 15 minutes of continuous rinsing of a 0.4 percent- ALA-solution, 1 hour of continuous inhalation and 3 hours after p.o. application. After excitation with violet light of a high pressure xenon arc lamp, fluorescence images in the red spectral range from the tumor tissue and the corresponding macroscopic visible tumor were recorded with a CCD-camera. A quantitative analysis of the fluorescence contrast in neoplastic and surrounding tissue was performed using an optical multichannel analyzer.

  8. Interference with the Jaffé Method for Creatinine Following 5-Aminolevulinic Acid Administration

    PubMed Central

    Quon, Harry; Grossman, Craig E.; King, Rebecca L.; Putt, Mary; Donaldson, Keri; Kricka, Larry; Finlay, Jarod; Malloy, Kelly; Cengel, Keith A.; Busch, Theresa M.

    2013-01-01

    Background The photosensitizer pro-drug 5-aminolevulinic acid (5-ALA) has been administered systemically for photodynamic therapy. Although several toxicities have been reported, nephrotoxicity has never been observed. Materials and Methods Patients with head and neck mucosal dysplasia have been treated on a phase 1 study of escalating light doses in combination with 60 mg/kg of oral 5-ALA. Serum creatinine was measured with the modified Jaffe method or an enzymatic method in the first 24 hours after 5-ALA. Interference by 5-ALA, as well as by its photosensitizing product protoporphyrin IX, was assessed. Results Among 11 subjects enrolled to date, 9 of 11 had blood chemistries collected within the first 5 hours with 7 demonstrating significant grade 3 creatinine elevations (p=0.030). There was no additional evidence of compromised renal function or increased PDT-induced mucositis. Creatinine levels measured by the Jaffe assay increased linearly as a function of the ex-vivo addition of ALA (p<.0001). The exogenous addition of PpIX did not alter creatinine levels. ALA did not interfere with creatinine levels as measured by an enzymatic assay. A total of 4 of the 11 subjects had creatinine levels prospectively measured by both the Jaffe and the enzymatic assays. Only the Jaffe method demonstrated significant elevations as a function of time after ALA administration. Conclusions The transient increase in creatinine after systematic ALA can be attributed, in part, if not entirely, to interference of ALA in the Jaffe reaction. Alternative assays should be employed in situations calling for monitoring of kidney function after systemic ALA. PMID:21112550

  9. A Formulation Study of 5-Aminolevulinic Encapsulated in DPPC Liposomes in Melanoma Treatment

    PubMed Central

    Lin, Ming-Wei; Huang, Yaw-Bin; Chen, Chun-Lin; Wu, Pao-Chu; Chou, Chien-Ying; Wu, Ping-Ching; Hung, Shih-Ya

    2016-01-01

    Photodynamic therapy (PDT) is a widely used technique for epithelial skin cancer treatment. 5-aminolevulinic acid (5-ALA) is a drug currently used for PDT and is a hydrophilic molecule at its physiological pH, and this limits its capacity to cross the stratum corneum of skin. Since skin penetration is a key factor in the efficacy of topical 5-ALA-mediated PDT, numerous strategies have been proposed to improve skin penetration. Yet this problem is still ongoing. The results of a previous study showed a low rate of 5-ALA encapsulated in liposomes (5.7%) that were 400 nm in size. In the present study, we used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as vehicles and tested their delivery efficacy of 5-ALA-medicated PDT both in vitro and in vivo. Our data shows that 5-ALA encapsulated in 0.1 or 0.5% DPPC liposomes (5-ALA/DPPC) had a better encapsulated rate (15~16%) and were smaller in size (84~89 nm). We found the 5-ALA/DPPC formulation reduced cell viability, mitochondria membrane potential, and enhanced intracellular ROS accumulation as compared to 5-ALA alone in melanoma cells. Furthermore, the 5-ALA/DPPC formulation also had better skin penetration ability as compared to the 5-ALA in our ex vivo data by assaying 5-ALA converted into protoporphyrin IX (PpIX) in the skin of the mice that were experimented on. In melanoma xenograft models, 5-ALA/DPPC enhanced PpIX accumulation only in tumor tissue but not normal skin. In conclusion, we found DPPC liposomes to be good carriers for 5-ALA delivery and believe that they may prove useful in 5-ALA-mediated PDT in the future. PMID:27429584

  10. Mesoporous nanocarriers for the loading and stabilization of 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Miletto, Ivana; Bottinelli, Emanuela; Siviero, Andrea; Fabbri, Debora; Calza, Paola; Berlier, Gloria

    2016-08-01

    Mesoporous nanoparticles bearing different surface functionalizations were proposed as host carrier for the loading and stabilization of 5-aminolevulinic acid: unmodified mesoporous silica nanoparticles exposing native silanols and aminopropyltriethoxysilane-grafted mesoporous silica nanoparticles exposing amino groups. The stability of 5-aminolevulinic acid at different steps of drug loading was monitored via electronic and vibrational spectroscopies. Unmodified mesoporous nanoparticles were found to be a host system ensuring the stability of 5-aminolevulinic acid and its availability as protoporphyrin IX precursor, whilst silica surface exposing amino groups was found to strongly favour the dimerization of 5-aminolevulinic acid, leading to the formation of the derived compound pyrazine-2,5-dipropionic acid which is considered to be the major ALA degradation product in aerated solutions, which is no longer active as precursor of protoporphyrin IX. This phenomenon is interpreted in terms of the basic character of amino-modified silica.

  11. 5-AMINOLEVULINATE SYNTHASE: CATALYSIS OF THE FIRST STEP OF HEME BIOSYNTHESIS

    PubMed Central

    Hunter, G. A.; Ferreira, G. C.

    2010-01-01

    5-Aminolevulinate synthase is a homodimeric pyridoxal 5’-phosphate-dependent enzyme that catalyzes the first step of the heme biosynthetic pathway in animals, fungi, and the α-subclass of the photosynthetic purple bacteria. The reaction cycle involves condensation of glycine with succinyl-coenzyme A to yield 5-aminolevulinate, carbon dioxide, and CoA. Mutations in the human erythroid-specific aminolevulinate synthase gene are associated with the erythropoietic disorder X-linked sideroblastic anemia. Recent kinetic and crystallographic data have facilitated an unprecedented understanding of how this important enzyme produces 5-aminolevulinate, and suggest possible directions for future research that may lead to treatments not only for X-linked sideroblastic anemia, but also other diseases. PMID:19268008

  12. Fluorescent detection of peritoneal metastasis in human colorectal cancer using 5-aminolevulinic acid

    PubMed Central

    KONDO, YUTAKA; MURAYAMA, YASUTOSHI; KONISHI, HIROTAKA; MORIMURA, RYO; KOMATSU, SHUHEI; SHIOZAKI, ATSUSHI; KURIU, YOSHIAKI; IKOMA, HISASHI; KUBOTA, TAKESHI; NAKANISHI, MASAYOSHI; ICHIKAWA, DAISUKE; FUJIWARA, HITOSHI; OKAMOTO, KAZUMA; SAKAKURA, CHOUHEI; TAKAHASHI, KIWAMU; INOUE, KATSUSHI; NAKAJIMA, MOTOWO; OTSUJI, EIGO

    2014-01-01

    A precise diagnosis of peritoneal dissemination is necessary to determine the appropriate treatment strategy for colorectal cancer. However, small peritoneal dissemination is difficult to diagnose. 5-aminolevulinic acid (5-ALA) is an intermediate substrate of heme metabolism. The administration of 5-ALA to cancer patients results in tumor-specific accumulation of protoporphyrin IX (PpIX), which emits red fluorescence with blue light irradiation. We evaluated the usefulness of photodynamic diagnosis (PDD) using 5-ALA to detect the peritoneal dissemination of colorectal cancer. EGFP-tagged HT-29 cells were injected into the peritoneal cavity of BALB/c nude mice. After 2 weeks, the mice were given 5-ALA hydrochloride, and metastatic nodules in the omentum were observed with white light and fluorescence images. Twelve colorectal cancer patients suspected to have serosal invasion according to preoperative computed tomography (CT) were enrolled in this study. 5-ALA (15-20 mg per kg body weight) was administered orally to the patients 3 h before surgery. The abdominal cavity was observed under white light and fluorescence. Fluorescence images were analyzed with image analysis software (ImageJ 1.45s, National Institutes of Health, Bethesda, MD, USA). The mice developed peritoneal disseminations. The observed 5-ALA-induced red fluorescence was consistent with the EGFP fluorescent-positive nodules. Peritoneal dissemination was observed with conventional white light imaging in 8 patients. All nodules suspected as being peritoneal dissemination lesions by white light observation were similarly detected by ALA-induced fluorescence. In 1 patient, a small, flat lesion that was missed under white light observation was detected by ALA-induced fluorescence; the lesion was pathologically diagnosed as peritoneal metastasis. In the quantitative fluorescence image analysis, the red/(red + green + blue) ratio was higher in the metastatic nodules compared to the non-metastatic sites of

  13. 5-aminolevulinic acid for quantitative seek-and-treat of high-grade dysplasia in Barrett's esophagus cellular models.

    PubMed

    Yeh, Shu-Chi Allison; Ling, Celine S N; Andrews, David W; Patterson, Michael S; Diamond, Kevin R; Hayward, Joseph E; Armstrong, David; Fang, Qiyin

    2015-02-01

    High-grade dysplasia (HGD) in Barrett’s esophagus (BE) poses increased risk for developing esophageal adenocarcinoma. To date, early detection and treatment of HGD regions are still challenging due to the sampling error from tissue biopsy and relocation error during the treatment after histopathological analysis. In this study, CP-A (metaplasia) and CP-B (HGD) cell lines were used to investigate the “seek-and-treat” potential using 5-aminolevulinic acid-induced protoporphyrin IX (PpIX). The photodynamic therapy photosensitizer then provides both a phototoxic effect and additional image contrast for automatic detection and real-time laser treatment. Complementary to our studies on automatic classification, this work focused on characterizing subcellular irradiation and the potential phototoxicity on both metaplasia and HGD. The treatment results showed that the HGD cells are less viable than metaplastic cells due to more PpIX production at earlier times. Also, due to mitochondrial localization of PpIX, a better killing effect was achieved by involving mitochondria or whole cells compared with just nucleus irradiation in the detected region. With the additional toxicity given by PpIX and potential morphological/textural differences for pattern recognition, this cellular platform serves as a platform to further investigate real-time “seek-and-treat” strategies in three-dimensional models for improving early detection and treatment of BE.

  14. 5-aminolevulinic acid for quantitative seek-and-treat of high-grade dysplasia in Barrett's esophagus cellular models

    NASA Astrophysics Data System (ADS)

    Yeh, Shu-Chi Allison; Ling, Celine S. N.; Andrews, David W.; Patterson, Michael S.; Diamond, Kevin R.; Hayward, Joseph E.; Armstrong, David; Fang, Qiyin

    2015-02-01

    High-grade dysplasia (HGD) in Barrett's esophagus (BE) poses increased risk for developing esophageal adenocarcinoma. To date, early detection and treatment of HGD regions are still challenging due to the sampling error from tissue biopsy and relocation error during the treatment after histopathological analysis. In this study, CP-A (metaplasia) and CP-B (HGD) cell lines were used to investigate the "seek-and-treat" potential using 5-aminolevulinic acid-induced protoporphyrin IX (PpIX). The photodynamic therapy photosensitizer then provides both a phototoxic effect and additional image contrast for automatic detection and real-time laser treatment. Complementary to our studies on automatic classification, this work focused on characterizing subcellular irradiation and the potential phototoxicity on both metaplasia and HGD. The treatment results showed that the HGD cells are less viable than metaplastic cells due to more PpIX production at earlier times. Also, due to mitochondrial localization of PpIX, a better killing effect was achieved by involving mitochondria or whole cells compared with just nucleus irradiation in the detected region. With the additional toxicity given by PpIX and potential morphological/textural differences for pattern recognition, this cellular platform serves as a platform to further investigate real-time "seek-and-treat" strategies in three-dimensional models for improving early detection and treatment of BE.

  15. Enhancement of 5-aminolevulinic acid-based fluorescence detection of side population-defined glioma stem cells by iron chelation

    PubMed Central

    Wang, Wenqian; Tabu, Kouichi; Hagiya, Yuichiro; Sugiyama, Yuta; Kokubu, Yasuhiro; Murota, Yoshitaka; Ogura, Shun-ichiro; Taga, Tetsuya

    2017-01-01

    Cancer stem cells (CSCs) are dominantly responsible for tumor progression and chemo/radio-resistance, resulting in tumor recurrence. 5-aminolevulinic acid (ALA) is metabolized to fluorescent protoporphyrin IX (PpIX) specifically in tumor cells, and therefore clinically used as a reagent for photodynamic diagnosis (PDD) and therapy (PDT) of cancers including gliomas. However, it remains to be clarified whether this method could be effective for CSC detection. Here, using flow cytometry-based analysis, we show that side population (SP)-defined C6 glioma CSCs (GSCs) displayed much less 5-ALA-derived PpIX fluorescence than non-GSCs. Among the C6 GSCs, cells with ultralow PpIX fluorescence exhibited dramatically higher tumorigenicity when transplanted into the immune-deficient mouse brain. We further demonstrated that the low PpIX accumulation in the C6 GSCs was enhanced by deferoxamine (DFO)-mediated iron chelation, not by reserpine-mediated inhibition of PpIX-effluxing ABCG2. Finally, we found that the expression level of the gene for heme oxygenase-1 (HO-1), a heme degradation enzyme, was high in C6 GSCs, which was further up-regulated when treated with 5-ALA. Our results provide important new insights into 5-ALA-based PDD of gliomas, particularly photodetection of SP-defined GSCs by iron chelation based on their ALA-PpIX-Heme metabolism. PMID:28169355

  16. Spectroscopic measurements of photoinduced processes in human skin after topical application of the hexyl ester of 5-aminolevulinic acid.

    PubMed

    Zhao, Lu; Nielsen, Kristian Pagh; Juzeniene, Asta; Juzenas, Petras; Lani, Vladimir; Ma, Li-wei; Stamnes, Knut; Stamnes, Jakob J; Moan, Johan

    2006-01-01

    Although 5-aminolevulinic acid, ALA, and its derivatives, have been widely studied and applied in clinical photodynamic therapy (PDT), there is still a lack of reliable and non-invasive methods and technologies to evaluate physiological parameters of relevance for the therapy, such as erythema, melanogenesis, and oxygen level. We have investigated the kinetics of these parameters in human skin in vivo during and after PDT with the hexyl ester of ALA, ALA-Hex. Furthermore, the depth of photosensitizer (protoporphyrin IX, PpIX) production after different application times was investigated. It was found that the depth increased with increasing application time of ALA-Hex. We also investigated the depth of PpIX before and after light exposure causing 50% photobleaching at 407 nm. The PpIX localized in superficial layers of the normal tissue was removed during the bleaching. Thus, after bleaching, the remaining PpIX was localized mainly in the deeper layers of normal tissue. We have applied fluorescence emission spectroscopy, fluorescence excitation spectroscopy, and reflectance spectroscopy in the study of the above-mentioned parameters. In conclusion, fluorescence excitation spectroscopy and reflectance spectroscopy are simple, useful, reliable, and noninvasive techniques in the evaluation of the processes taking place in human skin in vivo during and after PDT. Using these methods we were able to quantify melanogenesis, O2 level, erythema, vasoconstriction, and vasodilatation.

  17. Formation and accumulation of protoporphyrin IX in tumor and nontumor cell lines induced by 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Fernandez, Sandra R.; Milanetto, Marilia; Bagnato, Vanderlei S.; Imasato, Hidetake; Perussi, Janice R.

    2005-04-01

    The endogenous photosensitizer 5-aminolevulinic acid (ALA) is a haem precursor and induces the synthesis of protoporphyrin IX (PpIX) in mitochondria-containing cells. Due to the slow conversion of porphyrins to haem, high levels of PPIX are found in the tissues, sufficient to produce a photodynamic effect following exposure to light. Since PpIX accumulates effectively in tumor cells, the use of ALA leads to a better photoselectivity than Photofrin. However, this selectivity has not been sufficiently studied. As far as we know there is just one study comparing the amount of accumulated PpIX in non-tumor and tumor cell lines. In this work we attempt to compare not just the production but also the accumulation and cytotoxicity of PpIX in non-tumor (VERO) versus tumor (Hep-2) cells induced by the use of ALA. The results have shown that both non-tumor and tumor cell lines produce the same amount of PpIX but just the tumor cells can accumulate PpIX. So, under illumination, only the tumor cells will be killed.

  18. Early neoplastic and metastatic mammary tumours of transgenic mice detected by 5-aminolevulinic acid-stimulated protoporphyrin IX accumulation

    PubMed Central

    Dorward, A M; Fancher, K S; Duffy, T M; Beamer, W G; Walt, H

    2005-01-01

    A photodynamic technique for human breast cancer detection founded upon the ability of tumour cells to rapidly accumulate the fluorescent product protoporphyrin IX (PpIX) has been applied to transgenic mouse models of mammary tumorigenesis. A major goal of this investigation was to determine whether mouse mammary tumours are reliable models of human disease in terms of PpIX accumulation, for future mechanistic and therapeutic studies. The haeme substrate 5-aminolevulinic acid (5-ALA) (200 mg kg−1) was administered to mouse strains that develop mammary tumours of various histological subtypes upon expression of the transgenic oncogenes HRAS, Polyoma Virus middle T antigen, or Simian Virus 40 large T antigen in the mammary gland. Early neoplastic lesions, primary tumours and metastases showed consistent and rapid PpIX accumulation compared to the normal surrounding tissues, as evidenced by red fluorescence (635 nm) when the tumours were directly illuminated with blue light (380–440 nm). Detection of mouse mammary tumours at the stage of ductal carcinoma in situ by red fluorescence emissions suggests that enhanced PpIX synthesis is a good marker for early tumorigenic processes in the mammary gland. We propose the mouse models provide an ideal experimental system for further investigation of the early diagnostic and therapeutic potential of 5-ALA-stimulated PpIX accumulation in human breast cancer patients. PMID:16251872

  19. Heat shock protein 27 protects against aminolevulinic acid-mediated photodynamic therapy-induced apoptosis and necrosis in human breast cancer cells.

    PubMed

    Ziegler, Sarah A; Loucks, Cherisse; Madsen, Steen J; Carper, Stephen W

    2007-01-01

    This study utilized two breast cancer cell lines differing only in their expression of heat shock protein 27 (hsp27). The DB46 cell line was engineered to express high constitutive levels of hsp27, while the DC4 cell line expresses normal low levels of hsp27. The cells were incubated in 1 mM aminolevlinic acid (ALA) 4 hr prior to light exposures (635 nm) ranging from 1 to 20 J/cm2. Both cell lines displayed a dose response to photodynamic therapy (PDT) as assayed by clonogenic survival. LD50s of 2.68 and 1.27 J/cm2 were observed for DB46 and DC4 cells respectively. ALA-PDT-induced resistance to both apoptosis and necrosis in the DB46 cell line was found from TUNEL assays and fluorescence microscopy studies using propidium iodide and Hoechst staining.

  20. Isolation and characterization of a new mutant of Saccharomyces cerevisiae with altered synthesis of 5-aminolevulinic acid.

    PubMed Central

    Carvajal, E; Panek, A D; Mattoon, J R

    1990-01-01

    A new gene, RHM1, required for normal production of 5-aminolevulinic acid by Saccharomyces cerevisiae, was identified by a novel screening method. Ethyl methanesulfonate treatment of a fluorescent porphyric strain bearing the pop3-1 mutation produced nonfluorescent or weakly fluorescent mutants with defects in early stages of tetrapyrrole biosynthesis. Class I mutants defective in synthesis of 5-aminolevulinate regained fluorescence when grown on medium supplemented with 5-aminolevulinate, whereas class II mutants altered in later biosynthetic steps did not. Among six recessive class I mutants, at least three complementation groups were found. One mutant contained an allele of HEM1, the structural gene for 5-aminolevulinate synthase, and two mutants contained alleles of the regulatory gene CYC4. The remaining mutants contained genes complementary to both hem1 and cyc4. Mutant strain DA3-RS3/68 contained mutant gene rhm1, which segregated independently of hem1 and cyc4 during meiosis. 5-Aminolevulinate synthase activity of the rhm1 mutant was 35 to 40% of that of the parental pop3-1 strain, whereas intracellular 5-aminolevulinate concentration was only 3 to 4% of the parental value. Transformation of an rhm1 strain with a multicopy plasmid containing the cloned HEM1 gene restored normal levels of 5-aminolevulinate synthase activity, but intracellular 5-aminolevulinate was increased to only 9 to 10% of normal. We concluded that RHM1 could control either targeting of 5-aminolevulinate synthase to the mitochondrial matrix or the activity of the enzyme in vivo. PMID:2188943

  1. 5-Aminolevulinic acid-induced protoporphyrin-IX accumulation and associated phototoxicity in macrophages and oral cancer cell lines.

    PubMed

    Sharma, Sulbha; Jajoo, Anjana; Dube, Alok

    2007-09-25

    Studies were carried out on 5-aminolevulinic acid (ALA)-induced protoporphyrin (PpIX) synthesis in mice peritoneal macrophages and two human oral squamous cell carcinoma (OSCC) cell lines NT8e and 4451. Cells were treated with 200 microg/ml ALA for 15 h and PpIX accumulation was monitored by spectrofluorometry and phototoxicity to red light (630+/-20 nm) was measured by MTT assay. PpIX accumulation was higher in macrophages as compared to OSCC cells under both normal serum concentration (10%) and conditions of serum depletion. The results on phototoxicity measurements correlated well with the levels of PpIX accumulation in both macrophages and cancer cells. While red light caused 20% phototoxicity in macrophages, no phototoxicity was seen in 4451 cells at 10% serum. Decrease in serum concentration to 5% and 1% led to higher phototoxicity corresponding to 40% and 70% in macrophages and 10% and 15% in 4451 cells. Similar results were obtained in NT8e cell line. Propidium iodide staining followed by fluorescence microscopic observations on photodynamically treated co-culture of murine or human macrophages and cancer cells showed selective damage to macrophages. These results suggest that in OSCC, macrophages would contribute more to tumor PpIX level than tumor cells themselves and PDT may lead to selective killing of macrophages at the site of treatment. Since macrophages are responsible for production and secretion of various tumor growth mediators, the effect of selective macrophage killing on the outcome of PDT would be significant.

  2. A New Strategy for Production of 5-Aminolevulinic Acid in Recombinant Corynebacterium glutamicum with High Yield

    PubMed Central

    Yang, Peng; Liu, Wenjing; Cheng, Xuelian; Wang, Jing; Qi, Qingsheng

    2016-01-01

    ABSTRACT 5-Aminolevulinic acid (ALA), a nonprotein amino acid involved in tetrapyrrole synthesis, has been widely applied in agriculture, medicine, and food production. Many engineered metabolic pathways have been constructed; however, the production yields are still low. In this study, several 5-aminolevulinic acid synthases (ALASs) from different sources were evaluated and compared with respect to their ALA production capacities in an engineered Corynebacterium glutamicum CgS1 strain that can accumulate succinyl-coenzyme A (CoA). A codon-optimized ALAS from Rhodobacter capsulatus SB1003 displayed the best potential. Recombinant strain CgS1/pEC-SB produced 7.6 g/liter ALA using a mineral salt medium in a fed-batch fermentation mode. Employing two-stage fermentation, 12.46 g/liter ALA was produced within 17 h, with a productivity of 0.73 g/liter/h, in recombinant C. glutamicum. Through overexpression of the heterologous nonspecific ALA exporter RhtA from Escherichia coli, the titer was further increased to 14.7 g/liter. This indicated that strain CgS1/pEC-SB-rhtA holds attractive industrial application potential for the future. IMPORTANCE In this study, a two-stage fermentation strategy was used for production of the value-added nonprotein amino acid 5-aminolevulinic acid from glucose and glycine in a generally recognized as safe (GRAS) host, Corynebacterium glutamicum. The ALA titer represented the highest in the literature, to our knowledge. This high production capacity, combined with the potential easy downstream processes, made the recombinant strain an attractive candidate for industrial use in the future. PMID:26921424

  3. Evidence that isolated developing chloroplasts are capable of synthesizing chlorophyll b from 5-aminolevulinic acid

    SciTech Connect

    Huang, Laiqiang; Hoffman, N.E. )

    1990-09-01

    Developing chloroplasts isolated from cucumber (Cucumis sativus L. var Beit Alpha) cotyledons are capable of incorporating ({sup 14}C)5-aminolevulinic acid into chlorophyll (Chl) b and Chl a when incubated under photosynthetic illumination. Thin layer chromatography and high pressure liquid chromatography were employed to analyze the pigments. The specific radioactivity in Chl a was over three times higher than that found in Chl b. Both Chl a and b synthesizing activities in organello decayed rapidly at approximately the same rate. We conclude that concomitant synthesis of Chl a/b-binding apoprotein is not required for Chl b synthesis.

  4. Effects of medium composition on production of 5-aminolevulinic acid by recombinant Escherichia coli.

    PubMed

    Qin, Gang; Lin, Jianping; Liu, Xiaoxia; Cen, Peilin

    2006-10-01

    The recombinant Escherichia coli BL21(DE3) harboring hemA from Agrobacterium radiobacter, which was engineered in our previous work, was used for the extracellular production of 5-aminolevulinic acid (ALA). The effects of various physiological factors, such as the concentrations of precursors (glycine, succinic acid and glucose) and the inhibitor 5-aminolevulinate dehydratase (levulinic acid), on the ALA accumulation in the fermentation broth were investigated in both shake flasks and a jar fermentor. Among these precursors, glycine exhibited the strongest ability to inhibit cell growth, while glucose mainly inhibited ALA formation. The optimum initial concentrations of glycine, succinic acid and glucose were found to be 2.0, 10.0 and 2.0 g/l, respectively. Levulinic acid (LA; 30 mM) was fed to the fermentation broth at the end of the exponential cell growth phase (about 8 h), and the intracellular activity of ALA dehydratase was efficaciously suppressed. Repeating the optimum composition of the medium in a stirred tank fermenter resulted in 1.49 g/l ALA. Furthermore, the fed batch of the precursors and inhibitor further increased ALA production up to 3.01 g/l.

  5. Production of 5-aminolevulinic acid by cell free multi-enzyme catalysis.

    PubMed

    Meng, Qinglong; Zhang, Yanfei; Ju, Xiaozhi; Ma, Chunling; Ma, Hongwu; Chen, Jiuzhou; Zheng, Ping; Sun, Jibin; Zhu, Jun; Ma, Yanhe; Zhao, Xueming; Chen, Tao

    2016-05-20

    5-Aminolevulinic acid (ALA) is the precursor for the biosynthesis of tetrapyrroles and has broad agricultural and medical applications. Currently ALA is mainly produced by chemical synthesis and microbial fermentation. Cell free multi-enzyme catalysis is a promising method for producing high value chemicals. Here we reported our work on developing a cell free process for ALA production using thermostable enzymes. Cheap substrates (succinate and glycine) were used for ALA synthesis by two enzymes: 5-aminolevulinic acid synthase (ALAS) from Laceyella sacchari (LS-ALAS) and succinyl-CoA synthase (Suc) from Escherichia coli. ATP was regenerated by polyphosphate kinase (Ppk) using polyphosphate as the substrate. Succinate was added into the reaction system in a fed-batch mode to avoid its inhibition effect on Suc. After reaction for 160min, ALA concentration was increased to 5.4mM. This is the first reported work on developing the cell free process for ALA production. Through further process and enzyme optimization the cell free process could be an effective and economic way for ALA production.

  6. Noninvasive fluorescence excitation spectroscopy during application of 5-aminolevulinic acid in vivo.

    PubMed

    Juzenas, Petras; Juzeniene, Asta; Kaalhus, Olav; Iani, Vladimir; Moan, Johan

    2002-10-01

    The fluorescence of PpIX induced by topical application of 5-aminolevulinic acid (ALA) in normal mouse skin was studied noninvasively by means of a fibre optic probe. The fluorescence excitation spectrum of PpIX exhibits five distinct peaks at around 408. 510, 543, 583 and 633 nm under fluorescence monitoring at the second emission peak of PpIX (705 nm). The transmission of the excitation light is wavelength dependent: the long wavelength light (>600 nm) penetrates deeper into the tissues by a factor of 6 compared with the short wavelength light (<590 nm). Thus, the fluorescence excitation spectrum of PpIX measured on the surface of the skin can be used to estimate the depth of the penetration of topically applied ALA. The fluorescence excitation spectra calculated for the depth 1.1 mm obtained the best fit with the experimentally measured spectra after topical application of ALA.

  7. Topical glycerol monooleate/propylene glycol formulations enhance 5-aminolevulinic acid in vitro skin delivery and in vivo protophorphyrin IX accumulation in hairless mouse skin.

    PubMed

    Steluti, Regilene; De Rosa, Fernanda Scarmato; Collett, John; Tedesco, Antônio Cláudio; Bentley, Maria Vitória Lopes Badra

    2005-08-01

    Photodynamic therapy (PDT), a potential therapy for cancer treatment, utilizes exogenously applied or endogenously formed photosensitizers, further activated by light in an appropriate wavelength and dose to induce cell death through free radical formation. 5-Aminolevulinic acid (5-ALA) is a pro-drug which can be converted to the effective photosensitizer, protoporphyrin IX (PpIX). However, the use of 5-ALA in PDT is limited by the low penetration capacity of this highly hydrophilic molecule into appropriate skin layers. In the present study, we propose to increase 5-ALA penetration by using formulations containing glycerol monooleate (GMO), an interesting and useful component of pharmaceutical formulations. Propylene glycol solutions containing different concentrations of GMO significantly increased the in vitro skin permeation/retention of 5-ALA in comparison to control solutions. In vivo studies also showed increased PpIX accumulation in mouse hairless skin, after the use of topical 5-ALA formulations containing GMO in a concentration-dependent manner. The results show that skin 5-ALA penetration and PpIX accumulation, important factors for the success of topical 5-ALA-PDT in skin cancer, are optimized by GMO/propylene glycol formulations.

  8. Comparative study of two routes of administration of 5-aminolevulinic acid (oral and intratumoral via) and their effect on the accumulation of PpIX in tissues in murine model of breast cancer

    NASA Astrophysics Data System (ADS)

    González-Agüero, G.; Ramón-Gallegos, E.

    2012-10-01

    Protoporphyrin IX (PpIX) is a photosensitizer synthesized from 5-aminolevulinic acid (ALA) that has been used in photodynamic therapy (PDT) as a promising treatment for many types of cancer. In this work it was quantified the accumulation of PpIX in tumors and in different tissues of female mice (nu/nu) inoculated with breast cancer cells. Two routes of administration of ALA: gastric probe and intratumoral injection were used to find optimum time of accumulation and the via that induce the higher quantity of PpIX to improve the efficiency of PDT. The results show that the accumulation of PpIX using the intratumoral via is two times bigger than the oral via in tumors at 8 h of treatment. The concentrations obtained in the different tissues are not physiologically significant.

  9. Improvement of tumor localization of photosensitizers for photodynamic therapy and its application for tumor diagnosis.

    PubMed

    Ogura, Shun-Ichiro; Hagiya, Yuichiro; Tabata, Kenji; Kamachi, Toshiaki; Okura, Ichiro

    2012-01-01

    Photodynamic therapy (PDT) and photodynamic diagnosis of cancer are widely used in clinical fields. These are performed using photosensitizers. Many metalloporphyrin-related compounds have been developed as photosensitizers for use in PDT, and these tumor localization ability have been improved in recent research. Moreover, the precursor of porphyrin 5-aminolevulinic acid is used in fluorescence diagnosis using its tumor localization ability. In this review, these applications of photosensitizers in cancer therapy and diagnosis are summarized.

  10. Regulation of the hemA gene during 5-aminolevulinic acid formation in Pseudomonas aeruginosa.

    PubMed Central

    Hungerer, C; Troup, B; Römling, U; Jahn, D

    1995-01-01

    The general tetrapyrrole precursor 5-aminolevulinic acid is formed in bacteria via two different biosynthetic pathways. Members of the alpha group of the proteobacteria use 5-aminolevulinic acid synthase for the condensation of succinyl-coenzyme A and glycine, while other bacteria utilize a two-step pathway from aminoacylated tRNA(Glu). The tRNA-dependent pathway, involving the enzymes glutamyl-tRNA reductase (encoded by hemA) and glutamate-1-semialdehyde-2,1-aminomutase (encoded by hemL), was demonstrated to be used by Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Comamonas testosteroni, Azotobacter vinelandii, and Acinetobacter calcoaceticus. To study the regulation of the pathway, the glutamyl-tRNA reductase gene (hemA) from P. aeruginosa was cloned by complementation of an Escherichia coli hemA mutant. The hemA gene was mapped to the SpeI A fragment and the DpnIL fragment of the P. aeruginosa chromosome corresponding to min 24.1 to 26.8. The cloned hemA gene, coding for a protein of 423 amino acids with a calculated molecular mass of 46,234 Da, forms an operon with the gene for protein release factor 1 (prf1). This translational factor mediates the termination of the protein chain at the ribosome at amber and ochre codons. Since the cloned hemA gene did not possess one of the appropriate stop codons, an autoregulatory mechanism such as that postulated for the enterobacterial system was ruled out. Three open reading frames of unknown function transcribed in the opposite direction to the hemA gene were found. hemM/orf1 and orf2 were found to be homologous to open reading frames located in the 5' region of enterobacterial hemA genes. Utilization of both transcription start sites was changed in a P. aeruginosa mutant missing the oxygen regulator Anr (Fnr analog), indicating the involvement of the transcription factor in hemA expression. DNA sequences homologous to one half of an Anr binding site were detected at one of the determined

  11. Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas

    PubMed Central

    Kim, Ji Young; Kim, Sung Kwon; Kim, Seung-Ki; Park, Sung-Hye; Kim, Hyeonjin; Lee, Se-Hoon; Choi, Seung Hong; Park, Sunghyouk; Park, Chul-Kee

    2015-01-01

    Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132H cells. Next, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence. PMID:26008980

  12. Identification of regulatory sequences in the gene for 5-aminolevulinate synthase from rat.

    PubMed

    Braidotti, G; Borthwick, I A; May, B K

    1993-01-15

    The housekeeping enzyme 5-aminolevulinate synthase (ALAS) regulates the supply of heme for respiratory cytochromes. Here we report on the isolation of a genomic clone for the rat ALAS gene. The 5'-flanking region was fused to the chloramphenicol acetyltransferase gene and transient expression analysis revealed the presence of both positive and negative cis-acting sequences. Expression was substantially increased by the inclusion of the first intron located in the 5'-untranslated region. Sequence analysis of the promoter identified two elements at positions -59 and -88 bp with strong similarity to the binding site for nuclear respiratory factor 1 (NRF-1). Gel shift analysis revealed that both NRF-1 elements formed nucleoprotein complexes which could be abolished by an authentic NRF-1 oligomer. Mutagenesis of each NRF-1 motif in the ALAS promoter gave substantially lowered levels of chloramphenicol acetyltransferase expression, whereas mutagenesis of both NRF-1 motifs resulted in the almost complete loss of expression. These results establish that the NRF-1 motifs in the ALAS promoter are critical for promoter activity. NRF-1 binding sites have been identified in the promoters of several nuclear genes encoding mitochondrial proteins concerned with oxidative phosphorylation. The present studies suggest that NRF-1 may co-ordinate the supply of mitochondrial heme with the synthesis of respiratory cytochromes by regulating expression of ALAS. In erythroid cells, NRF-1 may be less important for controlling heme levels since an erythroid ALAS gene is strongly expressed and the promoter for this gene apparently lacks NRF-1 binding sites.

  13. Optimization of the heme biosynthesis pathway for the production of 5-aminolevulinic acid in Escherichia coli

    PubMed Central

    Zhang, Junli; Kang, Zhen; Chen, Jian; Du, Guocheng

    2015-01-01

    5-Aminolevulinic acid (ALA), the committed intermediate of the heme biosynthesis pathway, shows significant promise for cancer treatment. Here, we identified that in addition to hemA and hemL, hemB, hemD, hemF, hemG and hemH are also the major regulatory targets of the heme biosynthesis pathway. Interestingly, up-regulation of hemD and hemF benefited ALA accumulation whereas overexpression of hemB, hemG and hemH diminished ALA accumulation. Accordingly, by combinatorial overexpression of the hemA, hemL, hemD and hemF with different copy-number plasmids, the titer of ALA was improved to 3.25 g l−1. Furthermore, in combination with transcriptional and enzymatic analysis, we demonstrated that ALA dehydratase (HemB) encoded by hemB is feedback inhibited by the downstream intermediate protoporphyrinogen IX. This work has great potential to be scaled-up for microbial production of ALA and provides new important insights into the regulatory mechanism of the heme biosynthesis pathway. PMID:25716896

  14. Physiological and metabolic effects of 5-aminolevulinic acid for mitigating salinity stress in creeping bentgrass.

    PubMed

    Yang, Zhimin; Chang, Zuoliang; Sun, Lihong; Yu, Jingjin; Huang, Bingru

    2014-01-01

    The objectives of this study were to determine whether foliar application of a chlorophyll precursor, 5-aminolevulinic acid (ALA), could mitigate salinity stress damages in perennial grass species by regulating photosynthetic activities, ion content, antioxidant metabolism, or metabolite accumulation. A salinity-sensitive perennial grass species, creeping bentgrass (Agrostis stolonifera), was irrigated daily with 200 mM NaCl for 28 d, which were foliar sprayed with water or ALA (0.5 mg L-1) weekly during the experiment in growth chamber. Foliar application of ALA was effective in mitigating physiological damage resulting from salinity stress, as manifested by increased turf quality, shoot growth rate, leaf relative water content, chlorophyll content, net photosynthetic rate, stomatal conductance and transpiration rate. Foliar application of ALA also alleviated membrane damages, as shown by lower membrane electrolyte leakage and lipid peroxidation, which was associated with increases in the activities of antioxidant enzymes. Leaf content of Na+ was reduced and the ratio of K+/Na+ was increased with ALA application under salinity stress. The positive effects of ALA for salinity tolerance were also associated with the accumulation of organic acids (α-ketoglutaric acid, succinic acid, and malic acid), amino acids (alanine, 5-oxoproline, aspartic acid, and γ -aminobutyric acid), and sugars (glucose, fructose, galactose, lyxose, allose, xylose, sucrose, and maltose). ALA-mitigation of physiological damages by salinity could be due to suppression of Na+ accumulation and enhanced physiological and metabolic activities related to photosynthesis, respiration, osmotic regulation, and antioxidant defense.

  15. Physiological and Metabolic Effects of 5-Aminolevulinic Acid for Mitigating Salinity Stress in Creeping Bentgrass

    PubMed Central

    Yang, Zhimin; Chang, Zuoliang; Sun, Lihong; Yu, Jingjin; Huang, Bingru

    2014-01-01

    The objectives of this study were to determine whether foliar application of a chlorophyll precursor, 5-aminolevulinic acid (ALA), could mitigate salinity stress damages in perennial grass species by regulating photosynthetic activities, ion content, antioxidant metabolism, or metabolite accumulation. A salinity-sensitive perennial grass species, creeping bentgrass (Agrostis stolonifera), was irrigated daily with 200 mM NaCl for 28 d, which were foliar sprayed with water or ALA (0.5 mg L−1) weekly during the experiment in growth chamber. Foliar application of ALA was effective in mitigating physiological damage resulting from salinity stress, as manifested by increased turf quality, shoot growth rate, leaf relative water content, chlorophyll content, net photosynthetic rate, stomatal conductance and transpiration rate. Foliar application of ALA also alleviated membrane damages, as shown by lower membrane electrolyte leakage and lipid peroxidation, which was associated with increases in the activities of antioxidant enzymes. Leaf content of Na+ was reduced and the ratio of K+/Na+ was increased with ALA application under salinity stress. The positive effects of ALA for salinity tolerance were also associated with the accumulation of organic acids (α-ketoglutaric acid, succinic acid, and malic acid), amino acids (alanine, 5-oxoproline, aspartic acid, and γ -aminobutyric acid), and sugars (glucose, fructose, galactose, lyxose, allose, xylose, sucrose, and maltose). ALA-mitigation of physiological damages by salinity could be due to suppression of Na+ accumulation and enhanced physiological and metabolic activities related to photosynthesis, respiration, osmotic regulation, and antioxidant defense. PMID:25551443

  16. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas

    PubMed Central

    Halani, Sameer H; Adamson, D Cory

    2016-01-01

    Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas. PMID:27672334

  17. Catabolism of 5-aminolevulinic acid to CO2 by rat liver mitochondria.

    PubMed

    Medeiros, M H; Di Mascio, P; Gründel, S; Soboll, S; Sies, H; Bechara, E J

    1994-04-01

    5-Aminolevulinic acid (ALA), the heme precursor accumulated in plasma and several organs of carriers of acute intermittent porphyria, hereditary tyrosinemia, and saturnism, was previously shown to yield reactive oxygen species upon metal-catalyzed aerobic oxidation and to cause the in vivo and in vitro impairment of rat liver mitochondrial functions. We have studied the uptake and catabolism of [5-14C]ALA to CO2 by isolated rat liver mitochondria (RLM) with the aim of determining whether possible ALA-driven oxidative injury to mitochondria can also occur into the matrix. Using silicone oil centrifugation of [5-14C]ALA-treated RLM, ALA was found to partition evenly into the intra- and extramatrix space of the mitochondrial preparations. The yield of evolved 14CO2 is very low (0.2%), responds to the concentration of added ADP, and is inhibited by malonate (75% at 2 mM), iproniazid (45% at 2 mM), beta-chloroalanine (36% at 1 mM), and aminooxyacetate (55% at 0.1 mM). With both iproniazid and aminooxyacetate, the percentage of inhibition is the same as that observed with the latter inhibitor alone. These data indicate that ALA decarboxylation by the Krebs cycle is a minor process and that it is initiated enzymically (transaminase) and not by metal-catalyzed ALA autoxidation.

  18. Transcriptomic analysis for elucidating the physiological effects of 5-aminolevulinic acid accumulation on Corynebacterium glutamicum.

    PubMed

    Yu, Xiaoli; Jin, Haiying; Cheng, Xuelian; Wang, Qian; Qi, Qingsheng

    2016-11-01

    5-Aminolevulinic acid (ALA), the committed intermediate of the heme biosynthetic pathway, attracts close attention among researchers because of its potential applications to cancer treatment and agriculture. Overexpression of heterologous hemA and hemL, which encode glutamyl-tRNA reductase and glutamate-1-semialdehyde aminotransferase, respectively, in Corynebacterium glutamicum produces ALA, although whether ALA accumulation causes unintended effects on the host is unknown. Here we used an integrated systems approach to compare global transcriptional changes induced by the expression of hemA and hemL. Metabolic pathway such as glycolysis was inhibited, but tricarboxylic acid cycle, pentose phosphate pathway, and respiratory metabolism were stimulated. Moreover, the transcriptional levels of certain genes involved in heme biosynthesis were up-regulated, and the data implicate the two-component system (TCS) HrrSA was involved in the regulation of heme synthesis. With these understandings, it is proposed that ALA accumulation stimulates heme synthesis pathway and respiratory metabolism. Our study illuminates the physiological effects of overexpressing hemA and hemL on the phenotype of C. glutamicum and contributes important insights into the regulatory mechanisms of the heme biosynthetic pathways.

  19. Topical delivery of 5-aminolevulinic acid-encapsulated ethosomes in a hyperproliferative skin animal model using the CLSM technique to evaluate the penetration behavior.

    PubMed

    Fang, Yi-Ping; Huang, Yaw-Bin; Wu, Pao-Chu; Tsai, Yi-Hung

    2009-11-01

    Psoriasis, an inflammatory skin disease, exhibits recurring itching, soreness, and cracked and bleeding skin. Currently, the topical delivery of 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) is an optional treatment for psoriasis which provides long-term therapeutic effects, is non-toxic and enjoys better compliance with patients. However, the precursor of ALA is hydrophilic, and thus its ability to penetrate the skin is limited. Also, little research has provided a platform to investigate the penetration behavior in disordered skin. We employed a highly potent ethosomal carrier (phosphatidylethanolamine; PE) to investigate the penetration behavior of ALA and the recovery of skin in a hyperproliferative murine model. We found that the application of ethosomes produced a significant increase in cumulative amounts of 5-26-fold in normal and hyperproliferative murine skin samples when compared to an ALA aqueous solution; and the ALA aqueous solution appeared less precise in terms of the penetration mode in hyperproliferative murine skin. After the ethosomes had been applied, the protoporphyrin IX (PpIX) intensity increased about 3.64-fold compared with that of the ALA aqueous solution, and the penetration depth reached 30-80 microm. The results demonstrated that the ethosomal carrier significantly improved the delivery of ALA and the formation of PpIX in both normal and hyperproliferative murine skin samples, and the expression level of tumor necrosis factor (TNF)-alpha was reduced after the ALA-ethosomes were applied to treat hyperproliferative murine skin. Furthermore, the results of present study encourage more investigations on the mechanism of the interaction with ethosomes and hyperproliferative murine skin.

  20. The role of 5-aminolevulinic acid in the response to cold stress in soybean plants.

    PubMed

    Balestrasse, Karina B; Tomaro, María L; Batlle, Alcira; Noriega, Guillermo O

    2010-12-01

    In this study, the possibility of enhancing cold stress tolerance of soybean plants (Glycine max L.) by exogenous application of 5-aminolevulinic acid (ALA) was investigated. ALA was added to the Hoagland solution at various concentrations ranging from 0 to 40 μM for 12 h. After ALA treatment, the plants were subjected to cold stress at 4°C for 48 h. ALA at low concentrations (5-10 μM) provided significant protection against cold stress compared to non-ALA-treated plants, enhancing chlorophyll content (Chl) as well as relative water content (RWC). Increase of thiobarbituric acid reactive species (TBARS) levels was also prevented, whereas exposure to higher ALA concentrations (15-40 μM) brought about a dose dependent increase of these species, reaching a maximum of 117% in plants pre-treated with 40 μM ALA compared to controls. ALA pre-treatment also enhanced catalase (CAT) and heme oxygenase-1 (HO-1) activities. These findings indicate that HO-1 acts not only as the rate limiting enzyme in heme catabolism, but also as an antioxidant enzyme. The highest cold tolerance was obtained with 5 μM ALA pre-treatment. Results show that ALA, which is considered as an endogenous plant growth regulator, could be used effectively to protect soybean plants from the damaging effects of cold stress by enhancing the activity of heme proteins, e.g., catalase (CAT) and by promoting heme catabolism leading to the production of the highly antioxidant biliverdin and carbon monoxide, without any adverse effect on the plant growth.

  1. Unstable Reaction Intermediates and Hysteresis during the Catalytic Cycle of 5-Aminolevulinate Synthase

    PubMed Central

    Stojanovski, Bosko M.; Hunter, Gregory A.; Jahn, Martina; Jahn, Dieter; Ferreira, Gloria C.

    2014-01-01

    5-Aminolevulinate (ALA), an essential metabolite in all heme-synthesizing organisms, results from the pyridoxal 5′-phosphate (PLP)-dependent enzymatic condensation of glycine with succinyl-CoA in non-plant eukaryotes and α-proteobacteria. The predicted chemical mechanism of this ALA synthase (ALAS)-catalyzed reaction includes a short-lived glycine quinonoid intermediate and an unstable 2-amino-3-ketoadipate intermediate. Using liquid chromatography coupled with tandem mass spectrometry to analyze the products from the reaction of murine erythroid ALAS (mALAS2) with O-methylglycine and succinyl-CoA, we directly identified the chemical nature of the inherently unstable 2-amino-3-ketoadipate intermediate, which predicates the glycine quinonoid species as its precursor. With stopped-flow absorption spectroscopy, we detected and confirmed the formation of the quinonoid intermediate upon reacting glycine with ALAS. Significantly, in the absence of the succinyl-CoA substrate, the external aldimine predominates over the glycine quinonoid intermediate. When instead of glycine, l-serine was reacted with ALAS, a lag phase was observed in the progress curve for the l-serine external aldimine formation, indicating a hysteretic behavior in ALAS. Hysteresis was not detected in the T148A-catalyzed l-serine external aldimine formation. These results with T148A, a mALAS2 variant, which, in contrast to wild-type mALAS2, is active with l-serine, suggest that active site Thr-148 modulates ALAS strict amino acid substrate specificity. The rate of ALA release is also controlled by a hysteretic kinetic mechanism (observed as a lag in the ALA external aldimine formation progress curve), consistent with conformational changes governing the dissociation of ALA from ALAS. PMID:24920668

  2. Alleviation of salt-induced oxidative damage by 5-aminolevulinic acid in wheat seedlings

    NASA Astrophysics Data System (ADS)

    Genişel, Mucip; Erdal, Serkan

    2016-04-01

    The aim of this study was to elucidate how 5-aminolevulinic acid (ALA), the precursor of chlorophyll compounds, affects the defence mechanisms of wheat seedlings induced by salt stress. To determine the possible stimulative effects of ALA against salinity, 11-day old wheat seedlings were sprayed with ALA at two different concentrations (10 and 20 mg.l-1) and then stressed by exposure to salt (150 mM NaCl). The salt stress led to significant changes in the antioxidant activity. While guaiacol peroxidase activity decreased, the activities of superoxide dismutase, catalase, and ascorbate peroxidase markedly increased under salt stress. Compared to the salt stress alone, the application of ALA beforehand further increased the activity of these enzymes. This study is the first time the effects of ALA have been monitored with regard to protein content and the isoenzyme profiles of the antioxidant enzymes. Although the salt stress reduced both the soluble protein content and protein band intensities, pre-treating with ALA significantly mitigated these stress-induced reductions. The data for the isoenzyme profiles of the antioxidant enzymes paralleled that of the ALA-induced increases in antioxidant activity. As a consequence of the high antioxidant activity in the seedlings pre-treated with ALA, the stress-induced elevations in the reactive oxygen species, superoxide anion, and hydrogen peroxide contents and lipid peroxidation levels were markedly diminished. Taken together, this data demonstrated that pre-treating with ALA confers resistance to salt stress by modulating the protein synthesis and antioxidant activity in wheat seedlings.

  3. 5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence in Meningioma: Qualitative and Quantitative Measurements In Vivo

    PubMed Central

    Valdes, Pablo A.; Bekelis, Kimon; Harris, Brent T.; Wilson, Brian C.; Leblond, Frederic; Kim, Anthony; Simmons, Nathan E.; Erkmen, Kadir; Paulsen, Keith D.; Roberts, David W.

    2014-01-01

    BACKGROUND The use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence has shown promise as a surgical adjunct for maximizing the extent of surgical resection in gliomas. To date, the clinical utility of 5-ALA in meningiomas is not fully understood, with most descriptive studies using qualitative approaches to 5-ALA-PpIX. OBJECTIVE To assess the diagnostic performance of 5-ALA-PpIX fluorescence during surgical resection of meningioma. METHODS ALA was administered to 15 patients with meningioma undergoing PpIX fluorescence-guided surgery at our institution. At various points during the procedure, the surgeon performed qualitative, visual assessments of fluorescence by using the surgical microscope, followed by a quantitative fluorescence measurement by using an intra-operative probe. Specimens were collected at each point for subsequent neuropathological analysis. Clustered data analysis of variance was used to ascertain a difference between groups, and receiver operating characteristic analyses were performed to assess diagnostic capabilities. RESULTS Red-pink fluorescence was observed in 80% (12/15) of patients, with visible fluorescence generally demonstrating a strong, homogenous character. Quantitative fluorescence measured diagnostically significant PpIX concentrations (CPpIx) in both visibly and nonvisibly fluorescent tissues, with significantly higher CPpIx in both visibly fluorescent (P < .001) and tumor tissue (P = .002). Receiver operating characteristic analyses also showed diagnostic accuracies up to 90% for differentiating tumor from normal dura. CONCLUSION ALA-induced PpIX fluorescence guidance is a potential and promising adjunct in accurately detecting neoplastic tissue during meningioma resective surgery. These results suggest a broader reach for PpIX as a biomarker for meningiomas than was previously noted in the literature. PMID:23887194

  4. 5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1.

    PubMed

    Nishio, Yoshiaki; Fujino, Masayuki; Zhao, Mingyi; Ishii, Takuya; Ishizuka, Masahiro; Ito, Hidenori; Takahashi, Kiwamu; Abe, Fuminori; Nakajima, Motowo; Tanaka, Tohru; Taketani, Shigeru; Nagahara, Yukitoshi; Li, Xiao-Kang

    2014-04-01

    5-Aminolevulinic acid (5-ALA) is the naturally occurring metabolic precursor of heme. Heme negatively regulates the Maf recognition element (MARE) binding- and repressing-activity of the Bach1 transcription factor through its direct binding to Bach1. Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide. These metabolites of heme protect against apoptosis, inflammation and oxidative stress. Monocytes and macrophages play a critical role in the initiation, maintenance and resolution of inflammation. Therefore, the regulation of inflammation in macrophages is an important target under various pathophysiological conditions. In order to address the question of what is responsible for the anti-inflammatory effects of 5-ALA, the induction of HO-1 expression by 5-ALA and sodium ferrous citrate (SFC) was examined in macrophage cell line (RAW264 cells). HO-1 expression induced by 5-ALA combined with SFC (5-ALA/SFC) was partially inhibited by MEK/ERK and p38 MAPK inhibitor. The NF-E2-related factor 2 (Nrf2) was activated and translocated from the cytosol to the nucleus in response to 5-ALA/SFC. Nrf2-specific siRNA reduced the HO-1 expression. In addition, 5-ALA/SFC increased the intracellular levels of heme in cells. The increased heme indicated that the inactivation of Bach1 by heme supports the upregulation of HO-1 expression. Taken together, our data suggest that the exposure of 5-ALA/SFC to RAW264 cells enhances the HO-1 expression via MAPK activation along with the negative regulation of Bach1.

  5. [Effect of 5-aminolevulinic acid on photosynthetic characteristics of tomato seedlings under NaCl stress].

    PubMed

    Zhao, Yan-Yan; Yan, Fei; Hu, Li-Pan; Zhou, Xiao-Ting; Zou, Zhi-Rong

    2014-10-01

    In this research, the possibility of exogenous application of 5-aminolevulinic acid (ALA) on photosynthetic characteristics of tomato seedlings under NaCl stress was investigated. Five leaves seedlings of tomato (Solanum lycopersicum cv. Jinpeng No. 1) were used as starting materials, applied with 50 mg · L(-1) ALA by foliage spray or 10 mg · L(-1) ALA by root soaking to study the changes in their photosynthesis and fluorescence parameters under 100 mmol · L(-1) NaCl. The result showed that, photosynthetic gas exchange parameters (net photosynthetic rate P,, stomata conductance g(s), intercellular CO2 concentration Ci, transpiration Tr) and chlorophyll fluorescence parameters (Fv'/Fm', Fm', ΦPS II, ETR, qP, Pc) were severely reduced under NaCl treatment and ALA application by foliage spray or root soaking with proper concentrations exerted positive influences on tomato seedlings under salt stress, while there were some differences between foliage spray and root soaking in the influence on chlorophyll content, photosynthesis and chlorophyll fluorescence. Both foliage spray with 50 mg · L(-1) ALA and root soaking with 10 mg L(-1) ALA significantly increased Pn, Ci, g(s) and Tr of tomato seedlings under NaCl stress, alleviated photosynthetic inhibition. Root application of ALA had a better effect on the chlorophyll content than foliage application. However, the photosynthetic parameters showed that foliage application of ALA had a better effect than root application, and both treatments had no difference in the influence on chlorophyll fluorescence parameters of tomato seedlings. It could be deduced that the regulating effect of ALA on enhancing salt tolerance of tomato seedlings is attributed to its effect on improving chlorophyll biosynthesis and metabolism, increasing stomatal conductance and reducing stomatal limitation, thus, enhancing the photosynthetic capacity and PS II photochemical efficiency of tomato leaves under NaCl stress.

  6. Quantitative and qualitative 5-aminolevulinic acid–induced protoporphyrin IX fluorescence in skull base meningiomas

    PubMed Central

    Bekelis, Kimon; Valdés, Pablo A.; Erkmen, Kadir; Leblond, Frederic; Kim, Anthony; Wilson, Brian C.; Harris, Brent T.; Paulsen, Keith D.; Roberts, David W.

    2011-01-01

    Object Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection. Methods A 52-year-old patient with a sphenoid wing WHO Grade I meningioma underwent tumor resection as part of an institutional review board–approved prospective study of fluorescence-guided resection. A surgical microscope modified for fluorescence imaging was used for the qualitative assessment of visible fluorescence, and an intraoperative probe for in situ fluorescence detection was utilized for quantitative measurements of PpIX. The authors assessed the detection capabilities of both the qualitative and quantitative fluorescence approaches. Results The patient harboring a sphenoid wing meningioma with intraorbital extension underwent radical resection of the tumor with both visibly and nonvisibly fluorescent regions. The patient underwent a complete resection without any complications. Some areas of the tumor demonstrated visible fluorescence. The quantitative probe detected neoplastic tissue better than the qualitative modified surgical microscope. The intraoperative probe was particularly useful in areas that did not reveal visible fluorescence, and tissue from these areas was confirmed as tumor following histopathological

  7. Photodynamic therapy using light-emitting diodes for the treatment of viral warts.

    PubMed

    Ohtsuki, Akiko; Hasegawa, Toshio; Hirasawa, Yusuke; Tsuchihashi, Hitoshi; Ikeda, Shigaku

    2009-10-01

    Photodynamic therapy with topical 5-aminolevulinic acid is an effective and safe treatment for actinic keratosis and superficial non-melanoma skin cancer. Further, some studies have reported good efficacy when using photodynamic therapy to treat viral warts. The light-emitting diode is an incoherent, narrow-spectrum light source. The purpose of this study is to evaluate the efficacy of photodynamic therapy using a light-emitting diode for viral warts. Six patients with a total of 41 foot and hand warts were recruited in this study. They were treated with 20% 5-aminolevulinic acid cream under occlusion for 5 h. Thereafter, the treated area was irradiated with the light from a red light-emitting diode (633 +/- 6 nm) with a dose of 126 J/cm(2). This treatment was repeated at 2- or 3-week intervals. The rate of improvement observed in patients was 68.3%. The adverse effects included mild to moderate pain and erythema, which was well-tolerated by all six patients. No patients withdrew from the study due to the adverse effects. Photodynamic therapy with topical 5-aminolevulinic acid using the light from a red light-emitting diode has the advantage of non-invasiveness, minimal associated adverse reactions, and production of good results in a significant proportion of cases: therefore, it is an alternative treatment for recalcitrant viral warts.

  8. Evolution of cyclizing 5-aminolevulinate synthases in the biosynthesis of actinomycete secondary metabolites: outcomes for genetic screening techniques.

    PubMed

    Petříčková, Kateřina; Chroňáková, Alica; Zelenka, Tomáš; Chrudimský, Tomáš; Pospíšil, Stanislav; Petříček, Miroslav; Krištůfek, Václav

    2015-01-01

    A combined approach, comprising PCR screening and genome mining, was used to unravel the diversity and phylogeny of genes encoding 5-aminolevulinic acid synthases (ALASs, hemA gene products) in streptomycetes-related strains. In actinomycetes, these genes were believed to be directly connected with the production of secondary metabolites carrying the C5N unit, 2-amino-3-hydroxycyclopent-2-enone, with biological activities making them attractive for future use in medicine and agriculture. Unlike "classical" primary metabolism ALAS, the C5N unit-forming cyclizing ALAS (cALAS) catalyses intramolecular cyclization of nascent 5-aminolevulinate. Specific amino acid sequence changes can be traced by comparison of "classical" ALASs against cALASs. PCR screening revealed 226 hemA gene-carrying strains from 1,500 tested, with 87% putatively encoding cALAS. Phylogenetic analysis of the hemA homologs revealed strain clustering according to putative type of metabolic product, which could be used to select producers of specific C5N compound classes. Supporting information was acquired through analysis of actinomycete genomic sequence data available in GenBank and further genetic or metabolic characterization of selected strains. Comparison of 16S rRNA taxonomic identification and BOX-PCR profiles provided evidence for numerous horizontal gene transfers of biosynthetic genes or gene clusters within actinomycete populations and even from non-actinomycete organisms. Our results underline the importance of environmental and evolutionary data in the design of efficient techniques for identification of novel producers.

  9. Involvement of retinoblastoma-associated protein 48 during photodynamic therapy of cervical cancer cells.

    PubMed

    Wu, Shuxia; Wang, Lijun; Ren, Xingye; Pan, Yulu; Peng, Yan; Zou, Xiaoyan; Shi, Cuige; Zhang, Youzhong

    2017-03-01

    5-Aminolevulinic acid-mediated photodynamic therapy (ALA‑PDT) is an effective treatment option for cervical intraepithelial neoplasia, the precancerous lesion of cervical cancer, and early cervical cancer, particularly for young or nulliparous women who want to remain fertile. A previous report described the involvement of histone deacetylases (HDAC) during ALA‑PDT mediated apoptosis in the cerebral cortex of a mouse model. Retinoblastoma‑associated protein 48 (RbAp48), a highly abundant component of HDACs, is a critical mediator that controls the transforming activity of human papillomavirus 16 in cervical cancer cells. The aim of the present study was to investigate the involvement of RbAp48 in ALA‑PDT‑induced cell death in cervical cancer cells. RbAp48 was significantly upregulated in cervical cancer cell lines treated with ALA‑PDT, including SiHa and HeLa cells. To establish the relevance of RbAp48 and the efficacy of ALA‑PDT in cervical cancer cells, the effect of ALA‑PDT was investigated in SiHa or HeLa cells following the depletion of RbAp48 by small interfering RNA (siRNA). Reduction of RbAp48 led to the reduced suppression of proliferation and apoptosis induced by ALA‑PDT in cervical cancer cells, which was associated with a reduction in tumor suppressor protein 53 (p53), retinoblastoma (Rb), apoptosis‑related enzyme caspase‑3, and increased levels of the oncogenic genes, human papillomavirus E6 and E7. These results provide evidence that RbAp48 is an important contributor to the efficacy of ALA‑PDT in cervical cancer cells. RbAp48 may be a therapeutic target that may help to improve the treatment of cervical cancer.

  10. Transport properties and association behaviour of the zwitterionic drug 5-aminolevulinic acid in water. A precision conductometric study.

    PubMed

    Merclin, Nadia; Beronius, Per

    2004-02-01

    The behavior of the hydrochloride salt of 5-aminolevulinic acid (ALA-HCl) with respect to transport properties and dissociation in aqueous solution at 25 degrees C has been studied using precision conductometry within the concentration range 0.24-5.17mM. The conductivity data are interpreted according to elaborated conductance theory. The carboxyl group appears to be, in practice, undissociated. The dissociation constant, K(a), of the NH(3)(+) form of the amino acid molecules is determined to 6.78x10(-5) (molarity scale); pK(a)=4.17. The limiting molar conductivity of the ALA-H(+) ion, lambda(0)=33.5cm(2)Omega(-1)mol(-1); electric mobility u=3.47x10(-4)cm(2)V(-1)s(-1), is close to the electric mobilites of the acetate and benzoic ions.

  11. Uptake of topically applied 5-aminolevulinic acid and production of protoporphyrin IX in normal mouse skin: dependence on skin temperature.

    PubMed

    Juzenas, P; Sørensen, R; Iani, V; Moan, J

    1999-04-01

    The temperature dependence of the uptake phase of 5-aminolevulinic acid (ALA) and the following production phase of protoporphyrin IX (PpIX) in normal mouse skin was investigated. A cream containing 20% ALA was topically applied on the skin for 10 min. The amount of ALA-induced PpIX was evaluated by measuring the fluorescence of PpIX from the treated skin. No measurable amount of PpIX was found in the skin immediately after 10 min application of ALA. The penetration of ALA into the skin was almost temperature independent while the following production of PpIX was found to be a strongly temperature-dependent process. Practically no PpIX was formed in the skin as long as skin temperature was kept low (12 degrees C).

  12. Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt Conformational Equilibrium and Enhance Product Release†

    PubMed Central

    Fratz, Erica J.; Clayton, Jerome; Hunter, Gregory A.; Ducamp, Sarah; Breydo, Leonid; Uversky, Vladimir N.; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé; Ferreira, Gloria C.

    2015-01-01

    Regulation of 5-aminolevulinate synthase (ALAS) is at the origin of balanced heme production in mammals. Mutations in the C-terminal region of human erythroid-specific ALAS (hALAS2) are associated with X-linked protoporphyria (XLPP), a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. To investigate the molecular basis for this disease, recombinant hALAS2 and variants of the enzyme harboring the gain-of-function XLPP mutations were constructed, purified, and analyzed kinetically, spectroscopically and thermodynamically. Enhanced activities of the XLPP variants resulted from accelerations in the rate at which the product 5-aminolevulinate (ALA) was released from the enzyme. Circular dichroism spectroscopy revealed that the XLPP mutations altered the microenvironment of the pyridoxal 5’-phosphate cofactor, which underwent further and specific alterations upon succinyl-CoA binding. Transient kinetic analyses of the variant-catalyzed reactions and protein fluorescence quenching upon ALA binding to the XLPP variants demonstrated that the protein conformational transition step associated with product release was predominantly affected. Of relevance, XLPP could also be modeled in cell culture. We propose that 1) the XLPP mutations destabilize the succinyl-CoA-induced hALAS2 closed conformation and thus accelerate ALA release, 2) the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, and 3) this control is disrupted in XLPP, resulting in porphyrin accumulation. PMID:26300302

  13. Evolution of cyclizing 5-aminolevulinate synthases in the biosynthesis of actinomycete secondary metabolites: outcomes for genetic screening techniques

    PubMed Central

    Petříčková, Kateřina; Chroňáková, Alica; Zelenka, Tomáš; Chrudimský, Tomáš; Pospíšil, Stanislav; Petříček, Miroslav; Krištůfek, Václav

    2015-01-01

    A combined approach, comprising PCR screening and genome mining, was used to unravel the diversity and phylogeny of genes encoding 5-aminolevulinic acid synthases (ALASs, hemA gene products) in streptomycetes-related strains. In actinomycetes, these genes were believed to be directly connected with the production of secondary metabolites carrying the C5N unit, 2-amino-3-hydroxycyclopent-2-enone, with biological activities making them attractive for future use in medicine and agriculture. Unlike “classical” primary metabolism ALAS, the C5N unit-forming cyclizing ALAS (cALAS) catalyses intramolecular cyclization of nascent 5-aminolevulinate. Specific amino acid sequence changes can be traced by comparison of “classical” ALASs against cALASs. PCR screening revealed 226 hemA gene-carrying strains from 1,500 tested, with 87% putatively encoding cALAS. Phylogenetic analysis of the hemA homologs revealed strain clustering according to putative type of metabolic product, which could be used to select producers of specific C5N compound classes. Supporting information was acquired through analysis of actinomycete genomic sequence data available in GenBank and further genetic or metabolic characterization of selected strains. Comparison of 16S rRNA taxonomic identification and BOX-PCR profiles provided evidence for numerous horizontal gene transfers of biosynthetic genes or gene clusters within actinomycete populations and even from non-actinomycete organisms. Our results underline the importance of environmental and evolutionary data in the design of efficient techniques for identification of novel producers. PMID:26300877

  14. Effect of 5-aminolevulinic acid on erythropoiesis: a preclinical in vitro characterization for the treatment of congenital sideroblastic anemia.

    PubMed

    Fujiwara, Tohru; Okamoto, Koji; Niikuni, Ryoyu; Takahashi, Kiwamu; Okitsu, Yoko; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Ichinohasama, Ryo; Nakamura, Yukio; Nakajima, Motowo; Tanaka, Tohru; Harigae, Hideo

    2014-11-07

    Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly expressed in erythroid cells. Thus, gamma-aminobutyric acid (GABA) was added to K562 cells to competitively inhibit SLC36A1-mediated transport. GABA treatment significantly impeded the ALA-mediated increase in the number of hemoglobinized cells as well as the induction of HBG, HBA, and HMOX1. Finally, small-interfering RNA

  15. Effect of 5-aminolevulinic acid on erythropoiesis: A preclinical in vitro characterization for the treatment of congenital sideroblastic anemia

    SciTech Connect

    Fujiwara, Tohru; Takahashi, Kiwamu; Okitsu, Yoko; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Ichinohasama, Ryo; Nakamura, Yukio; Nakajima, Motowo; Tanaka, Tohru; Harigae, Hideo

    2014-11-07

    Highlights: • Treatment with ALA induces erythroid differentiation of K562 cells. • Transportation of ALA into erythroid cells occurs predominantly via SLC36A1. • ALA restores defects in ALAS2 in human iPS cell-derived erythroblasts. • ALA may represent a novel therapeutic option for CSA caused by ALAS2 mutations. - Abstract: Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly

  16. Formation of protoporphyrin IX in mouse skin after topical application of 5-aminolevulinic acid and its methyl esther

    NASA Astrophysics Data System (ADS)

    Sorensen, Roar; Juzenas, Petras; Iani, Vladimir; Moan, Johan

    1999-02-01

    Normal skin of nude mice (Balb/c) was treated topically with 5-aminolevulinic acid (ALA) and its methyl ester (ALA-Me) for 24 hours. Approximately 0.1 gram of freshly prepared cream was applied to a spot of 1 cm2 on the flank of the mice, which was then covered with a transparent dressing. The ALA induced protoporphyrin IX (PpIX) was studied by means of a noninvasive fiber-optic fluorescence probe connected to a luminescence spectrometer. The excitation wavelength was 407 nm, and the emission wavelength was 637 nm. For the first hour a slight lag in PpIX production was observed for the mice treated with ALA-Me compared to the mice treated with ALA. After approximately 12 hours the ALA and the ALA-Me treated mice showed the same PpIX fluorescence intensity. From 12 hours until 24 hours the PpIX fluorescence intensity decreased for both treatment modalities, even though ALA and ALA-Me were continuously present. At 24 hours ALA-Me-treated mice had less than half the amount of PpIX in their skin compared with ALA- treated mice.

  17. 5-aminolevulinic acid alleviates the salinity-induced changes in Brassica napus as revealed by the ultrastructural study of chloroplast.

    PubMed

    Naeem, Muhammad S; Warusawitharana, Hasitha; Liu, Hongbo; Liu, Dan; Ahmad, Rashid; Waraich, Ejaz Ahmad; Xu, Ling; Zhou, Weijun

    2012-08-01

    5-Aminolevulinic acid (ALA) is an important plant growth regulator which is derived from 5-carbon aliphatic amino acid. The present study investigates the interaction of increasing NaCl-salinity and ALA on plant growth, leaf pigment composition, leaf and root Na(+)/K(+) ratio and chloroplast ultrastructure in mesophyll cells of oilseed rape (Brassica napus) leaves. The plants were treated hydroponically with three different salinity levels (0, 100, 200 mM) and foliar application of ALA (30 mg l(-1)) simultaneously. Ten days after treatment, higher NaCl-salinity significantly reduced the plant biomass and height. However, ALA application restored the plant biomass and plant height under saline conditions. A concentration-dependent increase in Na(+) uptake was observed in the aerial parts of B. napus plants. On the other hand, ALA reduced Na(+) uptake, leading to a significant decrease in Na(+)/K(+) ratio. Accumulation of Na(+) augmented the oxidative stress, which was evident by electron microscopic images, highlighting several changes in cell shape and size, chloroplast swelling, increased number of plastogloubli, reduced starch granules and dilations of the thylakoids. Foliar application of ALA improved the energy supply and investment in mechanisms (higher chlorophyll and carotenoid contents, enhanced photosynthetic efficiency), reduced the oxidative stress as evident by the regular shaped chloroplasts with more intact thylakoids. On the basis of these results we can suggest that ALA is a promising plant growth regulator which can improve plant survival under salinity.

  18. Optimization of Biomass and 5-Aminolevulinic Acid Production by Rhodobacter sphaeroides ATCC17023 via Response Surface Methodology.

    PubMed

    Liu, Shuli; Zhang, Guangming; Li, Jianzheng; Li, Xiangkun; Zhang, Jie

    2016-06-01

    Microbial 5-aminolevulinic acid (ALA) produced from wastewater is considered as potential renewable energy. However, many hurdles are needed to be overcome such as the regulation of key influencing factors on ALA yield. Biomass and ALA production by Rhodobacter sphaeroides was optimized using response surface methodology. The culturing medium was artificial volatile fatty acids wastewater. Three additives were optimized, namely succinate and glycine that are precursors of ALA biosynthesis, and D-glucose that is an inhibitor of ALA dehydratase. The optimal conditions were achieved by analyzing the response surface plots. Statistical analysis showed that succinate at 8.56 mmol/L, glycine at 5.06 mmol/L, and D-glucose at 7.82 mmol/L were the best conditions. Under these optimal conditions, the highest biomass production and ALA yield of 3.55 g/L and 5.49 mg/g-biomass were achieved. Subsequent verification experiments at optimal values had the maximum biomass production of 3.41 ± 0.002 g/L and ALA yield of 5.78 ± 0.08 mg/g-biomass.

  19. Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice.

    PubMed

    Malik, Z; Kostenich, G; Roitman, L; Ehrenberg, B; Orenstein, A

    1995-06-01

    Topical 5-aminolevulinic acid (ALA) application in three different creams was carried out on mice bearing subcutaneously transplanted C26 colon carcinoma. The creams contained (a) 20% ALA alone, (b) ALA with 2% dimethylsulphoxide (DMSO) and (c) ALA, DMSO and 2% edetic acid disodium salt (EDTA). Protoporphyrin IX (PP) production in the tumour and in the skin overlying the tumour was studied by two methods: laser-induced fluorescence (LIF) and chemical extraction. The kinetics of PP production in the skin and in the tumour, as studied by the LIF method, was similar for all three cream preparations. The PP fluorescence intensity in the tissues reached its maximum 4-6 h after application of the creams. Quantitative analysis showed that the PP concentration after treatment was more pronounced in the skin than in the tumour. The efficiency of porphyrin production in the skin by the creams used was in the following order: ALA-DMSO-EDTA > ALA-DMSO > ALA. In the tumour the enhancing effect of DMSO and EDTA on PP accumulation induced by ALA was observed mainly in the upper 2 mm section. However, the concentration of PP in the tumour was found to be approximately the same for ALA-DMSO and ALA-DMSO-EDTA cream combinations. The possible mechanisms of the effect of DMSO and EDTA are discussed.

  20. Pale-Green Phenotype of atl31 atl6 Double Mutant Leaves Is Caused by Disruption of 5-Aminolevulinic Acid Biosynthesis in Arabidopsis thaliana

    PubMed Central

    Maekawa, Shugo; Takabayashi, Atsushi; Huarancca Reyes, Thais; Yamamoto, Hiroko; Tanaka, Ayumi; Sato, Takeo; Yamaguchi, Junji

    2015-01-01

    Arabidopsis ubiquitin ligases ATL31 and homologue ATL6 control the carbon/nitrogen nutrient and pathogen responses. A mutant with the loss-of-function of both atl31 and atl6 developed light intensity-dependent pale-green true leaves, whereas the single knockout mutants did not. Plastid ultrastructure and Blue Native-PAGE analyses revealed that pale-green leaves contain abnormal plastid structure with highly reduced levels of thylakoid proteins. In contrast, the pale-green leaves of the atl31/atl6 mutant showed normal Fv/Fm. In the pale-green leaves of the atl31/atl6, the expression of HEMA1, which encodes the key enzyme for 5-aminolevulinic acid synthesis, the rate-limiting step in chlorophyll biosynthesis, was markedly down-regulated. The expression of key transcription factor GLK1, which directly promotes HEMA1 transcription, was also significantly decreased in atl31/atl6 mutant. Finally, application of 5-aminolevulinic acid to the atl31/atl6 mutants resulted in recovery to a green phenotype. Taken together, these findings indicate that the 5-aminolevulinic acid biosynthesis step was inhibited through the down-regulation of chlorophyll biosynthesis-related genes in the pale-green leaves of atl31/atl6 mutant. PMID:25706562

  1. In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

    PubMed Central

    Suzuki, Shigeo; Hikosaka, Kenji; Balogun, Emmanuel O.; Komatsuya, Keisuke; Niikura, Mamoru; Kobayashi, Fumie; Takahashi, Kiwamu; Tanaka, Tohru; Nakajima, Motowo

    2015-01-01

    5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe2+) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug. PMID:26324278

  2. Promotion of 5-aminolevulinic acid on photosynthesis of melon (Cucumis melo) seedlings under low light and chilling stress conditions.

    PubMed

    Wang, Liang Ju; Jiang, Wei Bing; Huang, Bao Jian

    2004-06-01

    When melon seedlings (Cucumis melo L. Ximiya No. 1) were cultured in a growth chamber with about 150 micro mol m(-2) s(-1) photon flux density, the leaf photosynthetic ability reduced dramatically as leaf position decreased from the top. The application of 5-aminolevulinic acid (ALA) solutions significantly increased the net photosynthetic rate (P(n)) as well as apparent quantum yield (AQY), carboxylation efficiency (CE) and stomata conductance (G(s)). After irrigation with 10 ml of ALA solution (10 mg l(-1) or 100 mg l(-1)) per container filled with approximately 250 g clean sand for 3 days, the leaf P(n) was about 40-200% higher than that of controls, and AQY, CE and G(s) increased 21-271%, 55-210% and 60-335%, respectively. Furthermore, ALA treatments increased leaf chlorophyll content and soluble sugar levels, as well as the rate of dark respiration, but decreased the rate of respiration under light. On the other hand, after melon seedlings that had been cultured in the chamber suffered chilling at 8 degrees C for 4 h and then recovered at 25-30 degrees C for 2 and 20 h, the P(n) of the water-irrigated plants was only 12-18% and 37-47%, respectively, compared with the initial P(n) before chilling treatment. If the seedlings underwent the same treatment but with ALA (10 mg l(-1)), the respective P(n) was 22-38% and 76-101%, compared with that of the control before chilling stress. If chilling was prolonged for 6 h, the ALA-pre-treated plants only showed a few symptoms in the leaf margins whereas all water-irrigated plants died, which suggested that ALA presumably promoted chilling tolerance of the plants under low light.

  3. Regulation of Cadmium-Induced Proteomic and Metabolic Changes by 5-Aminolevulinic Acid in Leaves of Brassica napus L.

    PubMed

    Ali, Basharat; Gill, Rafaqat A; Yang, Su; Gill, Muhammad B; Farooq, Muhammad A; Liu, Dan; Daud, Muhammad K; Ali, Shafaqat; Zhou, Weijun

    2015-01-01

    It is evident from previous reports that 5-aminolevulinic acid (ALA), like other known plant growth regulators, is effective in countering the injurious effects of heavy metal-stress in oilseed rape (Brassica napus L.). The present study was carried out to explore the capability of ALA to improve cadmium (Cd2+) tolerance in B. napus through physiological, molecular, and proteomic analytical approaches. Results showed that application of ALA helped the plants to adjust Cd2+-induced metabolic and photosynthetic fluorescence changes in the leaves of B. napus under Cd2+ stress. The data revealed that ALA treatment enhanced the gene expressions of antioxidant enzyme activities substantially and could increase the expression to a certain degree under Cd2+ stress conditions. In the present study, 34 protein spots were identified that differentially regulated due to Cd2+ and/or ALA treatments. Among them, 18 proteins were significantly regulated by ALA, including the proteins associated with stress related, carbohydrate metabolism, catalysis, dehydration of damaged protein, CO2 assimilation/photosynthesis and protein synthesis/regulation. From these 18 ALA-regulated proteins, 12 proteins were significantly down-regulated and 6 proteins were up-regulated. Interestingly, it was observed that ALA-induced the up-regulation of dihydrolipoyl dehydrogenase, light harvesting complex photo-system II subunit 6 and 30S ribosomal proteins in the presence of Cd2+ stress. In addition, it was also observed that ALA-induced the down-regulation in thioredoxin-like protein, 2, 3-bisphosphoglycerate, proteasome and thiamine thiazole synthase proteins under Cd2+ stress. Taken together, the present study sheds light on molecular mechanisms involved in ALA-induced Cd2+ tolerance in B. napus leaves and suggests a more active involvement of ALA in plant physiological processes than previously proposed.

  4. Regulation of Cadmium-Induced Proteomic and Metabolic Changes by 5-Aminolevulinic Acid in Leaves of Brassica napus L.

    PubMed Central

    Ali, Basharat; Gill, Rafaqat A.; Yang, Su; Gill, Muhammad B.; Farooq, Muhammad A.; Liu, Dan; Daud, Muhammad K.; Ali, Shafaqat; Zhou, Weijun

    2015-01-01

    It is evident from previous reports that 5-aminolevulinic acid (ALA), like other known plant growth regulators, is effective in countering the injurious effects of heavy metal-stress in oilseed rape (Brassica napus L.). The present study was carried out to explore the capability of ALA to improve cadmium (Cd2+) tolerance in B. napus through physiological, molecular, and proteomic analytical approaches. Results showed that application of ALA helped the plants to adjust Cd2+-induced metabolic and photosynthetic fluorescence changes in the leaves of B. napus under Cd2+ stress. The data revealed that ALA treatment enhanced the gene expressions of antioxidant enzyme activities substantially and could increase the expression to a certain degree under Cd2+ stress conditions. In the present study, 34 protein spots were identified that differentially regulated due to Cd2+ and/or ALA treatments. Among them, 18 proteins were significantly regulated by ALA, including the proteins associated with stress related, carbohydrate metabolism, catalysis, dehydration of damaged protein, CO2 assimilation/photosynthesis and protein synthesis/regulation. From these 18 ALA-regulated proteins, 12 proteins were significantly down-regulated and 6 proteins were up-regulated. Interestingly, it was observed that ALA-induced the up-regulation of dihydrolipoyl dehydrogenase, light harvesting complex photo-system II subunit 6 and 30S ribosomal proteins in the presence of Cd2+ stress. In addition, it was also observed that ALA-induced the down-regulation in thioredoxin-like protein, 2, 3-bisphosphoglycerate, proteasome and thiamine thiazole synthase proteins under Cd2+ stress. Taken together, the present study sheds light on molecular mechanisms involved in ALA-induced Cd2+ tolerance in B. napus leaves and suggests a more active involvement of ALA in plant physiological processes than previously proposed. PMID:25909456

  5. Comprehensive Analysis of 5-Aminolevulinic Acid Dehydrogenase (ALAD) Variants and Renal Cell Carcinoma Risk among Individuals Exposed to Lead

    PubMed Central

    van Bemmel, Dana M.; Boffetta, Paolo; Liao, Linda M.; Berndt, Sonja I.; Menashe, Idan; Yeager, Meredith; Chanock, Stephen; Karami, Sara; Zaridze, David; Matteev, Vsevolod; Janout, Vladimir; Kollarova, Hellena; Bencko, Vladimir; Navratilova, Marie; Szeszenia-Dabrowska, Neonilia; Mates, Dana; Slamova, Alena; Rothman, Nathaniel; Han, Summer S.; Rosenberg, Philip S.; Brennan, Paul; Chow, Wong-Ho; Moore, Lee E.

    2011-01-01

    Background Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. Methods The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results The adjusted risk associated with the ALAD variant rs8177796CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (pint = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results. Conclusion A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure. PMID:21799727

  6. Nitric Oxide Mediates 5-Aminolevulinic Acid-Induced Antioxidant Defense in Leaves of Elymus nutans Griseb. Exposed to Chilling Stress.

    PubMed

    Fu, Juanjuan; Chu, Xitong; Sun, Yongfang; Miao, Yanjun; Xu, Yuefei; Hu, Tianming

    2015-01-01

    Nitric oxide (NO) and 5-aminolevulinic acid (ALA) are both extremely important signalling molecules employed by plants to control many aspects of physiology. In the present study, the role of NO in ALA-induced antioxidant defense in leaves of two sources of Elymus nutans Griseb. (Damxung, DX and Zhengdao, ZD) was investigated. Chilling stress enhanced electrolyte leakage, accumulation of malondialdehyde (MDA), hydrogen peroxide (H2O2) and superoxide radical in two E. nutans, which were substantially alleviated by exogenous ALA and NO application. Pretreatment with NO scavenger PTIO or NOS inhibitor L-NNA alone and in combination with ALA induced enhancements in electrolyte leakage and the accumulation of MDA, H2O2 and superoxide radical in leaves of DX and ZD exposed to chilling stress, indicating that the inhibition of NO biosynthesis reduced the chilling resistance of E. nutans and the ALA-enhanced chilling resistance. Further analyses showed that ALA and NO enhanced antioxidant defense and activated plasma membrane (PM) H+-ATPase and decreased the accumulation of ROS induced by chilling stress. A pronounced increase in nitric oxide synthase (NOS) activity and NO release by exogenous ALA treatment was found in chilling-resistant DX plants exposed to chilling stress, while only a little increase was observed in chilling-sensitive ZD. Furthermore, inhibition of NO accumulation by PTIO or L-NNA blocked the protective effect of exogenous ALA, while both exogenous NO treatment and inhibition of endogenous NO accumulation did not induce ALA production. These results suggested that NO might be a downstream signal mediating ALA-induced chilling resistance in E. nutans.

  7. Expression pattern and intensity of protoporphyrin IX induced by liposomal 5-aminolevulinic acid in rat pilosebaceous unit throughout hair cycle.

    PubMed

    Han, Insook; Jun, Mee Sook; Kim, Soo-Kyun; Kim, Moonkyu; Kim, Jung Chul

    2005-11-01

    We have developed liposomal formulation of 5-aminolevulinic acid (ALA) to enhance topical delivery and examined ALA-induced protoporpyrin (PpIX) expression in rat pilosebaceous unit throughout hair cycle. Two types of liposomes--glycerol dilaulate (GDL) and phosphatidylcholine (PC)--were formulated and both liposomal ALA increased PpIX expression in rat dorsal skin and pilosebaceous units when compared with free ALA. However, iontophoresis combined with liposomal ALA reduced the expression intensity of PpIX in hair bulbs although it achieved deeper and wider expression of PpIX through transfollicular pathway. After topical application in intact or depilated rat skin, liposomal ALA produced excellent PpIX expression in pilosebaceous units. The expression pattern and intensity of PpIX changed in hair cycle-dependent manner: specific expression only in sebaceous glands was observed at telogen; strong expression in whole pilosebaceous units was shown at anagen with intense expressions in hair bulbs and sebaceous glands; and a pattern similar to anagen but reduced intensity in the hair bulbs was seen at catagen. Throughout hair cycle, the expression pattern and intensity were dramatically changed in hair follicular epithelial cells depending on the cell density and proliferation activity of those cells, whereas those were consistent in sebaceous glands regardless of hair cycle. Little expression was shown in dermis. Photoactivation effect of 20% liposomal ALA-PDT using a red filtered-halogen lamp damaged sebaceous glands, hair follicles and epidermal layers. Formation of a thicker epidermal layer was observed, and hair induction after depilation was inhibited along with damage in sebaceous glands.

  8. Expression of the Rhodobacter sphaeroides hemA and hemT genes, encoding two 5-aminolevulinic acid synthase isozymes.

    PubMed Central

    Neidle, E L; Kaplan, S

    1993-01-01

    The nucleotide sequences of the Rhodobacter sphaeroides hemA and hemT genes, encoding 5-aminolevulinic acid (ALA) synthase isozymes, were determined. ALA synthase catalyzes the condensation of glycine and succinyl coenzyme A, the first and rate-limiting step in tetrapyrrole biosynthesis. The hemA and hemT structural gene sequences were 65% identical to each other, and the deduced HemA and HemT polypeptide sequences were 53% identical, with an additional 16% of aligned amino acids being similar. HemA and HemT were homologous to all characterized ALA synthases, including two human ALA synthase isozymes. In addition, they were evolutionarily related to 7-keto-8-aminopelargonic acid synthetase (BioF) and 2-amino-3-ketobutyrate coenzyme A ligase (Kbl), enzymes which catalyze similar reactions. Two hemA transcripts were identified, both expressed under photosynthetic conditions at levels approximately three times higher than those found under aerobic conditions. A single transcriptional start point was identified for both transcripts, and a consensus sequence at this location indicated that an Fnr-like protein may be involved in the transcriptional regulation of hemA. Transcription of hemT was not detected in wild-type cells under the physiological growth conditions tested. In a mutant strain in which the hemA gene had been inactivated, however, hemT was expressed. In this mutant, hemT transcripts were characterized by Northern (RNA) hybridization, primer extension, and ribonuclease protection techniques. A small open reading frame of unknown function was identified upstream of, and transcribed in the same direction as, hemA. Images PMID:8468290

  9. Efficacy of a Complex of 5-Aminolevulinic Acid and Glycyl-Histidyl-Lysine Peptide on Hair Growth

    PubMed Central

    Sim, Hyun Bo; Jang, Yong Hyun; Lee, Seok-Jong; Kim, Do Won; Yim, Soon-Ho

    2016-01-01

    Background Pattern hair loss is a very common problem. Although effective therapeutics for the treatment of pattern hair loss have been used, novel therapeutic modalities are still required to enhance hair growth. Objective We investigated the efficacy and safety of a complex (ALAVAX) of 5-aminolevulinic acid (5-ALA) and glycyl-histidyl-lysine (GHK) peptide for the treatment of pattern hair loss. Methods Forty-five patients with male pattern hair loss were treated with ALAVAX 100 mg/ml (group A), ALAVAX 50 mg/ml (group B) or placebo (group C) once a day for 6 months. Total hair count, hair length, hair thickness, patient's assessment and adverse events were evaluated at month 1, 3, and 6. Results An increase in hair count for 6 months was 52.6 (p<0.05) in group A, 71.5 (p<0.05) in group B, and 9.6 in group C. The ratio of changes in hair count between group B (2.38) and group C (1.21) at 6 months showed a statistically significant difference (p<0.05). The proportion above good satisfaction was higher in group A (26.7%) than in the other groups (group B: 14.3%, group C: 7.1%). There was no statistically significant difference in hair length and hair thickness among 3 groups at 6 months. There was no adverse event in 3 groups. Conclusion Our study showed that a complex of 5-ALA and GHK peptide may be considered as one of the complementary agents for the treatment of male pattern hair loss. PMID:27489425

  10. Role of 5-aminolevulinic acid (ALA) on active oxygen-scavenging system in NaCl-treated spinach (Spinacia oleracea).

    PubMed

    Nishihara, Eiji; Kondo, Kensuke; Parvez, Mohammad Masud; Takahashi, Kuniaki; Watanabe, Keitaro; Tanaka, Kiyoshi

    2003-09-01

    ALA is a key precursor in the biosynthesis of porphyrins such as chlorophyll and heme, and was found to induce temporary elevations in the photosynthesis rate, APX, and CAT; furthermore, treatment with ALA at a low concentration might be correlated to the increase of NaCl tolerance of spinach plants. The photosynthetic rate and the levels of active oxygen-scavenging system in the 3rd leaf of spinach (Spinacia oleracea) plants grown by foliar treatment with 0, 0.18, 0.60 and 1.80 mmol/L 5-aminolevulinic acid under 50 and 100 mmol/L NaCl were analyzed. Plants treated with 0.60 and 1.80 mmol/L ALA showed significant increases in the photosynthetic rate at 50 and 100 mmol/L NaCl, while that of 0.18 mmol/L ALA did not show any changes at 50 mmol/L NaCl and a gradual decrease at 100 mmol/L NaCl. In contrast, the rate with 0 mmol/L ALA showed reduction at both concentrations of NaCl. The increase of hydrogen peroxide content by treatment with 0.60 and 1.80 mmol/L ALA were more controlled than that of 0 mmol/L ALA under both NaCl conditions. These ALA-treated spinach leaves also exhibited a lower oxidized/reduced ascorbate acid ratio and a higher reduced/oxidized glutathione ratio than the 0 mmol/L-treated spinach leaves when grown at both NaCl conditions. With regard to the antioxidant enzyme activities in the leaves, ascorbate peroxidase, catalase, and glutathione reductase activities were enhanced remarkably, most notably at day 3, by treatment with 0.60 and 1.80 mmol/L ALA under both NaCl conditions in comparison to that of 0 and 0.18 mmol/L ALA. These data indicate that the protection against oxidative damage by higher levels of antioxidants and enzyme activities, and by a more active ascorbate-glutathione cycle related to the increase of the photosynthesis rate, could be involved in the increased salt tolerance observed in spinach by treatment with 0.60 to 1.80 mmol/L ALA with NaCl.

  11. Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study

    PubMed Central

    Teixidor, Pilar; Vidal, Xavier; Montané, Eva

    2016-01-01

    Background During the last decade, the use of 5-aminolevulinic acid (5-ALA) has been steadily increasing in neurosurgery. The study's main objectives were to prospectively evaluate the effectiveness and safety of 5-ALA when used in clinical practice setting on high-grade gliomas’ patients. Methods National, multicenter and prospective observational study. Inclusion criteria: authorized conditions of use of 5-ALA. Exclusion criteria: contraindication to 5-ALA, inoperable or partial resected tumors, pregnancy and children. Epidemiological, clinical, laboratory, radiological, and safety data were collected. Effectiveness was assessed using complete resection of the tumor, and progression-free and overall survival probabilities. Results Between May 2010 and September 2014, 85 patients treated with 5-ALA were included, and 77 were suitable for the effectiveness analysis. Complete resection was achieved in 41 patients (54%). Surgeons considered suboptimal the fluorescence of 5-ALA in 40% of the patients assessed. The median duration of follow-up was 12.3 months. The progression-free survival probability at 6 months was 58%. The median duration overall survival was 14.2 months. Progression tumor risk factors were grade of glioma, age and resection degree; and death risk factors were grade of glioma and gender. No severe adverse effects were reported. At one month after surgery, new or increased neurological morbidity was 6.5%. Hepatic enzymes were frequently increased within the first month after surgery; however, they subsequently normalized, and this was found to have no clinical significance. Conclusion In clinical practice, the 5-ALA showed a good safety profile, but the benefits related to 5-ALA have not been yet clearly shown. The improved differentiation expected by fluorescence between normal and tumor cerebral tissue was suboptimal in a relevant number of patients; in addition, the expected higher degree of resection was lower than in clinical trials as well as

  12. A first-principles study of functionalized clusters and carbon nanotubes or fullerenes with 5-Aminolevulinic acid as vehicles for drug delivery

    NASA Astrophysics Data System (ADS)

    Kia, Majid; Golzar, Maryam; Mahjoub, Kosar; Soltani, Alireza

    2013-10-01

    At present work, we explore the adsorption properties of the 5-Aminolevulinic acid (5ALA) interacting with SWCNTs, C60, and C24 by density functional ab initio (DFT) calculations. It was found that the electronic structure of C60 is more sensitive to the presence of 5ALA in comparison with C24, (5, 5), and (9, 0) SWCNT. Our results demonstrate that the interactions between 5ALA and the nanostructures are chemisorption. The natural bond orbital (NBO) and density of states (DOSs) analyses represent that the nature of 5ALA adsorption on the applied nanostructures is permanently electrostatic rather than covalent.

  13. Expression of a hemA gene from Agrobacterium radiobacter in a rare codon optimizing Escherichia coli for improving 5-aminolevulinate production.

    PubMed

    Fu, Weiqi; Lin, Jianping; Cen, Peilin

    2010-01-01

    The 5-aminolevulinate (ALA) synthase gene (hemA) from Agrobacterium radiobacter zju-0121, which was cloned previously in our laboratory, contains several rare codons. To enhance the expression of this gene, Escherichia coli Rosetta(DE3), which is a rare codon optimizer strain, was picked out as the host to construct an efficient recombinant strain. Cell extracts of the recombinant E. coli were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under the appropriate conditions. The results indicated that the activity of ALA synthase expressed in Rosetta(DE3)/pET-28a(+)-hemA was about 20% higher than that in E. coli BL21(DE3). Then the effects of precursors (glycine and succinate) and glucose, which is an inhibitor for ALA dehydratase as well as the carbon sources for cell growth, on the production of 5-aminolevulinate were investigated. Based on an optimal fed-batch culture system described in our previous work, up to 6.5 g/l (50 mM) ALA was produced in a 15-l fermenter.

  14. Photodynamic therapy of acne vulgaris.

    NASA Astrophysics Data System (ADS)

    Ershova, Ekaterina Y.; Karimova, Lubov N.; Kharnas, Sergey S.; Kuzmin, Sergey G.; Loschenov, Victor B.

    2003-06-01

    Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) was tested for the treatment of acne vulgaris. Patients with acne were treated with ALA plus red light. Ten percent water solution of ALA was applied with 1,5-2 h occlusion and then 18-45 J/cm2 630 nm light was given. Bacterial endogenous porphyrins fluorescence also was used for acne therapy. Treatment control and diagnostics was realized by fluorescence spectra and fluorescence image. Light sources and diagnostic systems were used: semiconductor laser (λ=630 nm, Pmax=1W), (LPhT-630-01-BIOSPEC); LED system for PDT and diagnostics with fluorescent imager (λ=635 nm, P=2W, p=50 mW/cm2), (UFPh-630-01-BIOSPEC); high sensitivity CCD video camera with narrow-band wavelength filter (central wavelength 630 nm); laser electronic spectrum analyzer for fluorescent diagnostics and photodynamic therapy monitoring (LESA-01-BIOSPEC). Protoporphyrin IX (PP IX) and endogenous porphyrins concentrations were measured by fluorescence at wavelength, correspondingly, 700 nm and 650 nm. It was shown that topical ALA is converted into PP IX in hair follicles, sebaceous glands and acne scars. The amount of resulting PP IX is sufficient for effective PDT. There was good clinical response and considerable clearance of acne lesion. ALA-PDT also had good cosmetic effect in treatment acne scars. PDT with ALA and red light assist in opening corked pores, destroying Propionibacterium acnes and decreasing sebum secretion. PDT treatment associated with several adverse effects: oedema and/or erytema for 3-5 days after PDT, epidermal exfoliation from 5th to 10th day and slight pigmentation during 1 month after PDT. ALA-PDT is effective for acne and can be used despite several side effects.

  15. Protoporphyrin IX distribution after intra-articular and systemic application of 5-aminolevulinic acid in healthy and arthritic joints

    NASA Astrophysics Data System (ADS)

    Huettmann, Gereon; Hendrich, Christian; Birngruber, Reginald; Lehnert, Christiane; Seara, Jose; Siebert, Werner E.; Diddens, Heyke C.

    1996-04-01

    Arthroscopic synovectomy, which is limited today to the large joints, is an important early treatment of rheumatoid arthritis (RA). Photodynamic therapy (PDT) is potentially to be a less invasive method of removing the synovial membrane. Therefore, in a rabbit model of RA, the accumulation of the photosensitizer Protoporphyrin IX (PPIX) after intra-articular and systemic application of ALA into arthritic rabbit knee joints was studied in skin, patella, synovial tissue, and meniscus by fluorescence microscopy. PPIX fluorescence was measured in biopsies taken at different times after application of neutral and acid ALA solutions. Significant PPIX fluorescence was observed in the synovial membrane and skin 2 and 4 hours after application. Using intra-articular application, ALA solutions prepared with pH 5.5 were at least as efficient as neutral solutions in sensitizing the synovial membrane. Skin also showed PPIX within 4 hours after application. After 24 hours, a marginal PPIX fluorescence was detected in these tissues. On the other hand, in cartilage and meniscus significant PPIX accumulation was still observed 24 hours after ALA injection. Systemic application of ALA also showed a good accumulation of PPIX. Further experiments are needed to show whether accumulation of the photosensitizer and tissue selectivity are sufficient for a successful treatment of rheumatoid synovitis.

  16. Catalytically active alkaline molten globular enzyme: Effect of pH and temperature on the structural integrity of 5-aminolevulinate synthase.

    PubMed

    Stojanovski, Bosko M; Breydo, Leonid; Hunter, Gregory A; Uversky, Vladimir N; Ferreira, Gloria C

    2014-12-01

    5-Aminolevulinate synthase (ALAS), a pyridoxal-5'phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in mammals. Circular dichroism (CD) and fluorescence spectroscopies were used to examine the effects of pH (1.0-3.0 and 7.5-10.5) and temperature (20 and 37°C) on the structural integrity of ALAS. The secondary structure, as deduced from far-UV CD, is mostly resilient to pH and temperature changes. Partial unfolding was observed at pH2.0, but further decreasing pH resulted in acid-induced refolding of the secondary structure to nearly native levels. The tertiary structure rigidity, monitored by near-UV CD, is lost under acidic and specific alkaline conditions (pH10.5 and pH9.5/37°C), where ALAS populates a molten globule state. As the enzyme becomes less structured with increased alkalinity, the chiral environment of the internal aldimine is also modified, with a shift from a 420nm to 330nm dichroic band. Under acidic conditions, the PLP cofactor dissociates from ALAS. Reaction with 8-anilino-1-naphthalenesulfonic acid corroborates increased exposure of hydrophobic clusters in the alkaline and acidic molten globules, although the reaction is more pronounced with the latter. Furthermore, quenching the intrinsic fluorescence of ALAS with acrylamide at pH1.0 and 9.5 yielded subtly different dynamic quenching constants. The alkaline molten globule state of ALAS is catalytically active (pH9.5/37°C), although the kcat value is significantly decreased. Finally, the binding of 5-aminolevulinate restricts conformational fluctuations in the alkaline molten globule. Overall, our findings prove how the structural plasticity of ALAS contributes to reaching a functional enzyme.

  17. Evaluating the efficacy and safety of a novel endoscopic fluorescence imaging modality using oral 5-aminolevulinic acid for colorectal tumors

    PubMed Central

    Tsuruki, Eriko So; Saito, Yutaka; Abe, Seiichiro; Takamaru, Hiroyuki; Yamada, Masayoshi; Sakamoto, Taku; Nakajima, Takeshi; Matsuda, Takahisa; Sekine, Shigeki; Taniguchi, Hirokazu

    2016-01-01

    Background and study aims: Five-aminolevulinic acid (5-ALA) is being increasingly used for photodynamic diagnosis and therapy of various types of tumors including brain, urologic, and other neoplasias. The use of 5-ALA to treat Barrett’s carcinomas has been documented, but its clinical effectiveness for diagnosis of gastrointestinal tumors, particularly early cancers, remains unknown. Patients and methods: The aim of our feasibility study was to evaluate the visibility of colorectal tumors using endoscopic fluorescence imaging (EFI) after oral administration of 5-ALA. The lesions identified by direct visualization and by the spectrums produced using EFI modality with 5-ALA were compared to the clinicopathologic features of resected specimens. Results: Twenty-three patients with a total of 27 known colorectal lesions were enrolled in the study. The median tumor size was 30 mm (range 10 – 75). Eleven of the lesions were flat or depressed lesions and 16 were sessile. Red fluorescence was observed in 22 out of 27 lesions. Red fluorescence was negative in 4 out of 11 flat or depressed lesions. In comparison with histopathologic findings, the rates of red fluorescence visibility were 62.5 % in low-grade intraepithelial neoplasia, 77.8 % in high-grade neoplasia, and 100 % in submucosal carcinoma. Red fluorescence visibility increased with the degree of dysplasia. There were no significant adverse events identified in this study. Conclusions: This feasibility study using EFI with 5-ALA demonstrated high visibility of superficial colorectal neoplasia. EFI with 5-ALA appears to be a novel, safe technique for improving real-time colorectal tumor imaging. PMID:26793782

  18. Photodynamic Therapy for Non-Melanoma Skin Cancers

    PubMed Central

    Cohen, Diana K.; Lee, Peter K.

    2016-01-01

    Non-melanoma skin cancer (NMSC) is traditionally treated with surgical excision. Non-surgical methods such as cryotherapy and topical chemotherapeutics, amongst other treatments, are other options. Actinic keratosis (AKs) are considered precancerous lesions that eventually may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) offers an effective treatment for AKs, and is also effective for superficial basal cell carcinoma (BCC). Nodular BCC and Bowen’s disease (SCC in situ) have shown acceptable response rates with PDT, although recurrence rates are higher for these two NMSC subtypes. Methylaminolevulinate (MAL) PDT is a more effective treatment option than 5-aminolevulinic acid (ALA) PDT for nodular BCC. Several studies have shown that PDT results in superior cosmetic outcomes compared to surgical treatment. PDT is overall well-tolerated, with pain being the most common side effect. PMID:27782043

  19. Photodynamic therapy for the treatment of actinic cheilitis.

    PubMed

    Kodama, Makiko; Watanabe, Daisuke; Akita, Yoichi; Tamada, Yasuhiko; Matsumoto, Yoshinari

    2007-10-01

    Although actinic cheilitis is a common disease, it should be treated carefully because it can undergo malignant transformation. We report a case of actinic cheilitis treated with photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA), with satisfactory outcome in both clinical and pathological aspects. Actinic cheilitis is a pathologic condition affecting mainly the lower lip caused by long-term exposure of the lips to the UV radiation in sunlight. Analogous to actinic keratosis of the skin, actinic cheilitis is considered as a precancerous lesion and it may develop into squamous cell carcinoma. We report a case of actinic cheilitis treated with PDT using ALA, with satisfactory outcome in both clinical and pathological aspects.

  20. Photodynamic therapy (ALA-PDT) in the treatment of pathological states of the cornea

    NASA Astrophysics Data System (ADS)

    Switka-Wieclawska, Iwona; Kecik, Tadeusz; Kwasny, Miroslaw; Graczyk, Alfreda

    2003-10-01

    Each year an increasing amount of research is published on the use of photodynamic therapy in medicine. The most recent research has focused mostly on the use of photosensitizer called vertoporphyrin (Visudyne) is the treatment of subretinal neovascularization in age-related macular degeneration (AMD) or myopia, following a substantial amount of ophthalmology research mostly experimental on the application of the method in diagnosis and treatment of some eye tumors. In the Department of Ophthalmology of Polish Medical University in Warsaw, PDT was used as supplementary method in a selected group of patients with chronic virus ulcer of the cornea and keratopathies. During the treatment 5-aminolevulinic acid (5-ALA) was applied in ointment form as a photosensitizer activated with light wave of 633 nm. It appears, on the basis of the results obtained, that photodynamic therapy (ALA-PDT) may become in the future a valuable supplement to the methods being used at the present treating pathological states of the cornea.

  1. A Pilot Cost-Effectiveness Analysis of Treatments in Newly Diagnosed High-Grade Gliomas: The Example of 5-Aminolevulinic Acid Compared With White-Light Surgery

    PubMed Central

    Alves, Marta; Castel-Branco, Marta; Stummer, Walter

    2015-01-01

    BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on

  2. Alleviation of Lead Toxicity by 5-Aminolevulinic Acid Is Related to Elevated Growth, Photosynthesis, and Suppressed Ultrastructural Damages in Oilseed Rape

    PubMed Central

    Tian, Tian; Qin, Yebo; Gill, Rafaqat A.; Ali, Shafaqat

    2014-01-01

    Lead (Pb) is a widely spread pollutant and leads to diverse morphological and structural changes in the plants. In this study, alleviating role of 5-aminolevulinic acid (ALA) in oilseed rape (Brassica napus L.) was investigated with or without foliar application of ALA (25 mg L−1) in hydroponic environment under different Pb levels (0, 100, and 400 µM). Outcomes stated that plant morphology and photosynthetic attributes were reduced under the application of Pb alone. However, ALA application significantly increased the plant growth and photosynthetic parameters under Pb toxicity. Moreover, ALA also lowered the Pb concentration in shoots and roots under Pb toxicity. The microscopic studies depicted that exogenously applied ALA ameliorated the Pb stress and significantly improved the cell ultrastructures. After application of ALA under Pb stress, mesophyll cell had well-developed nucleus and chloroplast having a number of starch granules. Moreover, micrographs illustrated that root tip cell contained well-developed nucleus, a number of mitochondria, and golgi bodies. These results proposed that under 15-day Pb-induced stress, ALA improved the plant growth, chlorophyll content, photosynthetic parameters, and ultrastructural modifications in leaf mesophyll and root tip cells of the B. napus plants. PMID:24683549

  3. Promotive role of 5-aminolevulinic acid on chromium-induced morphological, photosynthetic, and oxidative changes in cauliflower (Brassica oleracea botrytis L.).

    PubMed

    Ahmad, Rehan; Ali, Shafaqat; Hannan, Fakhir; Rizwan, Muhammad; Iqbal, Muhammad; Hassan, Zaidul; Akram, Nudrat Aisha; Maqbool, Saliha; Abbas, Farhat

    2017-03-01

    Chromium (Cr) is among the most toxic pollutants in the environment that adversely affect the living organisms and physiological processes in different plants. The present study investigated the effect of 15 mg L(-1) of 5-aminolevulinic acid (ALA) on morpho-physiological attributes of cauliflower (Brassica oleracea botrytis L.) under different Cr concentrations (0, 10, 100, and 200 μM) in the growth medium. The results showed that Cr stress decreased the growth, biomass, photosynthetic, and gas exchange parameters. Chromium stress enhanced the activities of enzymatic antioxidants, catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) in response to oxidative stress caused by the elevated levels of malondialdehyde (MDA), hydrogen peroxide (H2O2), and electrolyte leakage (EL) in both roots and leaves of cauliflower. Chromium concentrations and total Cr uptake were increased in leaves, stems, and roots with increasing Cr levels in the culture medium. Foliar application of ALA increased the plant growth parameters, biomass, gas exchange parameters, and photosynthetic pigments under Cr stress compared to the treatments without ALA. Foliar application ALA decreased the levels of MDA, EL, and H2O2 while further improved the performance of antioxidant in both leaves and roots compared to only Cr-stressed plant. Chromium concentrations and total Cr uptake were decreased by the ALA application compared to treatments without ALA application. The results of the present study indicated that foliar application of ALA might be beneficial in minimizing Cr uptake and its toxic effects in cauliflower.

  4. High light inhibits chlorophyll biosynthesis at the level of 5-aminolevulinate synthesis during de-etiolation in cucumber (Cucumis sativus) cotyledons.

    PubMed

    Aarti, D; Tanaka, R; Ito, H; Tanaka, A

    2007-01-01

    Using the vascular plant Cucumis sativus (cucumber) as a model, we studied the effects of high (intense and excess) light upon chlorophyll biosynthesis during de-etiolation. When illuminated with high light (1500-1600 microE/m2/s), etiolated cucumber cotyledons failed to synthesize chlorophyll entirely. However, upon transfer to low light conditions (40-45 microE/m2/s), chlorophyll biosynthesis and subsequent accumulation resumed following an initial 2-12 h delay. Duration of high light treatment negatively correlated with chlorophyll biosynthetic activity. Specifically, we found that high light severely inhibited 5-aminolevulinic acid (ALA) synthesis. This effect partly could be because of the decrease in protein level of glutamyl-tRNA reductase (GluTR) observed. Protein level of glutamate-1-semialdehyde (GSA-AT) remained unchanged. It was also found that high light did not suppress HEMA 1 expression. Therefore, we speculated that this significant inhibition of ALA synthesis might have occurred mainly because of concomitant inactivation of GluTR and/or inhibition of complex formation between GluTR and GSA-AT. Our further observation that both methyl viologen and rose bengal similarly inhibit ALA synthesis under low light conditions suggested that reactive oxygen species (ROS) could be responsible for the inhibition of ALA synthesis in cotyledons exposed to high light conditions.

  5. 5-Aminolevulinic acid induces single-strand breaks in plasmid pBR322 DNA in the presence of Fe2+ ions.

    PubMed

    Onuki, J; Medeiros, M H; Bechara, E J; Di Mascio, P

    1994-02-22

    5-Aminolevulinic acid (ALA), a heme precursor accumulated in chemical and inborn porphyrias, has been demonstrated to produce reactive oxygen species upon metal-catalyzed aerobic oxidation and to cause oxidative damage to proteins, liposomes and subcellular structures. Exposure of plasmid pBR322 DNA to ALA (0.01-3 mM) in the presence of 10 microM Fe2+ ions causes DNA single-strand breaks (ssb), revealed by agarose gel electrophoresis as an increase in the proportion of the open circular form (75 +/- 7.5% at 3 mM ALA) at the expense of the supercoiled form. Addition of either anti-oxidant enzymes such as superoxide dismutase (10 micrograms/ml) and catalase (20 micrograms/ml), or a metal chelator (DTPA, 2.5 mM), or a HO. scavenger (mannitol, 100 mM) inhibited the damage (by 30, 45, 55, and 81%, respectively), evidencing the involvement of O2-., H2O2 and HO. (by the Haber-Weiss reaction) in this process. Hydrogen peroxide (100 microM) or Fe2+ (10 microM) alone were of little effect on the extent of DNA ssb. The present data may shed light on the correlation reported between primary liver-cell carcinoma and intermittent acute porphyria.

  6. The Safety and Tolerability of 5-Aminolevulinic Acid Phosphate with Sodium Ferrous Citrate in Patients with Type 2 Diabetes Mellitus in Bahrain

    PubMed Central

    Al-Saber, Feryal; Aldosari, Waleed; Alselaiti, Mariam; Khalfan, Hesham; Kaladari, Ahmed; Khan, Ghulam; Harb, George; Rehani, Riyadh; Kudo, Sizuka; Koda, Aya; Tanaka, Tohru

    2016-01-01

    Type 2 diabetes mellitus is prevalent especially in Gulf countries and poses serious long-term risks to patients. A multifaceted treatment approach can include nutritional supplements with antioxidant properties such as 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC). This prospective, randomized, single-blind, placebo-controlled, dose escalating pilot clinical trial assessed the safety of 5-ALA with SFC at doses up to 200 mg 5-ALA/229.42 mg SFC per day in patients living in Bahrain with type 2 diabetes mellitus that was uncontrolled despite the use of one or more antidiabetic drugs. Fifty-three patients (n = 53) from 3 sites at one center were enrolled by Dr. Feryal (Site #01), Dr. Hesham (Site #02), and Dr. Waleed (Site #03) (n = 35, 5-ALA-SFC; n = 18, placebo). There was no significant difference in incidence of adverse events reported, and the most frequent events reported were gastrointestinal in nature, consistent with the known safety profile of 5-ALA in patients with diabetes. No significant changes in laboratory values and no difference in hypoglycemia between patients receiving 5-ALA and placebo were noted. Overall, the current results support that use of 5-ALA-SFC up to 200 mg per day taken as 2 divided doses is safe in patients taking concomitant oral antidiabetic medications and may offer benefits in the diabetic population. This trial is registered with ClinicalTrials.gov NCT02481141. PMID:27738640

  7. Alleviation of lead toxicity by 5-aminolevulinic acid is related to elevated growth, photosynthesis, and suppressed ultrastructural damages in oilseed rape.

    PubMed

    Tian, Tian; Ali, Basharat; Qin, Yebo; Malik, Zaffar; Gill, Rafaqat A; Ali, Shafaqat; Zhou, Weijun

    2014-01-01

    Lead (Pb) is a widely spread pollutant and leads to diverse morphological and structural changes in the plants. In this study, alleviating role of 5-aminolevulinic acid (ALA) in oilseed rape (Brassica napus L.) was investigated with or without foliar application of ALA (25 mg L(-1)) in hydroponic environment under different Pb levels (0, 100, and 400 µM). Outcomes stated that plant morphology and photosynthetic attributes were reduced under the application of Pb alone. However, ALA application significantly increased the plant growth and photosynthetic parameters under Pb toxicity. Moreover, ALA also lowered the Pb concentration in shoots and roots under Pb toxicity. The microscopic studies depicted that exogenously applied ALA ameliorated the Pb stress and significantly improved the cell ultrastructures. After application of ALA under Pb stress, mesophyll cell had well-developed nucleus and chloroplast having a number of starch granules. Moreover, micrographs illustrated that root tip cell contained well-developed nucleus, a number of mitochondria, and golgi bodies. These results proposed that under 15-day Pb-induced stress, ALA improved the plant growth, chlorophyll content, photosynthetic parameters, and ultrastructural modifications in leaf mesophyll and root tip cells of the B. napus plants.

  8. 5-aminolevulinic acid induced lipid peroxidation after light exposure on human colon carcinoma cells and effects of alpha-tocopherol treatment.

    PubMed

    Gederaas, O A; Lagerberg, J W; Brekke, O; Berg, K; Dubbelman, T M

    2000-10-16

    This work relates to studies on modes of phototoxicity by protoporphyrin (PpIX) after incubation of 5-aminolevulinic acid (5-ALA) on cultured cells. Lipid peroxidation in the 5-ALA incubated primary adenocarcinoma cells from the rectosigmoid colon (WiDr cells) was determined by measurement of protein-associated thiobarbituric acid reactive substances (TBARS). TBARS were increased 2-fold in cells treated with 2 mM 5-ALA for 3.5 h in serum enriched medium. After illumination of 5-ALA incubated cells, TBARS were formed in a light dose dependent manner. TBARS analysis were compared with high-performance liquid chromatography (HPLC) analysis of malondialdehyde, and results indicate that 90% of the thiobarbituric reactive substances were due to malondialdehyde. Pretreating WiDr cells with alpha-tocopherol for 48 h inhibits the cytotoxic effect of 5-ALA and increases 5-fold the light dose needed to kill 50% of the cells. Pretreatment with alpha-tocopherol shows a considerable decrease (about 80%) on TBARS formation after illumination. The cellular content of alpha-tocopherol was determined by HPLC and found to be 15.3 pmol/10(6) cells.

  9. Production of uroporphyrinogen III, which is the common precursor of all tetrapyrrole cofactors, from 5-aminolevulinic acid by Escherichia coli expressing thermostable enzymes.

    PubMed

    Hibino, Aiko; Petri, René; Büchs, Jochen; Ohtake, Hisao

    2013-08-01

    Uroporphyrinogen III (urogen III) was produced from 5-aminolevulinic acid (ALA), which is a common precursor of all metabolic tetrapyrroles, using thermostable ALA dehydratase (ALAD), porphobilinogen deaminase (PBGD), and urogen III synthase (UROS) of Thermus thermophilus HB8. The UROS-coding gene (hemD₂) of T. thermophilus HB8 was identified by examining the gene product for its ability to produce urogen III in a coupled reaction with ALAD and PBGD. The genes encoding ALAD, PBGD, and UROS were separately expressed in Escherichia coli BL21 (DE3). To inactivate indigenous mesophilic enzymes, the E. coli transformants were heated at 70 °C for 10 min. The bioconversion of ALA to urogen III was performed using a mixture of heat-treated E. coli transformants expressing ALAD, PBGD, and UROS at a cell ratio of 1:1:1. When the total cell concentration was 7.5 g/l, the mixture of heat-treated E. coli transformants could convert about 88 % 10 mM ALA to urogen III at 60 °C after 4 h. Since eight ALA molecules are required for the synthesis of one porphyrin molecule, approximately 1.1 mM (990 mg/l) urogen III was produced from 10 mM ALA. The present technology has great potential to supply urogen III for the biocatalytic production of vitamin B₁₂.

  10. Photodynamic therapy for cancer

    MedlinePlus

    ... Cancer of the esophagus-photodynamic; Esophageal cancer-photodynamic; Lung cancer-photodynamic ... the light at the cancer cells. PDT treats cancer in the: Lungs, using a bronchoscope Esophagus, using upper endoscopy Doctors ...

  11. 5-ALA based photodynamic management of glioblastoma

    NASA Astrophysics Data System (ADS)

    Rühm, Adrian; Stepp, Herbert; Beyer, Wolfgang; Hennig, Georg; Pongratz, Thomas; Sroka, Ronald; Schnell, Oliver; Tonn, Jörg-Christian; Kreth, Friedrich-Wilhelm

    2014-03-01

    Objective: Improvement of the clinical outcome of glioblastoma (GBM) patients by employment of fluorescence and photosensitization on the basis of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX). Methods: In this report the focus is laid on the use of tumor selective PpIX fluorescence for stereotactic biopsy sampling and intra-operative treatment monitoring. In addition, our current concept for treatment planning is presented. For stereotactic interstitial photodynamic therapy (iPDT), radial diffusers were implanted into the contrast enhancing tumor volume. Spectroscopic measurements of laser light transmission and fluorescence between adjacent fibers were performed prior, during and post PDT. Results: PpIX concentrations in primary glioblastoma tissue show high intra- and inter-patient variability, but are usually sufficient for an effective PDT. During individual treatment attempts with 5-ALA based GBM-iPDT, transmission and fluorescence measurements between radial diffusers gave the following results: 1. In some cases, transmission after PDT is considerably reduced compared to the value before PDT, which may be attributable to a depletion of oxygenated hemoglobin and/or diffuse bleeding. 2. PpIX fluorescence is efficiently photobleached during PDT in all cases. Conclusion: iPDT with assessment of PpIX fluorescence and photobleaching is a promising treatment option. Individualization of treatment parameters appears to bear a potential to further improve clinical outcomes.

  12. Oil components modulate the skin delivery of 5-aminolevulinic acid and its ester prodrug from oil-in-water and water-in-oil nanoemulsions

    PubMed Central

    Zhang, Li-Wen; Al-Suwayeh, Saleh A; Hung, Chi-Feng; Chen, Chih-Chieh; Fang, Jia-You

    2011-01-01

    The study evaluated the potential of nanoemulsions for the topical delivery of 5-aminolevulinic acid (ALA) and methyl ALA (mALA). The drugs were incorporated in oil-in-water (O/W) and water-in-oil (W/O) formulations obtained by using soybean oil or squalene as the oil phase. The droplet size, zeta potential, and environmental polarity of the nanocarriers were assessed as physicochemical properties. The O/W and W/O emulsions showed diameters of 216–256 and 18–125 nm, which, respectively, were within the range of submicron- and nano-sized dispersions. In vitro diffusion experiments using Franz-type cells and porcine skin were performed. Nude mice were used, and skin fluorescence derived from protoporphyrin IX was documented by confocal laser scanning microscopy (CLSM). The loading of ALA or mALA into the emulsions resulted in slower release across cellulose membranes. The release rate and skin flux of topical drug application were adjusted by changing the type of nanocarrier, the soybean oil O/W systems showing the highest skin permeation. This formulation increased ALA flux via porcine skin to 180 nmol/cm2/h, which was 2.6-fold that of the aqueous control. The CLSM results showed that soybean oil systems promoted mALA permeation to deeper layers of the skin from ∼100 μm to ∼140 μm, which would be beneficial for treating subepidermal and subcutaneous lesions. Drug permeation from W/O systems did not surpass that from the aqueous solution. An in vivo dermal irritation test indicated that the emulsions were safe for topical administration of ALA and mALA. PMID:21556344

  13. Effects of exogenous 5-aminolevulinic acid on PIP1 and NIP aquaporin gene expression in seedlings of cucumber cultivars subjected to salinity stress.

    PubMed

    Yan, F; Qu, D; Zhao, Y Y; Hu, X H; Zhao, Z Y; Zhang, Y; Zou, Z R

    2014-01-22

    Aquaporins play a direct role in plant water relation under salt stress, but the effects of 5-aminolevulinic acid (ALA) on aquaporin gene expression in salt-treated plants remain unknown. This study investigated the potential effects of exogenous ALA (50 mg/dm3) on aquaporin expression levels under salt stress (75 mM NaCl) in the salt-sensitive (Jinchun No.4) and the relatively salt-tolerant cucumber (Jinyou No.1) seedlings. The expressions of cucumber PIP aquaporin gene (CsPIP1:1) and cucumber NIP aquaporin gene (CsNIP) were analyzed in 20-day-old seedling leaves at 2, 4, 8, 16, and 24 h after ALA treatment. After treatment with saline alone and ALA alone, CsPIP1:1 and CsNIP gene expression levels in the 2 cucumber cultivars increased to maximum at 2 h. The aquaporin gene expression in salt-treated cucumber seedling leaves was considerably higher than that in leaves subjected to exogenous ALA. Further, the aquaporin expression levels in Jinchun No.4 were higher than those in Jinyou No.1, reaching 5.20- and 2-fold induction levels, respectively. After treatment with both ALA and NaCl, the CsNIP gene expression was downregulated in both the cucumber cultivars, while that of CsPIP1:1 decreased at 2 h and then increased to 3.8-fold in Jinchun No.4. In Jinyou No.1, CsPIP1:1 gene expression gradually increased to 2.3-fold at 4 h, followed by a decline in expression. The results indicated that ALA might delay and counteract the upregulated expression of CsPIP1:1 and CsNIP genes in cucumber seedlings under NaCl stress. Thus, salt tolerance of cucumber seedlings might be enhanced by ALA application.

  14. Effects of exogenous 5-aminolevulinic acid on photosynthesis, stomatal conductance, transpiration rate, and PIP gene expression of tomato seedlings subject to salinity stress.

    PubMed

    Zhao, Y Y; Yan, F; Hu, L P; Zhou, X T; Zou, Z R; Cui, L R

    2015-06-11

    The effects of exogenous 5-aminolevulinic acid (ALA) on photosynthesis, plant growth, and the expression of two aquaporin genes in tomato seedlings under control and salinity conditions were investigated. Exogenous ALA application significantly improved net photosynthetic rate (Pn), total chlorophyll content, and plant biomass accumulation of tomato seedlings under salinity stress. As revealed by real-time PCR analyses, after treatment with ALA alone, expression of both LePIP1 and LePIP2 in the two tomato cultivars was up-regulated at 2 h and subsequently decreased to normal levels. Under salinity stress, transcript levels of LePIP1 in both leaves and roots of salt-sensitive cultivars (cv. Zhongza No.9) increased significantly and were considerably higher than in cultivars exposed to ALA alone. In contrast, the expression levels of LePIP1 and LePIP2 in cvs. Jinpeng No.1 cultivars were slightly lower under salinity stress than under ALA treatment. In addition, transcript levels of both LePIP1 and LePIP2 in the roots of Jinpeng No. 1 cultivars were considerably lower than those in the roots of Zhongza No. 9 cultivars under salinity stress, regardless of ALA supplementation, implying that Jinpeng No. 1 cultivars had a better capacity to maintain membrane intrinsic protein stability. Further, ALA application distinctly counteracted the up- or down-regulation of LePIP1 and LePIP2 in both cultivars under salinity stress, in accordance with the improvements instomatal conductance, transpiration rate, and Pn of tomato leaves. The results presented here indicate that ALA controls aquaporin expression, thus, presumably ALA regulates water homeostasis and enhances salt tolerance of tomato seedlings.

  15. The application of 5-aminolevulinic acid in the treatment of precancerous lesions, skin cancer, and a new approach to the control of therapy

    NASA Astrophysics Data System (ADS)

    Kulas, Zbigniew; Bereś-Pawlik, Elżbieta; Bieniek, Andrzej; Matusiak, Łukasz

    2009-02-01

    The aim of our work was to determine a therapeutic effect of photodynamic therapy (PDT). Twenty five patients with the Bowen's disease, actinic keratosis and basal cell carcinoma (superficial, nodular) were examined. They were treated with photosensitizer - aminolevulinic acid (metabolized in protoporphyrin IX), and the new red light source built of high-power diodes. A new method, based on numerical analysis of fluorescence imaging of tissues, was proposed as a way for controlling therapy.

  16. Effect of cell cycle phase on the sensitivity of SAS cells to sonodynamic therapy using low-intensity ultrasound combined with 5-aminolevulinic acid in vitro.

    PubMed

    Li, Nan; Sun, Miao; Wang, Yao; Lv, Yanhong; Hu, Zheng; Cao, Wenwu; Zheng, Jinhua; Jiao, Xiaohui

    2015-08-01

    Sonodynamic therapy (SDT) with 5-aminolevulinic acid (5-ALA) can effectively inhibit various types of tumor in vitro and in vivo. However, the association between the efficacy of SDT and the phase of the cell cycle remains to be elucidated. 5-ALA may generate different quantities of sonosensitizer, protoporphyrin IX (PpIX), in different phases of the cell cycle, which may result in differences in sensitivity to 5-ALA-induced SDT. The present study aimed to investigate the effect of the cell cycle on the susceptibility of SAS cells to SDT following synchronization to different cell cycle phases. These results indicates that the rates of cell death and apoptosis of the SAS cells in the S and G2/M phases were significantly higher following SDT, compared with those in the G1-phase cells and unsynchronized cells, with a corresponding increase in PpIX in the S and G2/M cells. In addition, the expression of caspase-3 increased, while that of B-cell lymphoma (Bcl)-2 decreased markedly in theS and G2/M cells following SDT. Cyclin A was also expressed at higher levels in the S and G2/M cells, compared with the G1-phase cells. SDT also caused a significant upregulation of cyclin A in all phases of the cell cycle, however this was most marked in the S and G2/M cells. It was hypothesized that high expression levels of cyclin A in the S and G2/M cells may promote the induction of caspase-3 and reduce the induction of Bcl-2 by SDT and, therefore, enhance apoptosis. Taken together, these data demonstrated that cells in The S and G2/M phases generate more intracellular PpIX, have higher levels of cyclin A and are, therefore, more sensitive to SDT-induced cytotoxicity. These findings indicate the potential novel approach to preventing the onset of cancer by combining cell-cycle regulators with SDT. This sequential combination therapy may be a simple and cost-effective way of enhancing the effects of SDT in clinical settings.

  17. Photodynamic therapy of diseased bone

    NASA Astrophysics Data System (ADS)

    Bisland, Stuart K.; Yee, Albert; Siewerdsen, Jeffery; Wilson, Brian C.; Burch, Shane

    2005-08-01

    Objective: Photodynamic therapy (PDT) defines the oxygen-dependent reaction that occurs upon light-mediated activation of a photosensitizing compound, culminating in the generation of cytotoxic, reactive oxygen species, predominantly, singlet oxygen. We are investigating PDT treatment of diseased bone. Methods: Using a rat model of human breast cancer (MT-1)-derived bone metastasis we confirmed the efficacy of benzoporphyrin-derivative monoacid (BPD-MA)-PDT for treating metastatic lesions within vertebrae or long bones. Results: Light administration (150 J) 15 mins after BPDMA (2.5 mg/Kg, i.v.) into the lumbar (L3) vertebra of rats resulted in complete ablation of the tumour and surrounding bone marrow 48 hrs post-PDT without paralysis. Porcine vertebrae provided a model comparable to that of human for light propagation (at 150 J/cm) and PDT response (BPD-MA; 6 mg/m2, i.v.) in non-tumour vertebrae. Precise fibre placement was afforded by 3-D cone beam computed tomography. Average penetration depth of light was 0.16 +/- 0.04 cm, however, the necrotic/non-necrotic interface extended 0.6 cm out from the treatment fiber with an average incident fluence rate of 4.3 mW/cm2. Non-necrotic tissue damage was evident 2 cm out from the treatment fiber. Current studies involving BPD-MA-PDT treatment of primary osteosarcomas in the forelimbs of dogs are very promising. Magnetic resonance imaging 24 hr post treatment reveal well circumscribed margins of treatment that encompass the entire 3-4 cm lesion. Finally, we are also interested in using 5-aminolevulinic acid (ALA) mediated PDT to treat osteomyelitis. Response to therapy was monitored as changes in bioluminescence signal of staphylococcus aureus (SA)-derived biofilms grown onto 0.5 cm lengths of wire and subjected to ALA-PDT either in vitro or in vivo upon implant into the intramedullary space of rat tibia. Transcutaneous delivery of PDT (75 J/cm2) effectively eradicated SAbiofilms within bone. Conclusions: Results support

  18. Dye laser photodynamic therapy for Bowen's disease in a patient with epidermodysplasia verruciformis.

    PubMed

    Sunohara, Mari; Ozawa, Toshiyuki; Morimoto, Kuniyuki; Harada, Teruichi; Ishii, Masamitsu; Fukai, Kazuyoshi

    2012-12-01

    Epidermodysplasia verruciformis (EV) is a rare heritable skin disease that results in unusual susceptibility to infection with specific types of human papillomavirus (HPV). Here we report a 53-year-old man with EV who developed Bowen's disease on his lower eyelid and the chest. Mutation analysis of EVER1 gene revealed homozygous splice acceptor site mutation (IVS8-2, A > T). In this patient, HPV3, HPV14, and HPV38 had been identified from the skin lesions. The Bowen's skin lesion on the left lower eye-lid was treated by photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) and pulsed dye laser (PDL). After two rounds of the PDT treatment, the skin lesion disappeared and a skin biopsy confirmed the efficacy of the treatment. This method was simple, less invasive than other treatments, and achieved a satisfactory cosmetic result.

  19. Photodynamic therapy potentiates the paracrine endothelial stimulation by colorectal cancer

    NASA Astrophysics Data System (ADS)

    Lamberti, María Julia; Florencia Pansa, María; Emanuel Vera, Renzo; Belén Rumie Vittar, Natalia; Rivarola, Viviana Alicia

    2014-11-01

    Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death worldwide. Recurrence is a major problem and is often the ultimate cause of death. In this context, the tumor microenvironment influences tumor progression and is considered as a new essential feature that clearly impacts on treatment outcome, and must therefore be taken into consideration. Photodynamic therapy (PDT), oxygen, light and drug-dependent, is a novel treatment modality when CRC patients are inoperable. Tumor vasculature and parenchyma cells are both potential targets of PDT damage modulating tumor-stroma interactions. In biological activity assessment in photodynamic research, three-dimensional (3D) cultures are essential to integrate biomechanical, biochemical, and biophysical properties that better predict the outcome of oxygen- and drug-dependent medical therapies. Therefore, the objective of this study was to investigate the antitumor effect of methyl 5-aminolevulinic acid-PDT using a light emitting diode for the treatment of CRC cells in a scenario that mimics targeted tissue complexity, providing a potential bridge for the gap between 2D cultures and animal models. Since photodynamic intervention of the tumor microenvironment can effectively modulate the tumor-stroma interaction, it was proposed to characterize the endothelial response to CRC paracrine communication, if one of these two populations is photosensitized. In conclusion, we demonstrated that the dialogue between endothelial and tumor populations when subjected to lethal PDT conditions induces an increase in angiogenic phenotype, and we think that it should be carefully considered for the development of PDT therapeutic protocols.

  20. Usefulness of Photodynamic Therapy in the Management of Onychomycosis.

    PubMed

    Robres, P; Aspiroz, C; Rezusta, A; Gilaberte, Y

    2015-12-01

    Onychomycosis, or fungal infection of the nails, is one of the most prevalent fungal diseases in the general population. Treatment is of limited effectiveness, tedious, and must be administered for long periods. Furthermore, systemic antifungal agents are associated with adverse effects. Photodynamic therapy (PDT) may prove to be a viable alternative in the treatment of superficial skin infections, including onychomycosis. We review articles relating to the usefulness of PDT in onychomycosis in both in vitro and in vivo settings and discuss the potential and limitations of various photosensitizing agents. In vivo, methylene blue and 5-aminolevulinic acid have led to cure rates in 80% and 43% of cases, respectively, at 12 months. Finally, based on data in the literature and our own experience, we propose a protocol of 3 PDT sessions, separated by an interval of 1 or 2 weeks, using methyl aminolevulinate 16% as a photosensitizing agent and red light (λ=630 nm, 37 J.cm(-2)). Each session is preceded by the topical application of urea 40% over several days. Clinical trials are needed to optimize PDT protocols and to identify those patients who will benefit most from this treatment.

  1. Photodynamic therapy improves the ultraviolet-irradiated hairless mice skin

    NASA Astrophysics Data System (ADS)

    Jorge, Ana Elisa S.; Hamblin, Michael R.; Parizotto, Nivaldo A.; Kurachi, Cristina; Bagnato, Vanderlei S.

    2014-03-01

    Chronic exposure to ultraviolet (UV) sunlight causes premature skin aging. In light of this fact, photodynamic therapy (PDT) is an emerging modality for treating cancer and other skin conditions, however its response on photoaged skin has not been fully illustrated by means of histopathology. For this reason, the aim of this study was analyze whether PDT can play a role on a mouse model of photoaging. Hence, SKH-1 hairless mice were randomly allocated in two groups, UV and UV/PDT. The mice were daily exposed to an UV light source (280-400 nm: peak at 350 nm) for 8 weeks followed by a single PDT session using 20% 5-aminolevulinic acid (ALA) topically. After the proper photosensitizer accumulation within the tissue, a non-coherent red (635 nm) light was performed and, after 14 days, skin samples were excised and processed for light microscopy, and their sections were stained with hematoxylin-eosin (HE) and Masson's Trichrome. As a result, we observed a substantial epidermal thickening and an improvement in dermal collagen density by deposition of new collagen fibers on UV/PDT group. These findings strongly indicate epidermal and dermal restoration, and consequently skin restoration. In conclusion, this study provides suitable evidences that PDT improves the UV-irradiated hairless mice skin, supporting this technique as an efficient treatment for photoaged skin.

  2. Fractionated illumination after topical application of 5-aminolevulinic acid on normal skin of hairless mice: the influence of the dark interval.

    PubMed

    de Bruijn, H S; van der Ploeg-van den Heuvel, A; Sterenborg, H J C M; Robinson, D J

    2006-12-01

    We have previously shown that light fractionation during topical aminolevulinic acid based photodynamic therapy (ALA-PDT) with a dark interval of 2h leads to a significant increase in efficacy in both pre-clinical and clinical PDT. However this fractionated illumination scheme required an extended overall treatment time. Therefore we investigated the relationship between the dark interval and PDT response with the aim of reducing the overall treatment time without reducing the efficacy. Five groups of mice were treated with ALA-PDT using a single light fraction or the two-fold illumination scheme with a dark interval of 30 min, 1, 1.5 and 2h. Protoporphyrin IX fluorescence kinetics were monitored during illumination. Visual skin response was monitored in the first seven days after PDT and assessed as PDT response. The PDT response decreases with decreasing length of the dark interval. Only the dark interval of 2h showed significantly more damage compared to all the other dark intervals investigated (P<0.05 compared to 1.5h and P<0.01 compared to 1h, 30 min and a single illumination). No relationship could be shown between the utilized PpIX fluorescence during the two-fold illumination and the PDT response. The rate of photobleaching was comparable for the first and the second light fraction and not dependent of the length of dark interval used. We conclude that in the skin of the hairless mouse the dark interval cannot be reduced below 2h without a significant reduction in PDT efficacy.

  3. Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments.

    PubMed

    Garland, Martin J; Cassidy, Corona M; Woolfson, David; Donnelly, Ryan F

    2009-07-01

    Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin(®) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of

  4. An irradiation system for photodynamic therapy with a fiber-optic sensor for measuring tissue oxygen

    NASA Astrophysics Data System (ADS)

    Quintanar, L.; Fabila, D.; Stolik, S.; de la Rosa, J. M.

    2013-11-01

    Photodynamic Therapy is a well known treatment based on the interaction of light of specific wavelength with a photosensitizing drug. In the presence of oxygen molecules, the illumination of the photosensitizer can activate the production of reactive oxygen species, which leads to the death of target cells within the treated tissue. In order to obtain the best therapy response, the tissue oxygen concentration should be measured to adjust the therapy parameters before and during the treatment. In this work, an irradiation system for 5-Aminolevulinic Acid Photodynamic Therapy is presented. It allows the application of visible light radiation of 630 nm using as a light source a high-brightness light emitting diode with an optical-power automatic control considering a light depth-distribution model. A module to measure the tissue oxygen saturation has been implemented into the system. It is based on two light emitting diodes of 660 nm and 940 nm as light sources, a photodiode as a detector and a new handheld fiber optic reflectance pulse oximetry sensor for estimating the blood oxygen saturation within the tissue. The pulse oximetry sensor was modeled through multilayered Monte Carlo simulations to study the behavior of the sensor with changes in skin thickness and melanin content.

  5. Topical delivery of a preformed photosensitizer for photodynamic therapy of cutaneous lesions

    NASA Astrophysics Data System (ADS)

    Oleinick, Nancy L.; Kenney, Malcolm E.; Lam, Minh; McCormick, Thomas; Cooper, Kevin D.; Baron, Elma D.

    2012-02-01

    Photosensitizers for photodynamic therapy (PDT) are most commonly delivered to patients or experimental animals via intravenous injection. After initial distribution throughout the body, there can be some preferential accumulation within tumors or other abnormal tissue in comparison to the surrounding normal tissue. In contrast, the photosensitizer precursor, 5-aminolevulinic acid (ALA) or one of its esters, is routinely administered topically, and more specifically, to target skin lesions. Following metabolic conversion to protoporphyrin IX, the target area is photoilluminated, limiting peripheral damage and targeting the effective agent to the desired region. However, not all skin lesions are responsive to ALA-PDT. Topical administration of fully formed photosensitizers is less common but is receiving increased attention, and some notable advances with selected approved and experimental photosensitizers have been published. Our team has examined topical administration of the phthalocyanine photosensitizer Pc 4 to mammalian (human, mouse, pig) skin. Pc 4 in a desired formulation and concentration was applied to the skin surface at a rate of 5-10 μL/cm2 and kept under occlusion. After various times, skin biopsies were examined by confocal microscopy, and fluorescence within regions of interest was quantified. Early after application, images show the majority of the Pc 4 fluorescence within the stratum corneum and upper epidermis. As a function of time and concentration, penetration of Pc 4 across the stratum corneum and into the epidermis and dermis was observed. The data indicate that Pc 4 can be delivered to skin for photodynamic activation and treatment of skin pathologies.

  6. Colloidal gold nanorings for improved photodynamic therapy through field-enhanced generation of reactive oxygen species

    NASA Astrophysics Data System (ADS)

    Hu, Yue; Yang, Yamin; Wang, Hongjun; Du, Henry

    2013-02-01

    Au nanostructures that exhibit strong localized surface plasmon resonance (SPR) have excellent potential for photo-medicine, among a host of other applications. Here, we report the synthesis and use of colloidal gold nanorings (GNRs) with potential for enhanced photodynamic therapy of cancer. The GNRs were fabricated via galvanic replacement reaction of sacrificial Co nanoparticles in gold salt solution with low molecular weight (Mw = 2,500) poly(vinylpyrrolidone) (PVP) as a stabilizing agent. The size and the opening of the GNRs were controlled by the size of the starting Co particles and the concentration of the gold salt. UV-Vis absorption measurements indicated the tunability of the SPR of the GNRs from 560 nm to 780 nm. MTT assay showed that GNRs were non-toxic and biocompatible when incubated with breast cancer cells as well as the healthy counterpart cells. GNRs conjugated with 5-aminolevulinic acid (5-ALA) photosensitizer precursor led to elevated formation of reactive oxygen species and improved efficacy of photodynamic therapy of breast cancer cells under light irradiation compared to 5-ALA alone. These results can be attributed to significantly enhance localized electromagnetic field of the GNRs.

  7. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.

    PubMed

    Cotter, P D; May, A; Li, L; Al-Sabah, A I; Fitzsimons, E J; Cazzola, M; Bishop, D F

    1999-03-01

    X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

  8. Concurrent bladder cancer in patients undergoing photodynamic diagnostic ureterorenoscopy: how many lesions do we miss under white light cystoscopy?

    PubMed Central

    Zreik, Abdullah; Ahmad, Sarfraz; Chłosta, Piotr; Aboumarzouk, Omar

    2016-01-01

    Introduction There is an ongoing debate on panurothelial changes in the upper and lower urinary tract as multifocal presentation of urothelial cancer is well recognised. Concurrent bladder cancer impacts the outcome of the upper urinary tract urothelial cancer treatment, while its detection still relies on the white light cystoscopy. Material and methods We retrospectively reviewed all patients who underwent photodynamic diagnostic ureterorenoscopy, choosing those who had synchronous bladder biopsies. Each patient received 20 mg/kg body weight of oral 5-Aminolevulinic acid around 3–4 hours before endoscopy. All procedures were performed by a single endourologist experienced in photodynamic diagnosis and flexible ureterorenoscopy. Results Between July 2009 and June 2013, 69 patients underwent bladder biopsies at the time of photodynamic diagnostic endoscopic inspection of the upper urinary tract. In total, 43.5% (30/69) patients were found to have bladder lesions, of which 43.3% (13/30) were proven to be carcinoma in situ. White light inspection of the bladder missed bladder cancer in 16 (23.1%) patients, of which 12 were carcinoma in situ. There were 14 bladder cancer lesions missed under white light which were concomitant to the upper urinary tract urothelial cancer. Twelve (17.4%) patients developed minor complications relevant to the photosensitizer. Conclusions The study raises a concern about missing small bladder cancer/carcinoma in situ lesions on the initial diagnosis or in surveillance of the upper urinary tract urothelial cancer. Higher than previously reported, the rate of concomitant bladder cancer may suggest utilisation of photodynamic diagnosis to ensure the cancer free status of the bladder, but this needs to be ratified in a multi-institutional randomised trial. PMID:28127447

  9. In-vitro study on ALA-induced endogenous protoporphyrin IX as photosensitizer for photodynamic tumor diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Ueberriegler, K.; Fiedler, D.; Verwanger, Thomas; Schnitzhofer, Gerlinde; Banieghbal, E.; Krammer, Barbara E.

    1998-07-01

    Photodynamic tumor diagnosis and therapy is efficiently carried out by endogenous protoporphyrin IX as photosensitizer, induced by external addition of the precursor 5-aminolevulinic acid (ALA). In the present study, PpIX localization and photodynamically induced damage was investigated in normal and transformed human fibroblasts. PpIX formation reaches its maximum after incubation for at least 20 h with 700 (mu) g/m1 ALA, and increases with the pH- value. ALA has to be given 20-30 times more than external PpIX in order to produce the same cytotoxic damage. As detected by Low Light Imaging, PpIX is generated in the mitochondria, released to the cytoplasm and distributed to cytoplasma and nuclear membranes.The nucleus is not stained. Intracellular targets of PpIX damage after irradiation are mainly mitochondria, ER and nuclear membrane. The organelles show a decomposition pattern, which resembles apoptotic morphology and occurs faster in the co-cultivated transformed than in the normal cells. ALA-treated hepatocytes produce micronuclei and chromosomal aberrations, which indicates some mutagenic potential. Expression studies of the (proto)oncogenes c-myc and bcl-2 sublethally treated fibroblasts by quantitative RT-PCR show high deviations from the constitutive expression level, which are accompanied by cell cycle disturbances, indicating a possible precursor role to apoptosis introduction.

  10. Routine experimental system for defining conditions used in photodynamic therapy and fluorescence photodetection of (non-) neoplastic epithelia

    NASA Astrophysics Data System (ADS)

    Lange, Norbert; Vaucher, Laurent; Marti, Alexandre; Etter, Anne-Lise; Gerber, Patrick; van den Bergh, Hubert; Jichlinski, Patrice; Kucera, Pavel

    2001-04-01

    A common method to induce enhanced short-term endogenous porphyrin synthesis and accumulation in cell is the topical, systemic application of 5-aminolevulinic acid or one of its derivatives. This circumvents the intravenous administration of photosensitizers normally used for photodynamic therapy (PDT) of fluorescence photodetection. However, in the majority of potential medical indications, optimal conditions with respect to the porphyrin precursor or its pharmaceutical formulation have not yet been found. Due to ethical restrictions and animal right directives, the number of available test objects is limited. Hence, definition and use of nonanimal test methods are needed. Tissue and organ cultures are a promising approach in replacing cost intensive animal models in early stages of drug development. In this paper, we present a tissue culture, which can among others be used routinely to answer specific questions emerging in the field of photodynamic therapy and fluorescence photodetection. This technique uses mucosae excised from sheep paranasal sinuses or pig bladder, which is cultured under controlled conditions. It allows quasiquantative testing of different protoporphyrin IX precursors with respect to dose-response curves and pharmacokinetics, as well as the evaluation of different incubation conditions and/or different drug formulations. Furthermore, this approach, when combined with the use of electron microscopy and fluorescence-based methods, can be used to quantitatively determine the therapeutic outcome following protoporphyrin IX-mediated PDT.

  11. Mechanistic studies of malonic acid-mediated in situ acylation.

    PubMed

    Chandra, Koushik; Naoum, Johnny N; Roy, Tapta Kanchan; Gilon, Chaim; Gerber, R Benny; Friedler, Assaf

    2015-09-01

    We have previously introduced an easy to perform, cost-effective and highly efficient acetylation technique for solid phase synthesis (SPPS). Malonic acid is used as a precursor and the reaction proceeds via a reactive ketene that acetylates the target amine. Here we present a detailed mechanistic study of the malonic acid-mediated acylation. The influence of reaction conditions, peptide sequence and reagents was systematically studied. Our results show that the methodology can be successfully applied to different types of peptides and nonpeptidic molecules irrespective of their structure, sequence, or conformation. Using alkyl, phenyl, and benzyl malonic acid, we synthesized various acyl peptides with almost quantitative yields. The ketenes obtained from the different malonic acid derived precursors were characterized by in situ (1) H-NMR. The reaction proceeded in short reaction times and resulted in excellent yields when using uronium-based coupling agents, DIPEA as a base, DMF/DMSO/NMP as solvents, Rink amide/Wang/Merrifield resins, temperature of 20°C, pH 8-12 and 5 min preactivation at inert atmosphere. The reaction was unaffected by Lewis acids, transition metal ions, surfactants, or salt. DFT studies support the kinetically favorable concerted mechanism for CO2 and ketene formation that leads to the thermodynamically stable acylated products. We conclude that the malonic acid-mediated acylation is a general method applicable to various target molecules.

  12. The effect of dimethylsulfoxide, 1-[2-(decylthio)ethyl]azacyclopentan-2-one and Labrafac(®)CC on porphyrin formation in normal mouse skin during topical application of methyl 5-aminolevulinate: A fluorescence and extraction study.

    PubMed

    Bugaj, Andrzej; Iani, Vladimir; Juzeniene, Asta; Juzenas, Petras; Ma, Li-Wei; Moan, Johan

    2006-03-01

    In this work, the effect of 10% of dimethylsulfoxide (DMSO), 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101) and Labrafac(®)CC (a mixture of caprylic and capric acid triglycerides) on porphyrin formation in mouse skin during topical application of methyl 5-aminolevulinate (MAL) was studied. The porphyrin level in mouse skin was determined by measuring directly fluorescence and by extraction method. The porphyrin fluorescence kinetics during continuous application of MAL in creams in concentrations 2, 10 and 20% (wt./wt.) for up to 7h showed that in this concentration range the kinetics of porphyrin production in the site of application does not depend significantly on the MAL concentration. After 24h of application of all studied creams the porphyrin fluorescence in the area of treatment was dramatically reduced to be about two-fold higher than the skin autofluorescence, suggesting a significant decrease of the porphyrin concentration in these sites, although in all cases traces of porphyrins were found. It was found by extraction method that a 10% MAL cream with 10% DMSO for 4h increased the concentration of porphyrin about four-fold compared with 10% MAL cream alone. The presence of 10% HPE-101 or 10% Labrafac(®)CC in the 10% MAL cream increased the porphyrin concentration in the area of application about 2.5- and 2-fold, respectively, as compared with MAL cream without enhancers. No statistically significant difference was found between the effects of the creams containing 10% MAL with 10% HPE-101 or 10% Labrafac(®)CC. The results obtained after 24h of mouse skin treatment with the same creams showed a large decrease of porphyrin formation in comparison with results found after 4h. All porphyrin concentrations measured after this time of MAL creams application were similar. Skin erythema was observed using MAL cream with DMSO and HPE-101, but not with Labrafac(®)CC. Our work suggests that the new penetration enhancer Labrafac(®)CC in creams with MAL

  13. Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling.

    PubMed

    Vignion-Dewalle, Anne-Sophie; Betrouni, Nacim; Tylcz, Jean-Baptiste; Vermandel, Maximilien; Mortier, Laurent; Mordon, Serge

    2015-05-01

    Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J∕cm2, 75 mW∕cm2, 500 s; blue light dose, 10 J∕cm2, 10 mW∕cm2, 1000 s; and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable.

  14. Study of false positives in 5-ALA induced photodynamic diagnosis of bladder carcinoma

    NASA Astrophysics Data System (ADS)

    Draga, Ronald O. P.; Grimbergen, Matthijs C. M.; Kok, Esther T.; Jonges, Trudy G. N.; Bosch, J. L. H. R.

    2009-02-01

    Photodynamic diagnosis (PDD) is a technique that enhances the detection of tumors during cystoscopy using a photosensitizer which accumulates primarily in cancerous cells and will fluoresce when illuminated by violetblue light. A disadvantage of PDD is the relatively low specificity. In this retrospective study we aimed to identify predictors for false positive findings in PDD. Factors such as gender, age, recent transurethral resection of bladder tumors (TURBT), previous intravesical therapy (IVT) and urinary tract infections (UTIs) were examined for association with the false positive rates in a multivariate analysis. Data of 366 procedures and 200 patients were collected. Patients were instilled with 5-aminolevulinic acid (5-ALA) intravesically and 1253 biopsies were taken from tumors and suspicious lesions. Female gender and TURBT are independent predictors of false positives in PDD. However, previous intravesical therapy with Bacille Calmette-Guérin is also an important predictor of false positives. The false positive rate decreases during the first 9-12 weeks after the latest TURBT and the latest intravesical chemotherapy. Although shortly after IVT and TURBT false positives increase, PDD improves the diagnostic sensitivity and results in more adequate treatment strategies in a significant number of patients.

  15. Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling

    NASA Astrophysics Data System (ADS)

    Vignion-Dewalle, Anne-Sophie; Betrouni, Nacim; Tylcz, Jean-Baptiste; Vermandel, Maximilien; Mortier, Laurent; Mordon, Serge

    2015-05-01

    Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J/cm2, 75 mW/cm2, 500 s blue light dose, 10 J/cm2, 10 mW/cm2, 1000 s and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable.

  16. Photodynamic and Antibiotic Therapy in Combination to Fight Biofilms and Resistant Surface Bacterial Infections

    PubMed Central

    Barra, Federica; Roscetto, Emanuela; Soriano, Amata A.; Vollaro, Adriana; Postiglione, Ilaria; Pierantoni, Giovanna Maria; Palumbo, Giuseppe; Catania, Maria Rosaria

    2015-01-01

    Although photodynamic therapy (PDT), a therapeutic approach that involves a photosensitizer, light and O2, has been principally considered for the treatment of specific types of cancers, other applications exist, including the treatment of infections. Unfortunately, PDT does not always guarantee full success since it exerts lethal effects only in cells that have taken up a sufficient amount of photosensitizer and have been exposed to adequate light doses, conditions that are not always achieved. Based on our previous experience on the combination PDT/chemotherapy, we have explored the possibility of fighting bacteria that commonly crowd infected surfaces by combining PDT with an antibiotic, which normally does not harm the strain at low concentrations. To this purpose, we employed 5-aminolevulinic acid (5-ALA), a pro-drug that, once absorbed by proliferating bacteria, is converted into the natural photosensitizer Protoporphyrin IX (PpIX), followed by Gentamicin. Photoactivation generates reactive oxygen species (ROS) which damage or kill the cell, while Gentamicin, even at low doses, ends the work. Our experiments, in combination, have been highly successful against biofilms produced by several Gram positive bacteria (i.e., Staphylococcus aureus, Staphylococcus epidermidis, etc.). This original approach points to potentially new and wide applications in the therapy of infections of superficial wounds and sores. PMID:26343645

  17. Photodynamic therapy induces epidermal thickening in hairless mice skin: an optical coherence tomography assessment

    NASA Astrophysics Data System (ADS)

    Jorge, Ana Elisa S.; Campos, Carolina P.; Freitas, Anderson Z.; Bagnato, Vanderlei S.

    2014-03-01

    Photodynamic therapy (PDT) promotes skin improvement according to many practitioners, however the immediately in vivo assessment of its response remains clinically inaccessible. As a non-invasive modality, optical coherence tomography (OCT) has been shown a feasible optical diagnostic technique that provides images in real time, avoiding tissue biopsies. For this reason, our investigation focused on evaluates the PDT effect on a rodent model by means of OCT. Therefore, a normal hairless mouse skin has undergone a single-session PDT, which was performed with topical 5- aminolevulinic acid (ALA) cream using a red (630 nm) light emitting diode (LED) which reached the light dose of 75 J/cm2. As the optical imaging tool, an OCT (930 nm) with axial resolution of 6.0 microns in air was used, generating images with contact to the mouse skin before, immediately after, 24 hours, and 2 weeks after the correspondent procedure. Our result demonstrates that, within 24 hours after ALA-PDT, the mouse skin from the PDT group has shown epidermal thickness (ET), which has substantially increased after 2 weeks from the treatment day. Moreover, the skin surface has become evener after ALA-PDT. Concluding, this investigation demonstrates that the OCT is a feasible and reliable technique that allows real-time cross-sectional imaging of skin, which can quantify an outcome and predict whether the PDT reaches its goal.

  18. Whole bladder wall photodynamic therapy using 5-ALA: an experimental study in pigs

    NASA Astrophysics Data System (ADS)

    van Staveren, Hugo J.; Beek, Johan F.; Verlaan, Cess W.; Edixhoven, Annie; Saarnak, Anne E.; Sterenborg, Dick; de Reijke, Theo M.; de la Riviere, Guy B.; Thomsen, Sharon L.; van Gemert, Martin J. C.; Star, Willem M.

    1996-01-01

    The agent 5-aminolevulinic acid (5-ALA) can be an alternative drug in whole bladder wall (WBW) photodynamic therapy (PDT), as its good tumor selectivity and the short time skin photosensitivity after systemic administration are advantageous for clinical use. To determine the maximum drug and light doses for reversible normal tissue damage, a pre-clinical study was performed using an in vivo normal piglet bladder model. First, the kinetics of PpIX production in 2 pigs was determined in vitro after oral administration of 75 and 150 mg/kg ALA respectively. The concentration of PpIX in plasma, and erythrocytes was determined by reversed phase high-performance liquid chromatography (HPLC) and the maximum was reached at approximately equals 5 hours after the administration of ALA. This provided a guideline for the optimum interval between ALA administration and light application. Next, various ALA doses were either administered orally or instilled in the bladder and different light doses were applied. Bladder biopsies were taken at regular intervals and normal tissue damage was investigated histologically. Reversible tissue damage was obtained using 60 mg/kg of 5-ALA in combination with a light dose of 100 J cm-2 (non-scattered plus scattered 630 nm wavelength light) in the case of oral administration. In the case of intravesical instillation, a drug dose of 2.5 gram and a light dose of 100 J cm-2 are still too high to obtain reversible tissue damage.

  19. Single LED-based device to perform widefield fluorescence imaging and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Grecco, Clovis; Buzzá, Hilde H.; Stringasci, Mirian D.; Andrade, Cintia T.; Vollet-Filho, Jose D.; Pratavieira, Sebastião.; Zanchin, Anderson L.; Tuboy, Aparecida M.; Bagnato, Vanderlei S.

    2015-06-01

    Photodynamic therapy (PDT) is a treatment modality that can be indicated for several cancer types and pre-cancer lesions. One of the main applications of PDT is the treatment of superficial skin lesions such as basal cell carcinoma, Bowen's disease and actinic keratosis. Three elements are necessary in PDT, a photosensitizer (PS); light at specific wavelength to be absorbed by the PS, and molecular oxygen. A typical PS used for skin lesion is protoporphyrin IX (PpIX), which is an intrinsic PS; its production is stimulated by a pro-drug, such as 5-aminolevulinic acid (ALA). Before starting a treatment, it is very important to follow up the PpIX production (to ensure that enough PS was produced prior to a PDT application) and, during a PDT session, to monitor its photodegradation (as it is evidence of the photodynamic effect taking place). The aim of this paper is to present a unique device, LINCE (MMOptics - São Carlos, Brazil), that brings together two probes that can, respectively, allow for fluorescence imaging and work as a light source for PDT treatment. The fluorescence probe of the system is optically based on 400 nm LED (light emitting diodes) arrays that allow observing the fluorescence emission over 450 nm. The PDT illumination probe options are constituted of 630 nm LED arrays for small areas and, for large areas, of both 630 nm and 450 nm LED arrays. Joining both functions at the same device makes PDT treatment simpler, properly monitorable and, hence, more clinically feasible. LINCE has been used in almost 1000 PDT treatments of superficial skin lesions in Brazil, with 88.4% of clearance of superficial BCC.

  20. Co-expression of autophagic markers following photodynamic therapy in SW620 human colon adenocarcinoma cells

    PubMed Central

    Ziółkowska, Barbara; Woźniak, Marta; Ziółkowski, Piotr

    2016-01-01

    Photodynamic therapy (PDT) is a minimally invasive cancer treatment. It involves the combination of a photosensitizer and light of a specific wavelength to generate singlet oxygen and other reactive oxygen species that lead to tumor cell death. Autophagy is one of the pathways that tumor cells undergo during photodamage and it is common in photodynamic therapy. The aim of this study was to examine the effect of in vitro PDT on the expression of autophagy-related proteins, autophagy related 7 (Atg7), light chain 3 (LC3) and Beclin-1. Human SW620 colon carcinoma cells were treated with 5-aminolevulinic acid (ALA)-based PDT at a dose of 3 mM. The irradiation was performed using 4.5 J/cm2 total light and a fluence rate of 60 mW/cm2. Autophagy was evaluated by immunocytochemistry using specific antibodies to Atg7, Beclin-1 and LC3. The evaluation was repeated at several time points (0, 4, 8 and 24 h) following irradiation. The induction of autophagy was observed directly following the 5-ALA-mediated PDT procedure with the strongest expression of autophagy-related proteins at 4 and 8 h after irradiation as demonstrated using immunocytochemistry. It was characterized by significantly increased expression of Beclin-1, Atg7 and LC3. To the best of our knowledge this is the first study to analyze Beclin-1, Atg7 and LC3 expression in a PDT-related experiment. This study enhances the understanding of the role of autophagy in PDT, which may contribute to better and more effective tumor responses to this therapy. PMID:27485939

  1. A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis

    PubMed Central

    Nishie, Hirotada; Kataoka, Hiromi; Yano, Shigenobu; Kikuchi, Jun-ichi; Hayashi, Noriyuki; Narumi, Atsushi; Nomoto, Akihiro; Kubota, Eiji; Joh, Takashi

    2016-01-01

    Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is not entirely satisfactory. We previously reported glucose-conjugated chlorin (G-chlorin) as a more effective photosensitizer than another widely used photosensitizer, talaporfin sodium (TS); however, G-chlorin is hydrophobic. We synthesized oligosaccharide-conjugated chlorin (O-chlorin) with improved water-solubility. We report herein on its accumulation and cytotoxicity. O-chlorin was synthesized and examined for solubility. Flow cytometric analysis was performed to evaluate O-chlorin accumulation in cancer cells. To evaluate the intracellular localization of photosensitizer, cells were stained with O-chlorin and organelle-specific fluorescent probes. We then measured the in vitro fluorescence of various photosensitizers and the half-maximal inhibitory concentrations to evaluate effects in PDD and PDT, respectively. Xenograft tumor models were established, and antitumor and visibility effects were analyzed. O-chlorin was first shown to be hydrophilic. Flow cytometry then revealed a 20- to 40-times higher accumulation of O-chlorin in cancer cells than of TS, and a 7- to 23-times greater fluorescence than 5-ALA. In vitro, the cytotoxicity of O-chlorin PDT was stronger than that of TS PDT, and O-chlorin tended to accumulate in lysosomes. In vivo, O-chlorin showed the best effect in PDT and PDD compared to other photosensitizers. O-chlorin was hydrophilic and showed excellent tumor accumulation and fluorescence. O-chlorin is promising as a next-generation bifunctional photosensitizer candidate for both PDT and PDD. PMID:27708235

  2. Tannic acid-mediated green synthesis of antibacterial silver nanoparticles.

    PubMed

    Kim, Tae Yoon; Cha, Song-Hyun; Cho, Seonho; Park, Youmie

    2016-04-01

    The search for novel antibacterial agents is necessary to combat microbial resistance to current antibiotics. Silver nanoparticles (AgNPs) have been reported to be effective antibacterial agents. Tannic acid is a polyphenol compound from plants with antioxidant and antibacterial activities. In this report, AgNPs were prepared from silver ions by tannic acid-mediated green synthesis (TA-AgNPs). The reaction process was facile and involved mixing both silver ions and tannic acid. The absorbance at 423 nm in the UV-Visible spectra demonstrated that tannic acid underwent a reduction reaction to produce TA-AgNPs from silver ions. The synthetic yield of TA-AgNPs was 90.5% based on inductively coupled plasma mass spectrometry analysis. High-resolution transmission electron microscopy and atomic force microscopy images indicated that spherical-shaped TA-AgNPs with a mean particle size of 27.7-46.7 nm were obtained. Powder high-resolution X-ray diffraction analysis indicated that the TA-AgNP structure was face-centered cubic with a zeta potential of -27.56 mV. The hydroxyl functional groups of tannic acid contributed to the synthesis of TA-AgNPs, which was confirmed by Fourier transform infrared spectroscopy. The in vitro antibacterial activity was measured using the minimum inhibitory concentration (MIC) method. The TA-AgNPs were more effective against Gram-negative bacteria than Gram-positive bacteria. The MIC for the TA-AgNPs in all of the tested strains was in a silver concentration range of 6.74-13.48 μg/mL. The tannic acid-mediated synthesis of AgNPs afforded biocompatible nanocomposites for antibacterial applications.

  3. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas.

    PubMed

    Lau, Darryl; Hervey-Jumper, Shawn L; Chang, Susan; Molinaro, Annette M; McDermott, Michael W; Phillips, Joanna J; Berger, Mitchel S

    2016-05-01

    OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating

  4. [Photodynamic therapy vs imiquimod].

    PubMed

    Serra-Guillén, C; Nagore, E; Guillén, C

    2012-01-01

    Photodynamic therapy and imiquimod are highly regarded treatments dermatologists frequently prescribe for actinic keratoses, basal cell carcinoma, and Bowen disease. The scarcity of evidence from comparative trials prevents us from drawing well-founded conclusions about the efficacy, tolerance, and adverse effects of these therapeutic options or to recommend one over the other in any particular type of lesion or patient. On the other hand, in certain conditions (eg, actinic chelitis, immunosuppression, and basal cell carcinoma affecting the eyelids), there is evidence to support the use of photodynamic therapy or imiquimod even though they might initially seem contraindicated. We critically review and compare the use of these 2 treatments in order to suggest which is more appropriate in specific cases.

  5. Photodynamic therapy with fullerenes†

    PubMed Central

    Mroz, Pawel; Tegos, George P.; Gali, Hariprasad; Wharton, Tim; Sarna, Tadeusz; Hamblin, Michael R.

    2010-01-01

    Fullerenes are a class of closed-cage nanomaterials made exclusively from carbon atoms. A great deal of attention has been focused on developing medical uses of these unique molecules especially when they are derivatized with functional groups to make them soluble and therefore able to interact with biological systems. Due to their extended π-conjugation they absorb visible light, have a high triplet yield and can generate reactive oxygen species upon illumination, suggesting a possible role of fullerenes in photodynamic therapy. Depending on the functional groups introduced into the molecule, fullerenes can effectively photoinactivate either or both pathogenic microbial cells and malignant cancer cells. The mechanism appears to involve superoxide anion as well as singlet oxygen, and under the right conditions fullerenes may have advantages over clinically applied photosensitizers for mediating photodynamic therapy of certain diseases. PMID:17973044

  6. Study of the efficacy of 5 ALA-mediated photodynamic therapy on human larynx squamous cell carcinoma (Hep2c) cell line

    NASA Astrophysics Data System (ADS)

    Khursid, A.; Atif, M.; Firdous, S.; Zaidi, S. S. Z.; Salman, R.; Ikram, M.

    2010-07-01

    5-aminolevulanic acid (ALA), a precursor of Protoporphyrin IX, was evaluated as an inducer of photodamage on Hep2c, human larynx squamous cell carcinoma, cell line. Porphyrins are used as active cytotoxic antitumor agents in photodynamic therapy (PDT). The present study evaluates the effects of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) using human larynx cells as experimental model. Hep2c cell line was irradiated with red light (a diode laser, λ = 635 nm). The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the cellular viability of Hep2c cells were studied. The optimal uptake of photosensitizer ALA in Hep-2c cells was investigated by means of spectrometric measurement. Cells viability was determined by means of neutral red assay (NR). It was observed that sensitizer or light doses have no significant effect on cells viability when studied independently. The spectrometric measurements showed that the maximal cellular uptake of 5-ALA occurred after 7 h in vitro incubation. The photocytotoxic assay showed that light dose of 85 J/cm2 gives effective PDT outcome for Hep2c cell line incubated with 55 μg/ml of 5-ALA with a conclusion that Hep2c cell line is sensitive to ALA-mediated PDT.

  7. Photodynamic immune modulation (PIM)

    NASA Astrophysics Data System (ADS)

    North, John R.; Hunt, David W. C.; Simkin, Guillermo O.; Ratkay, Leslie G.; Chan, Agnes H.; Lui, Harvey; Levy, Julia G.

    1999-09-01

    Photodynamic Therapy (PDT) is accepted for treatment of superficial and lumen-occluding tumors in regions accessible to activating light and is now known to be effective in closure of choroidal neovasculature in Age Related Macular Degeneration. PDT utilizes light absorbing drugs (photosensitizers) that generate the localized formation of reactive oxygen species after light exposure. In a number of systems, PDT has immunomodulatory effects; Photodynamic Immune Modulation (PIM). Using low- intensity photodynamic regimens applied over a large body surface area, progression of mouse autoimmune disease could be inhibited. Further, this treatment strongly inhibited the immunologically- medicated contact hypersensitivity response to topically applied chemical haptens. Immune modulation appears to result from selective targeting of activated T lymphocytes and reduction in immunostimulation by antigen presenting cells. Psoriasis, an immune-mediated skin condition, exhibits heightened epidermal cell proliferation, epidermal layer thickening and plaque formation at different body sites. In a recent clinical trial, approximately one-third of patients with psoriasis and arthritis symptoms (psoriatic arthritis) displayed a significant clinical improvement in several psoriasis-related parameters after four weekly whole-body PIM treatments with verteporfin. The safety profile was favorable. The capacity of PIM to influence other human immune disorders including rheumatoid arthritis is under extensive evaluation.

  8. Multifunctional gold nanoparticles for photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Khaing Oo, Maung Kyaw

    As an important and growing branch of photomedicine, photodynamic therapy (PDT) is being increasingly employed in clinical applications particularly for the treatment of skin cancer. This dissertation focuses on the synthesis, characterization and deployment of gold nanoparticles for enhanced PDT of fibrosarcoma cancer cells. We have developed robust strategies and methods in fabrication of gold nanoparticles with positively- and negatively-tethered surface charges by photo-reduction of gold chloride salt using branched polyethyleneimine and sodium citrate respectively. An optimal concentration window of gold salt has been established to yield the most stable and monodispersed gold nanoparticles. 5-aminolevulinic acid (5-ALA), a photosensitizing precursor, has been successfully conjugated on to positively charged gold nanoparticles through electrostatic interactions. The 5-ALA/gold nanoparticle conjugates are biocompatible and have shown to be preferably taken up by cancer cells. Subsequent light irradiation results in the generation of reactive oxygen species (ROS) in cancer cells, leading to their destruction without adverse effects on normal fibroblasts. We have demonstrated for the first time that gold nanoparticles can enhance PDT efficacy by 50% compared to the treatment with 5-ALA alone. Collected evidence has strongly suggested that this enhancement stems from the elevated formation of ROS via the strongly localized electric field of gold nanoparticles. Through single cell imaging using surface-enhanced Raman scattering enabled by the very same gold nanoparticles, we have shown that multifunctionality of gold nanoparticles can be harvested concurrently for biomedical applications in general and for PDT in specific. In other words, gold nanoparticles can be used not only for targeted drug delivery and field-enhanced ROS formation, but also for monitoring cell destructions during PDT. Finally, our COMSOL Multiphysics simulation of the size-dependent electric

  9. Photodynamic therapy using a novel irradiation source, LED lamp, is similarly effective to photodynamic therapy using diode laser or metal-halide lamp on DMBA- and TPA-induced mouse skin papillomas.

    PubMed

    Takahashi, Hidetoshi; Nakajima, Susumu; Ogasawara, Koji; Asano, Ryuji; Nakae, Yoshinori; Sakata, Isao; Iizuka, Hajime

    2014-08-01

    Photodynamic therapy (PDT) is useful for superficial skin tumors such as actinic keratosis and Bowen disease. Although PDT is non-surgical and easily-performed treatment modality, irradiation apparatus is large and expensive. Using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-ο-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin papilloma model, we compared the efficacy of TONS501- and ALA-PDT with a LED lamp, a diode laser lamp or a metal-halide lamp on the skin tumor regression. TONS501-PDT using 660 nm LED lamp showed anti-tumor effect at 1 day following the irradiation and the maximal anti-tumor effect was observed at 3 days following the irradiation. There was no significant difference in the anti-tumor effects among TONS501-PDT using LED, TONS501-PDT using diode laser, and 5-aminolevulinic acid hydrochloride (ALA)-PDT using metal-halide lamp. Potent anti-tumor effect on DMBA- and TPA-induced mouse skin papilloma was observed by TONS501-PDT using 660 nm LED, which might be more useful for clinical applications.

  10. Photodynamic therapy laser system

    NASA Astrophysics Data System (ADS)

    Shu, Xiaoqin; Lin, Qing; Wang, Feng; Shu, Chao; Wang, Jianhua

    2009-08-01

    Photodynamic therapy (PDT) treatment is a new treatment for tumour and Dermatology. With the successful development of the second-generation photosensitizer and the significant manifestations in clinics, PDT has shown a more extensive application potentials. To activate the photosensitizer, in this paper, we present a GaAs-based diode laser system with a wavelength of 635 nm. In this system, to prolong the working life-time of the diode lasers, we use specific feedback algorithm to control the current and the temperature of the diode laser with high precision. The clinic results show an excellent effect in the treatment of Condyloma combined with 5-ALA.

  11. Comparative in vivo study of precursors of PpIX (ALA and MAL) used topically in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Rego, Raquel F.; Inada, Natalia M.; Ferreira, Juliana; Araújo-Moreira, Fernando M.; Bagnato, Vanderlei S.

    2009-06-01

    The efficacy of Photodynamic Therapy (PDT) combined with aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) in treatment of cancer has been studied for over ten years. However, there is no established dose for the topical use of these drugs in PDT. The purpose of this study was the comparison of induced PDT response of ALAsense (5-aminolevulinic acid - ALA) and Metvix (methyl aminolevulinate - MAL). Depth of necrosis induced by PDT was analyzed in normal liver of male Wistar rats, using different light doses and topical application of both PpIX precursors - ALA and MAL. PDT was performed with a diode laser at 630 nm with different doses of light (20, 50, 100 and 200 J/cm2), and intensity of 250 mW/cm2. Depth of necrosis analysis was used to calculate the threshold dose for each drug. The results showed that MAL-PDT presented a better response than ALA-PDT, mainly due to formulation differences. Moreover, the ability of the ALA PpIX production was more efficient.

  12. Photodynamic therapy with 5-aminoolevulinic acid-induced porphyrins and DMSO/EDTA for basal cell carcinoma

    NASA Astrophysics Data System (ADS)

    Warloe, Trond; Peng, Qian; Heyerdahl, Helen; Moan, Johan; Steen, Harald B.; Giercksky, Karl-Erik

    1995-03-01

    Seven hundred sixty three basal cell carcinomas (BCCs) in 122 patients were treated by photodynamic therapy by 5-aminolevulinic acid (ALA) in cream topically applied, either alone, in combination with dimethyl sulphoxide (DMSO) and ethylenediaminetetraacetic acid disodium salt (EDTA), or with DMSO as a pretreatment. After 3 hours cream exposure 40 - 200 Joules/cm2 of 630 nm laser light was given. Fluorescence imaging of biopsies showed highly improved ALA penetration depth and doubled ALA-induced porphyrin production using DMSO/EDTA. Treatment response was recorded after 3 months. After a single treatment 90% of 393 superficial lesions responded completely, independent of using DMSO/EDTA. In 363 nodulo-ulcerative lesions the complete response rate increased from 67% to above 90% with DMSO/EDTA for lesions less than 2 mm thickness and from 34% to about 50% for lesions thicker than 2 mm. Recurrence rate observed during a follow-up period longer than 12 months was 2 - 5%. PDT of superficial thin BCCs with ALA-induced porphyrins and DMSO/EDTA equals surgery and radiotherapy with respect to cure rate and recurrence. Cosmetic results of ALA-based PDT seemed to be better than those after other therapies. In patients with the nevoid BCC syndrome the complete response rate after PDT was far lower.

  13. The Two Faces of Fractionated Photodynamic Therapy: Increasing Efficacy With Light Fractionation or Adjuvant Use of Fractional Laser Technology.

    PubMed

    Juhasz, Margit L W; Levin, Melissa K; Marmur, Ellen S

    2016-11-01

    "Fractionated photodynamic therapy (PDT)" is a new term being used by dermatologists to describe advances in PDT technology including fractionated light or the adjuvant use of fractional lasers. Although dermatologists have used PDT since the early 1990s for the treatment of photodamage and precancerous lesions, newer developments in technology have allowed for the treatment of non-melanoma skin cancers (NMSCs), in ammatory disorders, and even uses in the eld of anti-aging. Recent developments in fractionated light therapy have allowed for PDT with dark intervals and two-fold illumination schemes to increase cellular damage and apoptosis. Combining PDT with fractional laser technology has allowed for enhanced dermal penetration of topical photosensitizers including 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL), as well as increased ef cacy of treatment. These advances in PDT technology will allow for increased convenience, decreased treatment time, only one application of topical photosensitizer, and decreased cost to the patient and dermatologist. J Drugs Dermatol. 2016;15(11):1324-1328..

  14. Photodynamic therapy combined with terbinafine against chromoblastomycosis and the effect of PDT on Fonsecaea monophora in vitro.

    PubMed

    Hu, Yongxuan; Huang, Xiaowen; Lu, Sha; Hamblin, Michael R; Mylonakis, Eleftherios; Zhang, Junmin; Xi, Liyan

    2015-02-01

    Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis.

  15. Accelerated migration and invasion of prostate cancer cells after a photodynamic therapy-like challenge: Role of nitric oxide.

    PubMed

    Fahey, Jonathan M; Girotti, Albert W

    2015-09-15

    Employing an in vitro model for 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT), we recently reported that human prostate cancer PC3 cells rapidly and persistently overexpressed inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after a moderate ALA/light challenge. The upregulated iNOS/NO was shown to play a key role in cell resistance to apoptotic photokilling and also in the dramatic growth spurt observed in surviving cells. In the present study, we found that PC3 cells surviving an ALA/light insult not only proliferated faster than non-stressed controls, but migrated and invaded faster as well, these effects being abrogated by an iNOS inhibitor or NO scavenger. Photostressed prostate DU145 cells exhibited similar behavior. Using in-gel zymography, we showed that PC3 extracellular matrix metalloproteinase-9 (MMP-9) was strongly activated 24 h after ALA/light treatment and that MMP-9 inhibitor TIMP-1 was downregulated, consistent with MMP-9 involvement in enhanced invasiveness. We also observed a photostress-induced upregulation of α6 and β1 integrins, implying their involvement as well. The MMP-9, TIMP-1, and integrin effects were strongly attenuated by iNOS inhibition, confirming NO's role in photostress-enhanced migration/invasion. This study reveals novel, potentially tumor-promoting, side-effects of prostate cancer PDT which may be averted through use of iNOS inhibitors as PDT adjuvants.

  16. Photodynamic therapy in dermatology.

    PubMed

    Ceburkov, O; Gollnick, H

    2000-01-01

    Application of non-ionising radiation with or without photosensitizers is rather common in dermatology. Though the method itself was described in ancient times, its routine use in medicine based on scientific research started in the second half of the 20th century. Light can be used in three different patterns: phototherapy (UV-A or UV-B light), photochemotherapy (combination of psoralens with UV-A light) and photodynamic therapy (combination of photosensitizers with UV- and/or visible light). The following article deals with the photodynamic therapy or PDT. Using PDT implies the understanding of light dosimetry and calculation of light dose using different light sources and photosensitizers. The number of PDT sensitisers under investigation is rapidly increasing. The PDT itself, being a relatively new modality, quickly spreads its list of applications covering new indications in different areas of medicine. Though the main part of this list is made up of dermatological conditions, the use of PDT in other disciplines is also discussed to make dermatologists familiar with different aspects of the issue. PDT, like any treatment modality, has its benefits and adverse effects. The future of PDT is closely related to teamwork in physical, biochemical and clinical research which could provide better understanding of underlying mechanisms and help to create protocols for higher therapeutic efficacy.

  17. Use of Optical Fiber Imported Intra-Tissue Photodynamic Therapy for Treatment of Moderate to Severe Acne Vulgaris

    PubMed Central

    Wang, Qian; Yuan, Dan; Liu, Wei; Chen, Jin; Lin, Xinyu; Cheng, Shi; Li, Fumin; Duan, Xiling

    2016-01-01

    Background To treat moderate to severe acne vulgaris, we developed an optical fiber imported intra-tissue photodynamic therapy: the optical fiber irradiation 5-aminolevulinic acid photodynamic therapy (OFI-ALA-PDT). The aim of this study was to compare the treatment effect and tolerability of OFI-ALA-PDT versus traditional ALA-PDT in the treatment of moderate to severe acne vulgaris. Material/Methods 60 patients with facial acne enrolled into this study were randomly divided into an OFI-ALA-PDT group and a traditional ALA-PDT group, with 30 patients in each group. The difference between these 2 groups was the red light irradiation methods used. In the OFI-ALA-PDT group we used intra-tissue irradiation (import the red light directly into the target lesion with optical fiber) for 5 min, while the traditional ALA-PDT group received whole-face irradiation for 20 min. All patients received 1 irradiation every 7 to 10 days for a total of 6 irradiations. Treatment effects and adverse reactions were recorded after the 4th and 6th irradiation, and at 4, 8, 16 weeks after the entire treatment. Results After the 4th irradiation, significantly different effective rates were observed in these groups (90.0% for the OFI-ALA-PDT group and 66.7% for the control group). However, no significant difference in effective rate was recorded in the later observations. There were 182 adverse reactions in the OFI-ALA-PDT group and 497 in the control group, which showed a significant difference (P<0.05). Conclusions OFI-ALA-PDT showed improved treatment effective rate in the early stage of irradiation, and it had fewer adverse reactions. PMID:26839152

  18. Transition-metal-free acid-mediated synthesis of aryl sulfides from thiols and thioethers.

    PubMed

    Wagner, Anna M; Sanford, Melanie S

    2014-03-07

    The preparation of diaryl and alkyl aryl sulfides via acid-mediated coupling of thiols and thioethers with diaryliodonium salts is reported. The scope, limitations, and mechanism of the transformation are discussed.

  19. Neurotransmitter transporter family including SLC6A6 and SLC6A13 contributes to the 5-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin IX and photodamage, through uptake of ALA by cancerous cells.

    PubMed

    Tran, Tai Tien; Mu, Anfeng; Adachi, Yuka; Adachi, Yasushi; Taketani, Shigeru

    2014-01-01

    δ-Aminolevulinic acid (ALA)-induced protoporphyrin accumulation is widely used in the treatment of cancer, as photodynamic therapy (PDT). To clarify the mechanisms of ALA uptake by tumor cells, we have examined the ALA-induced accumulation of protoporphyrin by the treatment of colon cancer DLD-1 and epithelial cancer HeLa cells with γ-aminobutyric acid (GABA)-related compounds. When the cells were treated with GABA, taurine and β-alanine, the level of protoporphyrin was decreased, suggesting that plasma membrane transporters involved in the transport of neurotransmitters contribute to the uptake of ALA. By transfection with neurotransmitter transporters SLC6A6, SLC6A8 and SLC6A13 cDNA, the ALA- and ALA methylester-dependent accumulation of protoporphyrin markedly increased in HEK293T cells, dependent on an increase in the uptake of ALA. When ALA-treated cells were exposed to white light, the extent of photodamage increased in SLC6A6- and SLC6A13-expressing cells. Conversely, knockdown of SLC6A6 or SLC6A13 with siRNAs in DLD-1 and HeLa cells decreased the ALA-induced accumulation. The expression of SLC6A6 and SLC6A13 was found in some cancer cell lines. Immunohistochemical studies revealed that the presence of these transporters was elevated in colon cancerous cells. These results indicated that neurotransmitter transporters including SLC6A6 and SLC6A13 mediate the uptake of ALA and can play roles in the enhancement of ALA-induced accumulation of protoporphyrin in cancerous cells.

  20. ALA-mediated photodynamic therapy of experimental malignant glioma in the BD-IX rat model

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Angell-Petersen, Even; Peng, Qian; Sun, Chung-Ho; Sorensen, Dag R.; Carper, Steven W.; Madsen, Steen J.

    2005-04-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resec-tion indicating that a more aggressive form of local therapy could be of benefit. Photodynamic therapy (PDT) is a local form of treatment involving the administration of a tumor-localizing photosensitizing drug that is activated by light of a specific wavelength The results of in vitro experiments indicated that PDT, given at low fluence rates was substantially more effective at inhibiting glioma spheroid growth than short term high fluence rate regimes. This prompted the initia-tion of in vivo studies of low fluence rate 5-aminolevulinic acid (ALA) PDT in a rat glioma model. Methods:BT4C cell line tumors were established in the brains of inbred BD- IX rats. Eighteen days following tumor induction the animals were injected with 125 mg/kg ALA ip. and four hours later light treatment at various fluences and fluence rates were given after the introduction of an optical fiber. Tumor histology and animal survival were examined. Results: In vitro experiments verified that the cell line was sensitive to ALA PDT. Microfluorometry of frozen tissue sections showed that PpIX is produced with a greater than 20:1 tumor to normal tissue selectivity ratio four hours after ALA injection. Histological examination demonstrated neutrophil infiltration and tumor central necrosis in low fluence rate treated tumors. Conclusions: Low fluence rate long term ALA mediated PDT had a more pronounced effect on tumor histology than single shot short duration treatments at similar total fluence levels.

  1. Photodynamic damage study of HeLa cell line using ALA

    NASA Astrophysics Data System (ADS)

    AlSalhi, M. S.; Atif, M.; AlObiadi, A. A.; Aldwayyan, A. S.

    2011-04-01

    The present study evaluates the photodynamic damage with 5-aminolevulinic acid (5-ALA) using HeLa as experimental model. HeLa cell line was irradiated with red light (He-Ne laser, λ = 632.8 CW nm). The influence of different incubation times and concentrations of 5-ALA, different irradiation doses and various combinations of photosensitizer and light doses on the cellular viability of HeLa cells were studied. The optimal uptake of photosensitizer ALA in HeLa cells was investigated by means of PpIX fluorescence intensity by exciting the HeLa cell suspension at 450 nm and a detection wavelength set at 690 nm. Cells viability was determined by means of trypan blue solution. The spectrometric measurements showed that the maximal cellular uptake of 5-ALA occurred after 4 h in vitro incubation. We found that the combination with 5-ALA and laser irradiation leads to time/concentration-dependent increase of cells death and also energy doses-dependent enlarge the cells death. The fluorescence intensity after PDD of carcinoma cells reduce when compared with the control group. The fluorescence emission spectral profiles after PDD of carcinoma cells showed a dip around 425-525 nm when compared with the control group. This may be due to the damage of mitochondria component of cells. The percentage of HeLa cells after PDD shows that the percentage of cells survival rate as function of laser dose (power). Hence it is clear that at 200 μg/ml ALA and 20 mW laser irradiation, more than 70% of HeLa cells were dead after 15 min.

  2. Fluorescence image-guided photodynamic therapy of cancer cells using a scanning fiber endoscope

    NASA Astrophysics Data System (ADS)

    Woldetensae, Mikias H.; Kirshenbaum, Mark R.; Kramer, Greg M.; Zhang, Liang; Seibel, Eric J.

    2013-03-01

    A scanning fiber endoscope (SFE) and the cancer biomarker 5-aminolevulinic acid (5-ALA) were used to fluorescently detect and destroy superficial cancerous lesions, while experimenting with different dosimetry levels for concurrent or sequential imaging and laser therapy. The 1.6-mm diameter SFE was used to fluorescently image a confluent monolayer of A549 human lung cancer cells from culture, previously administered with 5 mM solution of 5-ALA for 4 hours. Twenty hours after therapy, cell cultures were stained to distinguish between living and dead cells using a laser scanning confocal microscope. To determine relative dosimetry for photodynamic therapy (PDT), 405-nm laser illumination was varied from 1 to 5 minutes with power varying from 5 to 18 mW, chosen to compare equal amounts of energy delivered to the cell culture. The SFE produced 500-line images of fluorescence at 15 Hz using the red detection channel centered at 635 nm. The results show that PDT of A549 cancer cell monolayers using 405nm light for imaging and 5-ALAinduced PpIX therapy was possible using the same SFE system. Increased duration and power of laser illumination produced an increased area of cell death upon live/dead staining. The ultrathin and flexible SFE was able to direct PDT using wide-field fluorescence imaging of a monolayer of cultured cancer cells after uptaking 5-ALA. The correlation between light intensity and duration of PDT was measured. Increased length of exposure and decreased light intensity yields larger areas of cell death than decreased length of exposure with increased light intensity.

  3. Vitamin D enhances the efficacy of photodynamic therapy in a murine model of breast cancer

    PubMed Central

    Rollakanti, Kishore R; Anand, Sanjay; Maytin, Edward V

    2015-01-01

    Cutaneous metastasis occurs more frequently in breast cancer than in any other malignancy in women, causing significant morbidity. Photodynamic therapy (PDT), which combines a porphyrin-based photosensitizer and activation by light, can be employed for breast cancer (especially cutaneous metastases) but tumor control after PDT has not surpassed traditional treatments methods such as surgery, radiation, and chemotherapy up to now. Here, we report that breast cancer nodules in mice can be effectively treated by preconditioning the tumors with 1α, 25-dihydroxyvitamin D3 (calcitriol; Vit D) prior to administering 5-aminolevulinate (ALA)-based PDT. Breast carcinoma tumors (MDA-MB-231 cells implanted subcutaneously in nude mice) received systemic Vit D (1 μg/kg) for 3 days prior to receiving ALA. The addition of Vit D increased intratumoral accumulation of protoporphyrin IX (PpIX) by 3.3 ± 0.5-fold, relative to mice receiving ALA alone. Bioluminescence imaging in vivo and immunohistochemical staining confirmed that tumor-specific cell death after ALA-PDT was markedly enhanced (36.8 ± 7.4-fold increase in TUNEL-positive nuclei; radiance decreased to 14% of control) in Vit D pretreated tumors as compared to vehicle-pretreated tumors. Vit D stimulated proliferation (10.7 ± 2.8-fold) and differentiation (9.62 ± 1.7-fold) in tumor cells, underlying an augmented cellular sensitivity to ALA-PDT. The observed enhancement of tumor responses to ALA-PDT after low, nontoxic doses of Vit D supports a new combination approach that deserves consideration in the clinical setting, and offers potential for improved remission of cutaneous breast cancer metastases. PMID:25712788

  4. Scavengers modifying the phototoxicity induced by ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Casas, Adriana; Perotti, Christian; Fukuda, Haydee; Batlle, Alcira

    2001-04-01

    The exogenously stimulated formation of intracellularly generated Protoporphyrin IX, a precursor of heme, is becoming one of the fastest developing areas in the field of Photodynamic Therapy (PDT). We have examined the degree of protection of several scavengers, aminoacids and compounds related to glutathione metabolism, to the photodamage induced by 5-aminolevulinic acid (ALA)-mediated PDT, employing the LM2 cell line, derived from a mammary murine adenocarcinoma. We have exposed the cells to different concentrations of the scavengers, 24 before PDT, during PDT, and 19 hr after treatment. We defined the protection grade (PG) as the ratio between cell survival after ALA-PDT treatment in the presence of the protector and cell survival after ALA-PDT treatment. We found that L-tryptophan (PG=8.3 at 2mM), N-acetyl-L-cysteine (PG= 7.9 at 30 mM), L-cysteine (PG=7.81 at 8mM), S-adenosyl-L-methionine (PG= 7.86 at 8mM), melatonin (PG=6.81 at 8mM) and glycine (PG=6.8 at 40 mM) are the best protectors to PDT damage, followed by L-methionine (PG=4.38 at 0.8 mM), mannitol (PG=2.32 at 2 mM) and reduced glutathione (PG=3.41 at 0.8 mM), whereas oxidized glutathione does not exert any protection. The implications of these results in the photodamage induced by ALA-PDT is discussed.

  5. Mechanisms in photodynamic therapy: part one—-photosensitizers, photochemistry and cellular localization

    PubMed Central

    Castano, Ana P.; Demidova, Tatiana N.; Hamblin, Michael R.

    2013-01-01

    Summary The use of non-toxic dyes or photosensitizers (PS) in combination with harmless visible light that is known as photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In a series of three reviews we will discuss the mechanisms that operate in the field of PDT. Part one discusses the recent explosion in discovery and chemical synthesis of new PS. Some guidelines on how to choose an ideal PS for a particular application are presented. The photochemistry and photophysics of PS and the two pathways known as Type I (radicals and reactive oxygen species) and Type II (singlet oxygen) photochemical processes are discussed. To carry out PDT effectively in vivo, it is necessary to ensure sufficient light reaches all the diseased tissue. This involves understanding how light travels within various tissues and the relative effects of absorption and scattering. The fact that most of the PS are also fluorescent allows various optical imaging and monitoring strategies to be combined with PDT. The most important factor governing the outcome of PDT is how the PS interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. Examples of PS that localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes are given. Finally the use of 5-aminolevulinic acid as a natural precursor of the heme biosynthetic pathway, stimulates accumulation of the PS protoporphyrin IX is described. PMID:25048432

  6. [Photodynamic therapy for actinic cheilitis].

    PubMed

    Castaño, E; Comunión, A; Arias, D; Miñano, R; Romero, A; Borbujo, J

    2009-12-01

    Actinic cheilitis is a subtype of actinic keratosis that mainly affects the lower lip and has a higher risk of malignant transformation. Its location on the labial mucosa influences the therapeutic approach. Vermilionectomy requires local or general anesthetic and is associated with a risk of an unsightly scar, and the treatment with 5-fluorouracil or imiquimod lasts for several weeks and the inflammatory reaction can be very intense. A number of authors have used photodynamic therapy as an alternative to the usual treatments. We present 3 patients with histologically confirmed actinic cheilitis treated using photodynamic therapy with methyl aminolevulinic acid as the photosensitizer and red light at 630 nm. The clinical response was good, with no recurrences after 3 to 6 months of follow-up. Our experience supports the use of photodynamic therapy as a good alternative for the treatment of actinic cheilitis.

  7. Hyperbaric oxygen therapy augments the photodynamic action of methylene blue against bacteria in vitro

    NASA Astrophysics Data System (ADS)

    Bisland, S. K.; Dadani, F. N.; Chien, C.; Wilson, B. C.

    2007-02-01

    Photodynamic therapy (PDT) entails the combination of photosensitizer and light to generate cytotoxic molecules that derive from molecular oxygen (O II). The presence of sufficient O II within the target tissues is critical to the efficiency of PDT. This study investigates the use of hyperbaric oxygen therapy in combination with PDT (HOTPDT) to augment the photodynamic action of methylene blue (MB) or 5-aminolevulinic acid (ALA) against gram positive and gram negative bacterial strains in vitro. Staphylococcus aureus or Pseudomonas aeruginosa were grown in trypticase soy broth as planktonic cultures (~10 8/mL) or as established biofilms in 48 well plates (3 days old) at 32°C. Dark toxicity and PDT response in the presence or absence of HOT (2 atmospheres, 100% O II for 30, 60 or 120 min) was established for both MB (0-0.1 mM) and ALA (0- 1 mM) for a range of incubation times. The number of surviving colonies (CFU/mL) was plotted for each treatment groups. Light treatments (5, 10, 20 or 30 J/cm2) were conducted using an array of halogen bulbs with a red filter providing 90% transmittance over 600-800 nm at 21 mW/cm2. HOT increased the dark toxicity of MB (30 min, 0.1 mM) from < 0.2 log cell kill to 0.5 log cell kill. Dark toxicity of ALA (4 hr, 1 mM) was negligible and did not increase with HOT. For non-dark toxic concentrations of MB or ALA, (0.05 mM and 1 mM respectively) HOT-PDT enhanced the antimicrobial effect of MB against Staphylococcus aureus in culture by >1 and >2 logs of cell kill (CFU/mL) at 5 and 10 J/cm2 light dose respectively as compared to PDT alone. HOT-PDT also increased the anti-microbial effects of MB against Staphylococcus aureus biofilms compared to PDT, albeit less so (> 2 logs) following 10 J/cm2 light dose. Anti-microbial effects of PDT using ALA were not significant for either strain with or without HOT. These data suggest that HOTPDT may be useful for improving the PDT treatment of bacterial infections.

  8. [Historical development of photodynamic therapy].

    PubMed

    Kick, G; Messer, G; Plewig, G

    1996-08-01

    Photodynamic therapy is based on the accumulation of photosensitizing drugs in tumours and subsequent activation by visible light, leading to the release of singlet oxygen in photochemical reactions. Besides the treatment of precancerous lesions and malignant tumours in superficial sites, new experimental indications, such as psoriasis, are being investigated. The development of new photosensitizing agents for topical application and appropriate light sources has led to increasing interest in this promising treatment modality among dermatologists. This historical review deals with the scientific investigations of photodynamic therapy and diagnosis that started with the experiments of Oscar Raab at the end of the nineteenth century.

  9. Phosphoric Acid-Mediated Synthesis of Vinyl Sulfones through Decarboxylative Coupling Reactions of Sodium Sulfinates with Phenylpropiolic Acids.

    PubMed

    Rong, Guangwei; Mao, Jincheng; Yan, Hong; Zheng, Yang; Zhang, Guoqi

    2015-08-07

    A novel phosphoric acid -mediated synthesis of vinyl sulfones through decarboxylative coupling reactions of sodium sulfinates with phenylpropiolic acids is described. This transformation is efficient and environmentally friendly.

  10. In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints.

    PubMed

    Mallidi, Srivalleesha; Mai, Zhiming; Rizvi, Imran; Hempstead, Joshua; Arnason, Stephen; Celli, Jonathan; Hasan, Tayyaba

    2015-04-01

    In view of the increase in cancer-related mortality rates in low- to middle-income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low-resource setting and compare an inexpensive, portable, battery-powered light-emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs.

  11. In vivo study of necrosis on the liver tissue of Wistar rats: a combination of photodynamic therapy and carbon dioxide laser ablation

    NASA Astrophysics Data System (ADS)

    Rego, R. F.; Nicolodelli, G.; Araujo, M. T.; Tirapelli, L. F.; Araujo-Moreira, F. M.; Bagnato, V. S.

    2013-07-01

    Photodynamic therapy (PDT) is known to be limited to applications in large volume tumors due to its limited penetration. Therefore, a combination of PDT and carbon dioxide (CO2) laser ablation may constitute a potential protocol to destroy bulk tumors because it involves an association of these two techniques allowing the removal of visible lesions with a high selectivity of destruction of remnant tumors. The main aim of this study is to investigate the most appropriate procedure to combine use of a CO2 laser and PDT on livers of healthy rats, and to analyze different techniques of this treatment using three types of photosensitizers (PSs). Forty eight animals were separated to form six groups: (1) only CO2 laser ablation, (2) drug and CO2 laser ablation, (3) only PDT, (4) drug and light (PDT) followed by CO2 laser ablation, (5) ablated with CO2 laser followed by PDT, and (6) drug followed by CO2 laser ablation and light. For each group, three types of photosensitization were used: topical 5-aminolevulinic acid (ALA), intravenous ALA and intravenous Photogem®. Thirty hours after the treatments, the animals were sacrificed and the livers removed. The depth of necrosis was analyzed and measured, considering microscopic and macroscopic aspects. The results show that the effects of the PDT were considerably enhanced when combined with CO2 laser ablation, especially when the PDT was performed before the CO2 laser ablation.

  12. Photodynamic tumor therapy and on-line fluorescence spectroscopy after ALA administration using 633-nm light as therapeutic and fluorescence excitation radiation

    NASA Astrophysics Data System (ADS)

    Koenig, Karsten; Kienle, Alwin; Boehncke, Wolf-Henning; Kaufmann, Roland; Rueck, Angelika C.; Meier, Thomas H.; Steiner, Rudolf W.

    1994-09-01

    Photodynamic therapy (PDT) and on-line fluorescence spectroscopy were carried out on human tumors after 5-aminolevulinic acid (ALA) administration using 633-nm light of a dye laser as therapeutic radiation and as fluorescence excitation radiation. This has the advantages of (1) enabling use of one laser for PDT and fluorescence diagnosis only, (2) enabling the possibility of on-line fluorescence measurements, and (3) exciting protoporphyrin molecules in deep tissue layers. Monte Carlo calculations were carried out to determine excitation and fluorescence phonon distribution in case of red and violet excitation radiation. The results show the possibility of depth-resolved measurements on the fluorophore distribution by variation of excitation wavelength. The high penetration depth of 633-nm radiation results in a higher ratio of the 700-nm protoporphyrin fluorescence of the xenotransplanted tumor It to Is compared with 407-nm excitation. No values greater than 1 for the ratio I/Is were found, however, in case of intravenous ALA injection even for red excitation. Therefore, a large amount of ALA will be metabolized in the skin and can cause photosensitivity of the patient when applied systematically. In contrast, protoporphyrin fluorescence limited to the pretreated skin area was detected in case of topically applied ALA to patients with mycosis funcoides and erythroplasy of Queyrat. The influence of remitted excitation light and of the spontaneous radiation from the laser as well as the possible excitation of foodbased degradation products of chlorophyll has to be considered in high-sensitivity fluorescence measurements.

  13. In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints

    PubMed Central

    Mallidi, Srivalleesha; Mai, Zhiming; Rizvi, Imran; Hempstead, Joshua; Arnason, Stephen; Celli, Jonathan; Hasan, Tayyaba

    2015-01-01

    Abstract. In view of the increase in cancer-related mortality rates in low- to middle-income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low-resource setting and compare an inexpensive, portable, battery-powered light-emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs. PMID:25909707

  14. The Effect of Coatings on the Affinity of Lanthanide Nanoparticles to MKN45 and HeLa Cancer Cells and Improvement in Photodynamic Therapy Efficiency.

    PubMed

    Sawamura, Takashi; Tanaka, Tatsumi; Ishige, Hiroyuki; Iizuka, Masayuki; Murayama, Yasutoshi; Otsuji, Eigo; Ohkubo, Akihiro; Ogura, Shun-Ichiro; Yuasa, Hideya

    2015-09-16

    An improvement in photodynamic therapy (PDT) efficiency against a human gastric cancer cell line (MKN45) with 5-aminolevulinic acid (ALA) and lanthanide nanoparticles (LNPs) is described. An endogenous photosensitizer, protoporphyrin IX, biosynthesized from ALA and selectively accumulated in cancer cells, is sensitizable by the visible lights emitted from up-conversion LNPs, which can be excited by a near-infrared light. Ten kinds of surface modifications were performed on LNPs, NaYF₄(Sc/Yb/Er) and NaYF₄(Yb/Tm), in an aim to distribute these irradiation light sources near cancer cells. Among these LNPs, only the amino-functionalized LNPs showed affinity to MKN45 and HeLa cancer cells. A PDT assay with MKN45 demonstrated that amino-modified NaYF₄(Sc/Yb/Er) gave rise to a dramatically enhanced PDT effect, reaching almost perfect lethality, whereas NaYF₄(Yb/Tm)-based systems caused little improvement in PDT efficiency. The improvement of PDT effect with the amino-modified NaYF₄(Sc/Yb/Er) is promising for a practical PDT against deep cancer cells that are reachable only by near-infrared lights.

  15. Medical complex for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Soldatov, Anatoly N.; Domanov, Michail S.; Lyabin, Nikolay A.; Chursin, Alexandr D.; Mirza, Sergey Y.; Sukhanov, Viktor B.; Polunin, Yu. P.; Ivanov, Aleksandr I.; Kirilov, Anatoly E.; Rubanov, Sergey N.

    2002-03-01

    Experimental results of initial testing dye-laser 'MLK-02' pumped by a copper vapor laser 'Kulon-10' are presented. Output parameters obtained are the following: average power - 1 and 1.5 W, efficiency - 17.6 and 18.7% at the wavelengths of 670 and 725 nm, respectively. The laser apparatus is supposed to be used for methods of photodynamic therapy.

  16. Photodynamic management of bladder cancer

    NASA Astrophysics Data System (ADS)

    Johansson, A.; Stepp, H.; Beyer, W.; Pongratz, T.; Sroka, R.; Bader, M.; Kriegmair, M.; Zaak, D.; Waidelich, R.; Karl, A.; Hofstetter, A.; Stief, C.; Baumgartner, R.

    2009-06-01

    Bladder cancer (BC) is among the most expensive oncological diseases. Any improvement in diagnosis or therapy carries a high potential for reducing costs. Fluorescence cystoscopy relies on a selective formation of Protoporphyrin IX (PpIX) or more general photoactive porphyrins (PAP) in malignant urothelium upon instillation of 5-aminolevulinic acid (5-ALA) or its hexyl-derivative h-ALA. Fluorescence cystoscopy equipment has been developed with the aim to compensate for the undesired distortion caused by the tissue optical properties by displaying the red fluorescence simultaneously with the backscattered blue light. Many clinical studies proved a high sensitivity in detecting flat carcinoma in situ and small papillary malignant tumours. As a result, recurrence rates were significantly decreased in most studies. The limitation lies in a low specificity, caused by false positive findings at inflamed bladder wall. Optical coherence tomography (OCT) is currently being investigated as a promising tool to overcome this limitation. H-ALA-PDT (8 or 16 mM h-ALA in 50 ml instillation for 1-2 h, white light source, catheter applicator) has recently been investigated in a phase I study. 17 patients were applied 100 J/cm2 (3 patients received incrementing doses of 25 - 50 - 100 J/cm2) during approx. 1 hour irradiation time in 3 sessions, 6 weeks apart. PDT was performed without any technical complications. Complete photobleaching of the PpIX-fluorescence, as intended, could be achieved in 43 of 45 PDT-sessions receiving 100 J/cm2. The most prominent side effects were postoperative urgency and bladder pain, all symptoms being more severe after 16 mM h-ALA. Preliminary evaluation shows complete response assessed at 3 months after the third PDT-session (i.e. 6 months after first treatment) in 9 of 12 patients. 2 of these patients were free of recurrence until final follow-up at 84 weeks.

  17. Photodynamic therapy using hemagglutinating virus of Japan envelope (HVJ-E): a novel therapeutic approach for the treatment of hormone antagonistic prostate cancer

    NASA Astrophysics Data System (ADS)

    Inai, Mizuho; Yamauchi, Masaya; Honda, Norihiro; Hazama, Hisanao; Tachikawa, Shoji; Nakamura, Hiroyuki; Nishida, Tomoki; Yasuda, Hidehiro; Kaneda, Yasufumi; Awazu, Kunio

    2015-03-01

    Traditional treatment options for prostate cancer are insufficient to cure advanced drug-resistant prostate cancer. Thus, as an alternative form of cancer therapy, photodynamic therapy (PDT) has become the main subject of intense investigation as a possible treatment modality. In this study, ultraviolet-inactivated viral vector, called hemagglutinating virus of Japan envelope (HVJ-E) was utilized to establish an effective delivery system for photosensitizer. Lipidated protoporphyrin IX (PpIX lipid) was inserted in HVJ-E by centrifugation to create a new drug delivering system that allows selective accumulation of photosensitizers in cancer cells. To study in vitro drug release mechanism of porphyrus envelope, the ultra-high voltage electron microscope tomography was applied. Next, to evaluate the photodynamic efficiency of porphyrus envelope for hormone antagonistic prostate cancer cells (PC-3), uptake of porphyrus envelope derived PpIX lipid and PpIX induced from exogenously administered precursor of 5-aminolevulinic acid hydrochloride (5-ALA) were compared by measuring fluorescence intensity of PpIX. Finally, to evaluate the efficacy of porphyrus envelope-PDT, laser light at a wavelength of 405 nm was irradiated to PC-3 cells. As a result, incorporation of porphyrus envelope-derived PpIX lipid occurred via membrane fusion, giving the highest fluorescence intensity when compared to 5-ALA-induced PpIX. Also, results from PDT experiment revealed the 28.6 × 103-fold and 206-fold increase in therapeutic efficacy when compared to those of PDT using 5-ALA induced PpIX and PpIX lipid, respectively. Our findings suggest how porphyrus envelope can induce efficient accumulation of PpIX lipid, which can enhance the therapeutic efficacy of PDT against hormone antagonistic prostate cancer.

  18. Photodynamic therapy for basal cell carcinoma.

    PubMed

    Fargnoli, Maria Concetta; Peris, Ketty

    2015-11-01

    Topical photodynamic therapy is an effective and safe noninvasive treatment for low-risk basal cell carcinoma, with the advantage of an excellent cosmetic outcome. Efficacy of photodynamic therapy in basal cell carcinoma is supported by substantial research and clinical trials. In this article, we review the procedure, indications and clinical evidences for the use of photodynamic therapy in the treatment of basal cell carcinoma.

  19. Enhancement and optimization of PpIX-based photodynamic therapy of skin cancer: translational studies from bench to clinic

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay; Baran, Christine; Honari, Golara; Lohser, Sara; Kyei, Angela; Bailin, Philip; Pogue, Brian W.

    2009-02-01

    Nonmelanoma skin carcinomas are the most common of all human cancers. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) has been used to treat these tumors, but has shown variable results. We are pursuing a multifaceted approach toward optimizing tumor responsiveness. First, a new paradigm is being developed in which tumors are pretreated with differentiation-inducing agents, e.g. methotrexate or Vitamin D, to enhance synthesis of protoporphyrin IX (PpIX) and improve tumor cell killing upon exposure to 635 nm light. This principle was first elucidated in cell culture studies, and has now been shown to hold true for murine skin tumors, and for a human subcutaneous tumor model (A431 cells injected in nude mice). Clinical trials to test methotrexate and Vitamin D as augmenting agents for ALA-PDT of nonmelanoma skin cancer are being designed. Second, better methods to measure PpIX in patients' skin tumors in real time are being developed. In a clinical study to measure PpIX in patients with dysplastic skin lesions, in vivo fluorescence dosimetry was used to measure the accumulation of PpIX over time, and revealed that intralesional PpIX may reach clinically-useful levels earlier than previously thought for the treatment of actinic keratoses. In a second clinical study to examine depth of PpIX production in nonmelanoma skin cancer, the depth of PpIX within BCC tumors was found at relatively deep levels (>1 mm) in some tumor nests, but not in others. Production of PpIX in deep squamous cell carcinoma was very low. In summary, molecular approaches such as differentiation therapy to enhance ALA-PDT for individual patients may ultimately be needed to help to improve skin cancer responses to this modality.

  20. 5-ALA Fluorescence in Native Pituitary Adenoma Cell Lines: Resection Control and Basis for Photodynamic Therapy (PDT)?

    PubMed Central

    Poeschke, Stephan; Greve, Burkhard; Prevedello, Daniel; Santacroce, Antonio; Stummer, Walter; Senner, Volker

    2016-01-01

    Objective: Pituitary adenomas (PA), especially invasive ones, are often not completely resectable. Usage of 5-aminolevulinic acid (5-ALA) for fluorescence guided surgery could improve the rate of total resection and, additionally, open the doors for photodynamic therapy (PDT) in case of unresectable or partially resected PAs. The aim of this study was to investigate the uptake of 5-ALA and the effect of 5-ALA based PDT in cell lines. Methods: GH3 and AtT-20 cell lines were incubated with different concentrations of 5-ALA, protoporphyrin IX (PPIX) fluorescence was measured by flow cytometry and fluorescencespectrometry. WST-1 assays were performed to determine the surviving fraction of cells after PDT. PPIX fluorescence intensities and PDT effect of the pituitary adenoma cells were compared to U373MG, a well-known glioblastoma cell line. Results: Both cell lines showed a 5-ALA dependent intracellular PPIX fluorescence. Significant differences after 24hrs of incubation were observed in AtT-20 cells in comparison to GH3. Regardless of the incubation or metabolism time, there was a proliferation inhibiting effect after PDT, with no statistical significance. Conclusion: Since GH3 cells showed a heterogenous uptake of 5-ALA in the flow cytometry profile, but not constantly high concentrations they might have a 5-ALA efflux mechanism, which still needs to be determined. In the case of AtT-20, the cells might need a longer time for the uptake due to their size or slow metabolism. We showed that the different cell lines have different uptake and metabolism mechanisms, which needs to be further investigated. The general uptake of 5-ALA allows the possibility of resection control and PDT for pituitary adenomas. But, the role of PDT for unresectable pituitary adenomas deserves further investigations. PMID:27583461

  1. Combination of Sonodynamic and Photodynamic Therapy against Cancer Would Be Effective through Using a Regulated Size of Nanoparticles

    PubMed Central

    Miyoshi, N.; Kundu, S. K.; Tuziuti, T.; Yasui, K.; Shimada, I.; Ito, Y.

    2016-01-01

    Nanoparticles have been used for many functional materials in nano-sciences and photo-catalyzing surface chemistry. The titanium oxide nanoparticles will be useful for the treatment of tumor by laser and/or ultrasound as the sensitizers in nano-medicine. We have studied the combination therapy of photo- and sono-dynamic therapies in an animal tumor model. Oral-administration of two sensitizers titanium oxide, 0.2%-TiO2 nanoparticles for sono-dynamic and 1 mM 5-aminolevulinic acid for photodynamic therapies have resulted in the best combination therapeutic effects for the cancer treatment. Our light microscopic and Raman spectroscopic studies revealed that the titanium nanoparticles were distributed inside the blood vessel of the cancer tissue (1–3 μm sizes). Among these nanoparticles with a broad size distribution, only particular-sized particles could penetrate through the blood vessel of the cancer tissue, while other particles may only exhibit the side effects in the model mouse. Therefore, it may be necessary to separate the optimum size particles. For this purpose we have separated TiO2 nanoparticles by countercurrent chromatography with a flat coiled column (1.6 mm ID) immersed in an ultrasonic bath (42 KHz). Separation was performed with a two-phase solvent system composed of 1-butanol-acetic acid-water at a volume ratio of 4:1:5 at a flow rate of 0.1 ml/min. Countercurrent chromatographic separation yielded fractions containing particle aggregates at 31 and 4400 nm in diameter. PMID:27088115

  2. Preclinical in vitro and in vivo studies to examine the potential use of photodynamic therapy in the treatment of osteomyelitis

    NASA Astrophysics Data System (ADS)

    Bisland, Stuart K.; Chien, Claudia; Wilson, Brian C.; Burch, Shane

    2005-04-01

    Osteomyelitis can lead to severe morbidity and even death resulting from an acute or chronic inflammation of the bone and contiguous structures due to fungal or bacterial infection. Incidence approximates 1 in 1,000 neonates and 1 in 5,000 children in the United States annually and increases up to 0.36% and 16% in adults with diabetes or sickle cell anaemia, respectively. Current regiments of treatment include antibiotics and/or surgery. However, the increasing number of antibiotic resistant pathogens suggests that alternate strategies are required. We are investigating photodynamic therapy (PDT) as one such alternate treatment for osteomyelitis using a bioluminescent strain of biofilm-producing staphylococcus aureus (SA) grown onto kirschner wires (K-wire). SA-coated K-wires were exposed to methylene blue (MB) or 5-aminolevulinic acid (ALA)-mediated PDT either in vitro or following implant into the tibial medullary cavity of Sprague-Dawley rats. The progression of SA biofilm was monitored non-invasively using bioluminescence and expressed as a percentage of the signal for each sample immediately prior to treatment. SA infections were subject to PDT 10 days post inoculation. Treatment comprised administration of ALA (300 mg/Kg) intraperitoneally followed 4 hr later by light (635 +/- 10 nm; 38 or 75 J/cm2) delivered transcutaneously via an optical fiber placed onto the tibia. In vitro, MB and ALA displayed similar cell kill with >= 4log10 cell kill. In vivo, ALA-mediated PDT inhibited biofilm implants in bone. These results confirm that MB or ALA-mediated PDT have potential to treat SA cultures grown in vitro or in vivo using an animal model of osteomyelitis.

  3. Future of oncologic photodynamic therapy.

    PubMed

    Allison, Ron R; Bagnato, Vanderlei S; Sibata, Claudio H

    2010-06-01

    Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncologic intervention. The relative simplicity of photosensitizer application followed by light activation resulting in the cytotoxic and vasculartoxic photodynamic reaction has allowed PDT to reach a worldwide audience. With several commercially available photosensitizing agents now on the market, numerous well designed clinical trials have demonstrated the efficacy of PDT on various cutaneous and deep tissue tumors. However, current photosensitizers and light sources still have a number of limitations. Future PDT will build on those findings to allow development and refinement of more optimal therapeutic agents and illumination devices. This article reviews the current state of the art and limitations of PDT, and highlight the progress being made towards the future of oncologic PDT.

  4. Photodynamic Diagnosis and Therapy of Cancer

    SciTech Connect

    Subiel, Anna

    2010-01-05

    This paper gives brief information about photodynamic method used in diagnosis and therapy for cancer and other human body disorders. In particular it concentrates on detection and analysis of fluorescent dye, i.e. protoporphyrin IX (PpIX) and its two-photon excitation (TPE) process, which offers photodynamic method many fascinating possibilities.

  5. Photodynamic therapy in endodontics: a literature review.

    PubMed

    Trindade, Alessandra Cesar; De Figueiredo, José Antônio Poli; Steier, Liviu; Weber, João Batista Blessmann

    2015-03-01

    Recently, several in vitro and in vivo studies demonstrated promising results about the use of photodynamic therapy during root canal system disinfection. However, there is no consensus on a standard protocol for its incorporation during root canal treatment. The purpose of this study was to summarize the results of research on photodynamic therapy in endodontics published in peer-reviewed journals. A review of pertinent literature was conducted using the PubMed database, and data obtained were categorized into sections in terms of relevant topics. Studies conducted in recent years highlighted the antimicrobial potential of photodynamic therapy in endodontics. However, most of these studies were not able to confirm a significant improvement in root canal disinfection for photodynamic therapy as a substitute for current disinfection methods. Its indication as an excellent adjunct to conventional endodontic therapy is well documented, however. Data suggest the need for protocol adjustments or new photosensitizer formulations to enhance photodynamic therapy predictability in endodontics.

  6. Clinical efficacy of photodynamic therapy

    PubMed Central

    Park, Ye-Kyu

    2016-01-01

    Objective The management of cervical intraepithelial neoplasia (CIN) and early invasive cancer of the uterine cervix is very difficult to approach, especially in case of young woman who wants to preserve her fertility. Conization of the cervix may have various kinds of disadvantage. The objective of this clinical retrospective study is to investigate the therapeutic effects and clinical efficacy of photodynamic therapy (PDT) including combined chemo-photodynamic therapy in patients with pre-malignant CIN and malignant invasive cervical cancer. Methods Total number of PDT trial case was 50 cases and total number of patient was 22 patients who registered to PDT clinic. We used photogem sensitizer and 632 nm diode laser in early two cases. After then we performed PDT using photofrin sensitizer and 630 nm diode laser in other cases. We used flat-cut, microlens, cylindrical diffuser, and interstitial type optic fibers in order to irradiate the lesions. 240 J/cm2 energy was irradiated to the lesions. Results CIN 2 were 4 cases (18.2%) and CIN 3 were 15 (68.2%) and invasive cervical cancer were 3 (13.6%). Complete remission (CR) was found in 20 patients (91%). One case of 19 patients with CIN lesion recurred at 18 months after PDT treatment. CR was found in 18 cases in the patients with CIN lesions (95%). CR was found in 2 cases in the patients with invasive cervical cancer (67%). Conclusion Our data showed that CR rate was fantastic in CIN group (95%). This study suggests that PDT can be recommended as new optimistic management modality on the patients with pre-malignant CIN lesions including carcinoma in situ and relatively early invasive cancer of the uterine cervix. Combined chemo-photodynamic therapy is essential in case of invasive cervical cancer. For the young age group who desperately want to preserve their fertility and have a healthy baby, PDT can be a beacon of hope. PMID:27896250

  7. Nuclear targets of photodynamic tridentate ruthenium complexes.

    PubMed

    Zhao, Ran; Hammitt, Richard; Thummel, Randolph P; Liu, Yao; Turro, Claudia; Snapka, Robert M

    2009-12-28

    Octahedral ruthenium complexes, capable of photodynamic singlet oxygen production at near 100% efficiency, were shown to cause light-dependent covalent crosslinking of p53 and PCNA subunits in mammalian cells and cell lysates. Azide, a singlet oxygen quencher, greatly reduced the p53 photocrosslinking, consistent with the idea that singlet oxygen is the reactive oxygen species involved in p53 photocrosslinking. A photodynamically inactive ruthenium complex, [Ru(tpy)(2)](2+) (tpy = [2,2';6',2'']-terpyridine), had no effect on p53 or PCNA photocrosslinking. Photodynamic damage to p53 has particular relevance since p53 status is an important determinant of phototoxicity and the effectiveness of photodynamic cancer therapy. The two photodynamic complexes studied, [Ru(tpy)(pydppn)](2+), where pydppn = (3-(pyrid-2'-yl)-4,5,9,16-tetraaza-dibenzo[a,c]naphthacene, and [Ru(pydppn)(2)](2+), differed in their efficiency of p53 and PCNA photocrosslinking in cells, but showed similar efficiency of photocrosslinking in cell lysates, suggesting that they differ in their ability to enter cells. Photocrosslinking of PCNA by [Ru(tpy)(pydppn)](2+) increased linearly with concentration, time of uptake, or light exposure. Both [Ru(tpy)(pydppn)](2+) and [Ru(pydppn)(2)](2+) caused photodynamic protein-DNA crosslinking in cells, but [Ru(tpy)(pydppn)](2+) was more efficient. The efficiency of photodynamic protein-DNA crosslinking by [Ru(tpy)(pydppn)](2+) in cells increased with increasing levels of photodynamic damage. Photodynamic damage by [Ru(tpy)(pydppn)](2+) caused inhibition of DNA replication in a classical biphasic response, suggesting that DNA damage signaling and cell cycle checkpoint pathways were still operative after significant damage to nuclear proteins.

  8. Photodynamic therapy for actinic keratoses.

    PubMed

    Kalisiak, Michal S; Rao, Jaggi

    2007-01-01

    Actinic keratoses (AKs) are one of the most common conditions that are treated by dermatologists and they have the potential to progress to squamous cell carcinoma if left untreated. Photodynamic therapy (PDT) has emerged as a novel and versatile method of treating those lesions. Topical preparations of aminolevulinic acid and methyl aminolevulinate are commercially available photosensitizers, and numerous light sources may be used for photoactivation. This article focuses on practical aspects of PDT in the treatment of AKs, outcomes of relevant clinical trials, and special applications of PDT in transplant recipients and other who are predisposed to AK formation. Step-by-step descriptions of PDT sessions are presented.

  9. Vascular effect of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fyodorov, Svyatoslav N.; Kopayeva, V. G.; Andreev, J. B.; Ponomarev, Gelii V.; Stranadko, Eugeny P.; Suchin, H. M.

    1996-01-01

    Vascular effect of PDT has been studied in patients with corneal vascularized leucomas (10 patients) and in patients with corneal neovascularized transplant (3 patients). For vascularized leucomas the method of photodynamic therapy consisted of the local injection of dimegin (deiteroporphyrin derivative) into the space of the newly-formed vessels under operating microscope (opton) with the microneedle (diameter 200 microns) and corneal irradiation by the operating microscope light. For corneal neovascularized transplant the injection of photogem (hematoporphyrin derivative) intravenously were made with subsequent irradiation by light of dye laser (5 hours after the injection) with light density of 150 mW/cm2 for 15 minutes. In all the cases at the time of irradiation the aggregated blood flow was appeared, followed by blood flow stasis. In postoperative period the vessels disintegrated into separate fragments which disappeared completely after 10 - 15 days. Taking into account the data of light microscopy, the disappearance of the vessels took place as a result of the vascular endothelium lisis along the vascular walls. Neovascularized cornea and newly-formed vessels in tumor stroms have much in common. The vessel alterations study presented in this paper, may serve to specify the mechanism of photodynamic destruction of neovascularized stroma of tumor.

  10. Photosensitizers for photodynamic immune modulation

    NASA Astrophysics Data System (ADS)

    North, John R.; Boch, Ronald; Hunt, David W. C.; Ratkay, Leslie G.; Simkin, Guillermo O.; Tao, Jing-Song; Richter, Anna M.; Levy, Julia G.

    2000-06-01

    PDT may be an effective treatment for certain immune-mediated disorders. The immunomodulatory action of PDT is likely a consequence of effects exerted at a number of levels including stimulation of specific cell signaling pathways, selective depletion of activated immune cells, alteration of receptor expression by immune and non-immune cells, and the modulation of cytokine availability. QLT0074, a potent photosensitizer that exhibits rapid clearance kinetics in vivo, is in development for the treatment of immune disorders. In comparison to the well-characterized and structurally related photosensitizer verteporfin, lower concentrations of QLT0074 were required to induce apoptosis in human blood T cells and keratinocytes using blue light for photoactivation. Both photosensitizers triggered the stress activated protein kinase (SAPK) and p38 (HOG1) pathways but not extracellularly regulated kinase (ERK) activity in mouse Pam212 keratinocytes. In cell signaling responses, QLT0074 was active at lower concentrations than verteporfin. For all in vitro test systems, the stronger photodynamic activity of QLT0074 was associated with a greater cell uptake of this photosensitize than verteporfin. In mouse immune models, sub-erythemogenic doses of QLT0074 in combination with whole body blue light irradiation inhibited the contact hypersensitivity response and limited the development of adjuvant-induced arthritis. QLT0074 exhibits activities that indicate it may be a favorable agent for the photodynamic treatment of human immune disease.

  11. Photodynamic Cancer Therapy - Recent Advances

    SciTech Connect

    Abrahamse, Heidi

    2011-09-22

    The basic principle of the photodynamic effect was discovered over a hundred years ago leading to the pioneering work on PDT in Europe. It was only during the 1980s, however, when 'photoradiation therapy' was investigated as a possible treatment modality for cancer. Photodynamic therapy (PDT) is a photochemotherapeutic process which requires the use of a photosensitizer (PS) that, upon entry into a cancer cell is targeted by laser irradiation to initiate a series of events that contribute to cell death. PSs are light-sensitive dyes activated by a light source at a specific wavelength and can be classified as first or second generation PSs based on its origin and synthetic pathway. The principle of PS activation lies in a photochemical reaction resulting from excitation of the PS producing singlet oxygen which in turn reacts and damages cell organelles and biomolecules required for cell function and ultimately leading to cell destruction. Several first and second generation PSs have been studied in several different cancer types in the quest to optimize treatment. PSs including haematoporphyrin derivative (HpD), aminolevulinic acid (ALA), chlorins, bacteriochlorins, phthalocyanines, naphthalocyanines, pheophorbiedes and purpurins all require selective uptake and retention by cancer cells prior to activation by a light source and subsequent cell death induction. Photodynamic diagnosis (PDD) is based on the fluorescence effect exhibited by PSs upon irradiation and is often used concurrently with PDT to detect and locate tumours. Both laser and light emitting diodes (LED) have been used for PDT depending on the location of the tumour. Internal cancers more often require the use of laser light delivery using fibre optics as delivery system while external PDT often make use of LEDs. Normal cells have a lower uptake of the PS in comparison to tumour cells, however the acute cytotoxic effect of the compound on the recovery rate of normal cells is not known. Subcellular

  12. Photodynamic therapy with ultrafast lasers

    NASA Astrophysics Data System (ADS)

    Wachter, Eric A.; Petersen, Mark G.; Dees, Craig

    1999-06-01

    The photodynamic properties of several photosensitive compounds have been evaluated in vivo using simultaneous two-photon excitation (TPE) and multi-photon excitation (MPE). TPE and MPE are effected using a mode-locked laser, such as the mode-locked titanium:sapphire or Nd:YLF laser, the near infrared output of which allows direct promotion of various non-resonant transitions. Such lasers are exceptionally well suited for non-linear activation of exogenous or endogenous PDT agents in biological systems due to their extremely short pulse width, modest pulse energy, and high repetition rate; these features combine to effect efficient PDT activation with minimal potential for non- specific biological damage, improved spatial localization of activation, and enhanced depth of penetration. Results in several murine models are presented.

  13. Stereocontrolled Cyanohydrin Ether Synthesis through Chiral Brønsted Acid-Mediated Vinyl Ether Hydrocyanation

    PubMed Central

    Lu, Chunliang; Su, Xiaoge; Floreancig, Paul E.

    2013-01-01

    Vinyl ethers can be protonated to generate oxocarbenium ions that react with Me3SiCN to form cyanohydrin alkyl ethers. Reactions that form racemic products proceed efficiently upon converting the vinyl ether to an α-chloro ether prior to cyanide addition in a pathway that proceeds through Brønsted acid-mediated chloride ionization. Enantiomerically enriched products can be accessed by directly protonating the vinyl ether with a chiral Brønsted acid to form a chiral ion pair. Me3SiCN acts as the nucleophile and PhOH serves as a stoichiometric proton source in a rare example of an asymmetric bimolecular nucleophilic addition reaction into an oxocarbenium ion. Computational studies provide a model for the interaction between the catalyst and the oxocarbenium ion. PMID:23968162

  14. DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids.

    PubMed

    Mikula, Hannes; Svatunek, Dennis; Skrinjar, Philipp; Horkel, Ernst; Hametner, Christian; Fröhlich, Johannes

    2014-05-01

    The synthesis of 3-acyltetramic acids by C-acylation of pyrrolidine-2,4-diones was studied by density functional theory (DFT). DFT was applied to the mycotoxin tenuazonic acid (TeA), an important representative of these bioactive natural compounds. Lewis acid mediated C-acylation in combination with previous pH-neutral domino N-acylation-Wittig cyclization can be used for the efficient preparation of 3-acyltetramic acids. Nevertheless, quite harsh conditions are still required to carry out this synthetic step, leading to unwanted isomerization of stereogenic centers in some cases. In the presented study, the reaction pathway for the C-acetylation of (5S,6S-5-s-butylpyrrolidine-2,4-dione was studied in terms of mechanism, solvent effects, and Lewis acid activation, in order to obtain an appropriate theoretical model for further investigations. Crucial steps were identified that showed rather high activation barriers and rationalized previously reported experimental discoveries. After in silico optimization, aluminum chlorides were found to be promising Lewis acids that promote the C-acylation of pyrrolidine-2,4-diones, whereas calculations performed in various organic solvents showed that the solvent had only a minor effect on the energy profiles of the considered mechanisms. This clearly indicates that further synthetic studies should focus on the Lewis-acidic mediator rather than other reaction parameters. Additionally, given the results obtained for different reaction routes, the stereochemistry of this C-acylation is discussed. It is assumed that the formation of Z-configured TeA is favored, in good agreement with our previous studies.

  15. Photodynamic inactivation of mammalian viruses and bacteriophages.

    PubMed

    Costa, Liliana; Faustino, Maria Amparo F; Neves, Maria Graça P M S; Cunha, Angela; Almeida, Adelaide

    2012-07-01

    Photodynamic inactivation (PDI) has been used to inactivate microorganisms through the use of photosensitizers. The inactivation of mammalian viruses and bacteriophages by photosensitization has been applied with success since the first decades of the last century. Due to the fact that mammalian viruses are known to pose a threat to public health and that bacteriophages are frequently used as models of mammalian viruses, it is important to know and understand the mechanisms and photodynamic procedures involved in their photoinactivation. The aim of this review is to (i) summarize the main approaches developed until now for the photodynamic inactivation of bacteriophages and mammalian viruses and, (ii) discuss and compare the present state of the art of mammalian viruses PDI with phage photoinactivation, with special focus on the most relevant mechanisms, molecular targets and factors affecting the viral inactivation process.

  16. Photodynamic Inactivation of Mammalian Viruses and Bacteriophages

    PubMed Central

    Costa, Liliana; Faustino, Maria Amparo F.; Neves, Maria Graça P. M. S.; Cunha, Ângela; Almeida, Adelaide

    2012-01-01

    Photodynamic inactivation (PDI) has been used to inactivate microorganisms through the use of photosensitizers. The inactivation of mammalian viruses and bacteriophages by photosensitization has been applied with success since the first decades of the last century. Due to the fact that mammalian viruses are known to pose a threat to public health and that bacteriophages are frequently used as models of mammalian viruses, it is important to know and understand the mechanisms and photodynamic procedures involved in their photoinactivation. The aim of this review is to (i) summarize the main approaches developed until now for the photodynamic inactivation of bacteriophages and mammalian viruses and, (ii) discuss and compare the present state of the art of mammalian viruses PDI with phage photoinactivation, with special focus on the most relevant mechanisms, molecular targets and factors affecting the viral inactivation process. PMID:22852040

  17. Nanoparticles in photodynamic therapy: an emerging paradigm.

    PubMed

    Chatterjee, Dev Kumar; Fong, Li Shan; Zhang, Yong

    2008-12-14

    Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in management of cancer and other diseases [M. Triesscheijn, P. Baas, J.H. Schellens, F.A. Stewart, Photodynamic therapy in oncology, Oncologist 11 (2006) 1034-1044]. Most photosensitizers are highly hydrophobic and require delivery systems. Previous classification of delivery systems was based on presence or absence of a targeting molecule on the surface [Y.N. Konan, R. Gurny, E. Allemann, State of the art in the delivery of photosensitizers for photodynamic therapy, J. Photochem. Photobiol., B 66 (2002) 89-106]. Recent reports have described carrier nanoparticles with additional active complementary and supplementary roles in PDT. We introduce a functional classification for nanoparticles in PDT to divide them into passive carriers and active participants in photosensitizer excitation. Active nanoparticles are distinguished from non-biodegradable carriers with extraneous functions, and sub-classified mechanistically into photosensitizer nanoparticles, [A.C. Samia, X. Chen, C. Burda, Semiconductor quantum dots for photodynamic therapy, J. Am. Chem. Soc. 125 (2003) 15736-15737, R. Bakalova, H. Ohba, Z. Zhelev, M. Ishikawa, Y. Baba, Quantum dots as photosensitizers? Nat. Biotechnol. 22 (2004) 1360-1361] self-illuminating nanoparticles [W. Chen, J. Zhang, Using nanoparticles to enable simultaneous radiation and photodynamic therapies for cancer treatment, J. Nanosci. Nanotechnology 6 (2006) 1159-1166] and upconverting nanoparticles [P. Zhang, W. Steelant, M. Kumar, M. Scholfield, Versatile photosensitizers for photodynamic therapy at infrared excitation, J. Am. Chem. Soc. 129 (2007) 4526-4527]. Although several challenges remain before they can be adopted for clinical use, these active or second-generation PDT nanoparticles probably offer the best hope for extending the reach of PDT to regions deep in the body.

  18. Inorganic nanoparticles for enhanced photodynamic cancer therapy.

    PubMed

    Cheng, Shih-Hsun; Lo, Leu-Wei

    2011-09-01

    Photodynamic therapy (PDT) in cancer treatment uses photosensitizers to generate singlet oxygen followed by photoirradiation. The efficacy of PDT is greatly determined by the dosimetry of activation light and the photosensitizer (PS), modulating the photodynamic reaction at depth in diseased tissue. Development of nano-formulated photosensitizer has emerged as a promising field because of the biocompatibility and the accessibility for multi-functionalization of nanoparticles. In this review, we summarize the contemporary progress in use of inorganic nanoparticles for improvement of PDT in cancer therapeutics.

  19. Can nanotechnology potentiate photodynamic therapy?

    PubMed Central

    Huang, Ying-Ying; Sharma, Sulbha K.; Dai, Tianhong; Chung, Hoon; Yaroslavsky, Anastasia; Garcia-Diaz, Maria; Chang, Julie; Chiang, Long Y.

    2015-01-01

    Photodynamic therapy (PDT) uses the combination of non-toxic dyes and harmless visible light to produce reactive oxygen species that can kill cancer cells and infectious microorganisms. Due to the tendency of most photosensitizers (PS) to be poorly soluble and to form nonphotoactive aggregates, drug-delivery vehicles have become of high importance. The nanotechnology revolution has provided many examples of nanoscale drug-delivery platforms that have been applied to PDT. These include liposomes, lipoplexes, nanoemulsions, micelles, polymer nanoparticles (degradable and nondegradable), and silica nanoparticles. In some cases (fullerenes and quantum dots), the actual nanoparticle itself is the PS. Targeting ligands such as antibodies and peptides can be used to increase specificity. Gold and silver nanoparticles can provide plasmonic enhancement of PDT. Two-photon excitation or optical upconversion can be used instead of one-photon excitation to increase tissue penetration at longer wavelengths. Finally, after sections on in vivo studies and nanotoxicology, we attempt to answer the title question, “can nano-technology potentiate PDT?” PMID:26361572

  20. New photosensitizers for photodynamic therapy.

    PubMed

    Abrahamse, Heidi; Hamblin, Michael R

    2016-02-15

    Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.

  1. Inorganic Nanoparticles for Photodynamic Therapy.

    PubMed

    Colombeau, L; Acherar, S; Baros, F; Arnoux, P; Gazzali, A Mohd; Zaghdoudi, K; Toussaint, M; Vanderesse, R; Frochot, C

    2016-01-01

    Photodynamic therapy (PDT) is a well-established technique employed to treat aged macular degeneration and certain types of cancer, or to kill microbes by using a photoactivatable molecule (a photosensitizer, PS) combined with light of an appropriate wavelength and oxygen. Many PSs are used against cancer but none of them are highly specific. Moreover, most are hydrophobic, so are poorly soluble in aqueous media. To improve both the transportation of the compounds and the selectivity of the treatment, nanoparticles (NPs) have been designed. Thanks to their small size, these can accumulate in a tumor because of the well-known enhanced permeability effect. By changing the composition of the nanoparticles it is also possible to achieve other goals, such as (1) targeting receptors that are over-expressed on tumoral cells or neovessels, (2) making them able to absorb two photons (upconversion or biphoton), and (3) improving singlet oxygen generation by the surface plasmon resonance effect (gold nanoparticles). In this chapter we describe recent developments with inorganic NPs in the PDT domain. Pertinent examples selected from the literature are used to illustrate advances in the field. We do not consider either polymeric nanoparticles or quantum dots, as these are developed in other chapters.

  2. Can nanotechnology potentiate photodynamic therapy?

    PubMed

    Huang, Ying-Ying; Sharma, Sulbha K; Dai, Tianhong; Chung, Hoon; Yaroslavsky, Anastasia; Garcia-Diaz, Maria; Chang, Julie; Chiang, Long Y; Hamblin, Michael R

    2012-03-01

    Photodynamic therapy (PDT) uses the combination of non-toxic dyes and harmless visible light to produce reactive oxygen species that can kill cancer cells and infectious microorganisms. Due to the tendency of most photosensitizers (PS) to be poorly soluble and to form nonphotoactive aggregates, drug-delivery vehicles have become of high importance. The nanotechnology revolution has provided many examples of nanoscale drug-delivery platforms that have been applied to PDT. These include liposomes, lipoplexes, nanoemulsions, micelles, polymer nanoparticles (degradable and nondegradable), and silica nanoparticles. In some cases (fullerenes and quantum dots), the actual nanoparticle itself is the PS. Targeting ligands such as antibodies and peptides can be used to increase specificity. Gold and silver nanoparticles can provide plasmonic enhancement of PDT. Two-photon excitation or optical upconversion can be used instead of one-photon excitation to increase tissue penetration at longer wavelengths. Finally, after sections on in vivo studies and nanotoxicology, we attempt to answer the title question, "can nano-technology potentiate PDT?"

  3. Functionalized Fullerenes in Photodynamic Therapy

    PubMed Central

    Huang, Ying-Ying; Sharma, Sulbha K.; Yin, Rui; Agrawal, Tanupriya; Chiang, Long Y.; Hamblin, Michael R.

    2014-01-01

    Since the discovery of C60 fullerene in 1985, scientists have been searching for biomedical applications of this most fascinating of molecules. The unique photophysical and photochemical properties of C60 suggested that the molecule would function well as a photosensitizer in photodynamic therapy (PDT). PDT uses the combination of non-toxic dyes and harmless visible light to produce reactive oxygen species that kill unwanted cells. However the extreme insolubility and hydrophobicity of pristine C60, mandated that the cage be functionalized with chemical groups that provided water solubility and biological targeting ability. It has been found that cationic quaternary ammonium groups provide both these features, and this review covers work on the use of cationic fullerenes to mediate destruction of cancer cells and pathogenic microorganisms in vitro and describes the treatment of tumors and microbial infections in mouse models. The design, synthesis, and use of simple pyrrolidinium salts, more complex decacationic chains, and light-harvesting antennae that can be attached to C60, C70 and C84 cages are covered. In the case of bacterial wound infections mice can be saved from certain death by fullerene-mediated PDT. PMID:25544837

  4. New photosensitizers for photodynamic therapy

    PubMed Central

    Abrahamse, Heidi; Hamblin, Michael R.

    2016-01-01

    Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound. PMID:26862179

  5. Photodynamic application in neurosurgery: present and future

    NASA Astrophysics Data System (ADS)

    Kostron, Herwig

    2009-06-01

    Photodynamic techniques such as photodynamic diagnosis (PDD), fluorescence guided tumor resection (FGR) and photodynamic therapy (PDT) are currently undergoing intensive clinical investigations as adjunctive treatment for malignant brain tumours. This review provides an overview on the current clinical data and trials as well as on photosensitisers, technical developments and indications for photodynamic application in Neurosurgery. Furthermore new developments and clinical significance of FGR for neurosurgery will be discussed. Over 1000 patients were enrolled in various clinical phase I/II trials for PDT for malignant brain tumours. Despite various treatment protocols, variation of photosensitisers and light dose there is a clear trend towards prolonging median survival after one single PDT as compared to conventional therapeutic modalities. The median survival after PDT for primary glioblastoma multiforme WHO IV was 19 months and for recurrent GBM 9 months as compared to standard convential treatment which is 15 months and 3 months, respectively. FGR in combination with adjunctive radiation was significantly superior to standard surgical resection followed by radiation. The combination of FGR/PDD and intraoperative PDT increased significantly survival in recurrent glioblastoma patients. The combination of PDD/ FGR and PDT offers an exciting approach to the treatment of malignant brain tumours "to see and to treat." PDT was generally well tolerated and side effects consisted of occasionally increased intracranial pressure and prolonged skin sensitivity against direct sunlight. This review covers the current available data and draws the future potential of PDD and PDT for its application in neurosurgery.

  6. Defluoridation of water using dicarboxylic acids mediated chitosan-polyaniline/zirconium biopolymeric complex.

    PubMed

    Muthu Prabhu, Subbaiah; Meenakshi, Sankaran

    2016-04-01

    The present investigation describes the preparation of hydrogen bonded chitosan-polyaniline/zirconium biopolymeric matrix by grafting method under dicarboxylic acid medium for the removal of fluoride, first time. Herein, the dicarboxylic acids, oxalic acid, malonic acid, succinic acid were used as medium. The synthesized complex was characterized by usual analytical techniques like FTIR, XRD, SEM and EDAX analysis. From the batch equilibrium experiments, the maximum defluoridation capacity (DC) was found to be 8.713 mg/g at room temperature with the minimum contact time of 24 min at 100mg of the sorbent dosage. The temperature study results of adsorption kinetics showed the adsorption behavior could be better described by the pseudo-second-order equation than pseudo-first-order kinetic model. The adsorption isotherm was well fitted by the Freundlich equation rather than Langmuir and D-R isotherms. The mechanism of fluoride removal was ligand exchange at neutral pH and electrostatic attraction at acidic pH of the medium. Regeneration studies were carried out to identify the best regenerant which makes the process cost-effective. Conclusions of this work demonstrate the potential applicability of the dicarboxylic acid mediated chitosan-polyaniline/zirconium complex as an effective adsorbent for fluoride removal from water.

  7. [The wider application of photodynamic therapy in dermatology].

    PubMed

    Thissen, M R T M; Kuijpers, D I M; Neumann, H A M

    2005-01-29

    Photodynamic treatment is increasingly employed in the detection and treatment of malignant and non-malignant skin disease. --Indications for photodynamic therapy so far are actinic keratosis, Bowen's disease and superficially growing basal cell carcinomas, and probably verrucae and acne vulgaris. --This technology is also currently under investigation for fluorescence diagnostics oftumour margins. --The exact position of photodynamic therapy has not yet been established because there are too less long-term comparative studies demonstrating its effectiveness. --Based on the short-term results, photodynamic therapy deserves a place within the total therapeutic arsenal of the dermatologist of today for the indications mentioned above.

  8. Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses.

    PubMed

    Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B; Sureshkumar, Chitta; Manna, Sunil K

    2011-02-11

    Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.

  9. Enhancing Perception of Contaminated Food through Acid-Mediated Modulation of Taste Neuron Responses

    PubMed Central

    Chen, Yan; Amrein, Hubert

    2015-01-01

    SUMMARY Background Natural foods not only contain nutrients, but also non-nutritious and potentially harmful chemicals. Thus, animals need to evaluate food content in order to make adequate feeding decisions. Results Here, we investigate the effects of acids on the taste neuron responses and on taste behavior of desirable, nutritious sugars and sugar/bitter compound mixtures in Drosophila melanogaster. Using Ca2+ imaging, we show that acids neither activate sweet nor bitter taste neurons in tarsal taste sensilla. However, they suppress responses to bitter compounds in bitter-sensing neurons. Moreover, acids reverse suppression of bitter compounds exerted on sweet-sensing neurons. Consistent with these observations, behavioral analyses show that bitter compound-mediated inhibition on feeding behavior is alleviated by acids. To investigate the cellular mechanism by which acids modulate these effects, we silenced bitter sensing gustatory neurons. Surprisingly, this intervention had little effect on acid-mediated de-repression of sweet neuron or feeding responses to either sugar/bitter compound mixtures, or sugar/bitter compound/acid mixtures, suggesting two independent pathways by which bitter compounds are sensed. Conclusions Our investigations reveal that acids, when presented in dietary relevant concentrations, enhance the perception of sugar/bitter compound mixtures. Drosophila’s natural food sources - fruits and cohabitating yeast - are rich in sugars and acids, but are rapidly colonized by microorganisms, such as fungi, protozoan parasites and bacteria, many of which produce bitter compounds. We propose that acids present in most fruits counteract the inhibitory effects of these bitter compounds during feeding. PMID:25131671

  10. In vitro effects of Panax ginseng in aristolochic acid-mediated renal tubulotoxicity: apoptosis versus regeneration.

    PubMed

    Bunel, Valérian; Antoine, Marie-Hélène; Nortier, Joëlle; Duez, Pierre; Stévigny, Caroline

    2015-03-01

    This in vitro study aimed to determine the effects of a Panax ginseng extract on aristolochic acid-mediated toxicity in HK-2 cells. A methanolic extract of ginseng (50 µg/mL) was able to reduce cell survival after treatment with 50 µM aristolochic acid for 24, 48, and 72 h, as evidenced by a resazurin reduction assay. This result was confirmed by a flow cytometric evaluation of apoptosis using annexin V-PI staining, and indicated higher apoptosis rates in cells treated with aristolochic acid and P. ginseng extract compared with aristolochic acid alone. However, P. ginseng extract by itself (5 and 50 µg/mL) increased the Ki-67 index, indicating an enhancement in cellular proliferation. Cell cycle analysis excluded a P. ginseng extract-mediated induction of G2/M cell cycle arrest such as the one typically observed with aristolochic acid. Finally, β-catenin acquisition was found to be accelerated when cells were treated with both doses of ginseng, suggesting that the epithelial phenotype of renal proximal tubular epithelial cells was maintained. Also, ginseng treatment (5 and 50 µg/mL) reduced the oxidative stress activity induced by aristolochic acid after 24 and 48 h. These results indicate that the ginseng extract has a protective activity towards the generation of cytotoxic reactive oxygen species induced by aristolochic acid. However, the ginseng-mediated alleviation of oxidative stress did not correlate with a decrease but rather with an increase in aristolochic acid-induced apoptosis and death. This deleterious herb-herb interaction could worsen aristolochic acid tubulotoxicity and reinforce the severity and duration of the injury. Nevertheless, increased cellular proliferation and migration, along with the improvement in the epithelial phenotype maintenance, indicate that ginseng could be useful for improving tubular regeneration and the recovery following drug-induced kidney injury. Such dual activities of ginseng certainly warrant further in vivo

  11. Rapid generation of molecular complexity in the Lewis or Brønsted acid-mediated reactions of methylenecyclopropanes.

    PubMed

    Shi, Min; Lu, Jian-Mei; Wei, Yin; Shao, Li-Xiong

    2012-04-17

    Although they are highly strained, methylenecyclopropanes (MCPs) are readily accessible molecules that have served as useful building blocks in organic synthesis. MCPs can undergo a variety of ring-opening reactions because the release of cyclopropyl ring strain (40 kcal/mol) can provide a thermodynamic driving force for reactions and the π-character of the bonds within the cyclopropane can afford the kinetic opportunity to initiate the ring-opening. Since the 1970s, the chemistry of MCPs has been widely explored in the presence of transition metal catalysts, but less attention had been paid to the Lewis or Brønsted acid mediated chemistry of MCPs. During the past decade, significant developments have also been made in the Lewis or Brønsted acid mediated reactions of MCPs. This Account describes chemistry developed in our laboratory and by other researchers. Lewis and Brønsted acids can be used as catalysts or reagents in the reactions of MCPs with a variety of substrates, and substituents on the terminal methylene or on the cyclopropyl ring of MCPs significantly affect the reaction pathways. During the past decade, we and other researchers have found interesting transformations based on this chemistry. These new reactions include the ring expansion of MCPs, cycloaddition reactions of MCPs with aldehydes and imines, cycloaddition reactions of MCPs with nitriles in the presence of strong Brønsted acid, radical reactions of MCPs with 1,3-dicarbonyl compounds, intramolecular Friedel-Crafts reactions of MCPs with arenes, acylation reactions of MCPs, and the reaction of MCPs with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers. These Lewis or Brønsted acid mediated reactions of MCPs can produce a variety of new compounds such as cyclobutanones, indenes, tetrahydrofurans, and tetrahydroquinolines. Finally, we have also carried out computational studies to explain the mechanism of the Brønsted acid mediated reactions of MCPs with acetonitrile.

  12. Photodynamic therapy (PDT) and waterfiltered infrared A (wIRA) in patients with recalcitrant common hand and foot warts

    PubMed Central

    Fuchs, Silke M.; Fluhr, Joachim W.; Bankova, Lora; Tittelbach, Jörg; Hoffmann, Gerd; Elsner, Peter

    2004-01-01

    Background: Common warts (verrucae vulgares) are human papilloma virus (HPV) infections with a high incidence and prevalence, most often affecting hands and feet, being able to impair quality of life. About 30 different therapeutic regimens described in literature reveal a lack of a single striking strategy. Recent publications showed positive results of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) in the treatment of HPV-induced skin diseases, especially warts, using visible light (VIS) to stimulate an absorption band of endogenously formed protoporphyrin IX. Additional experiences adding waterfiltered infrared A (wIRA) during 5-ALA-PDT revealed positive effects. Aim of the study: First prospective randomised controlled blind study including PDT and wIRA in the treatment of recalcitrant common hand and foot warts. Comparison of "5-ALA cream (ALA) vs. placebo cream (PLC)" and "irradiation with visible light and wIRA (VIS+wIRA) vs. irradiation with visible light alone (VIS)". Methods: Pre-treatment with keratolysis (salicylic acid) and curettage. PDT treatment: topical application of 5-ALA (Medac) in "unguentum emulsificans aquosum" vs. placebo; irradiation: combination of VIS and a large amount of wIRA (Hydrosun® radiator type 501, 4 mm water cuvette, waterfiltered spectrum 590-1400 nm, contact-free, typically painless) vs. VIS alone. Post-treatment with retinoic acid ointment. One to three therapy cycles every 3 weeks. Main variable of interest: "Percent change of total wart area of each patient over the time" (18 weeks). Global judgement by patient and by physician and subjective rating of feeling/pain (visual analogue scales). 80 patients with therapy-resistant common hand and foot warts were assigned randomly into one of the four therapy groups with comparable numbers of warts at comparable sites in all groups. Results: The individual total wart area decreased during 18 weeks in group 1 (ALA+VIS+wIRA) and in group 2 (PLC

  13. Expression of IL-10, TGF-β1 and TNF-α in Cultured Keratinocytes (HaCaT Cells) after IPL Treatment or ALA-IPL Photodynamic Treatment

    PubMed Central

    Byun, Ji Yeon; Choi, Hae Young; Myung, Ki Bum

    2009-01-01

    Background Depending on the light dose and concentration of photosensitizer for photodynamic treatment (PDT), a multitude of dose-related events are demonstrable in PDT-treated cells. Sublethal doses may result in the alteration of cytokine release and consequently modify immune actions, rather than cause cell death. Objective The purpose of this study was to investigate cytokine expression in cultured HaCaT cells after intense pulse light (IPL) treatment or PDT utilizing 5-aminolevulinic acid (ALA) and IPL at sublethal doses. Methods Cultured HaCaT cells were treated with either IPL only (4, 8 and 12 J/cm2) or ALA-IPL PDT (100µmol/L of ALA; 0, 4, 8, and 12 J/cm2 of IPL). The expression of IL-10, TGF-β1 and TNF-α was investigated by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Results IL-10 protein increased up to 5.95-fold after IPL treatment and up to 2.85-fold after PDT. TGF-β1 mRNA and protein showed slight increases after both IPL treatment and PDT, of which the latter induced slightly larger increases. TNF-α mRNA and protein showed no induction or reduction after PDT. Conclusion Increased expressions of IL-10 and TGF-β1 was observed after PDT. The induction of IL-10 may contribute to the anti-inflammatory effect, which explains the therapeutic benefit of PDT for inflammatory dermatoses, and that of TGF-β1 may be related to the therapeutic effect for psoriasis. The finding that IL-10 induction was more marked after IPL treatment than after PDT suggests that other mechanisms than IL-10 induction in keratinocytes after PDT may participate in the anti-inflammatory effect of PDT. PMID:20548849

  14. Cyanines as efficient photosensitizers in photodynamic reaction: photophysical properties and in vitro photodynamic activity.

    PubMed

    Kulbacka, J; Pola, A; Mosiadz, D; Choromanska, A; Nowak, P; Kotulska, M; Majkowski, M; Hryniewicz-Jankowska, A; Purzyc, L; Saczko, J

    2011-04-01

    The purpose of the present study was to explore the potential application of cyanines in photodynamic treatment. The photophysical features of four cyanines (KF570, HM118, FBF-749, and ER-139) were investigated by elemental and spectral analyses. Two malignant cell lines (MCF-7/WT and MCF-7/DOX) were used to test the potential for use in the photodynamic therapy. The cytotoxic effects of these dyes were determined by the MTT assay after 4 and 24 h of incubation with the cyanine. KF570 and HM118 were irradiated with red light (630-nm filter) and FBF-749 and ER-139 with green light (435-nm filter). The results showed that the cyanine HM118 demonstrated a major phototoxic effect. It was also noted that the efficiency of photodynamic therapy was higher in the doxorubicin-resistant cell line (MCF-7/DOX).

  15. Photodynamic therapy of cervical intraepithelial neoplasia

    NASA Astrophysics Data System (ADS)

    Inada, Natalia M.; Lombardi, Welington; Leite, Marieli F. M.; Trujillo, Jose R.; Kurachi, Cristina; Bagnato, Vanderlei S.

    2014-03-01

    Photodynamic therapy (PDT) is a technique that has been used for the treatment of tumors, especially in Gynecology. The photodynamic reaction is based on the production of reactive oxygen species after the activation of a photosensitizer. Advantages of the PDT in comparison to the surgical resection are: ambulatory treatment and tissue recovery highly satisfactory, through a non-invasive procedure. The cervical intraepithelial neoplasia (CIN) grades I and II presents potential indications for PDT. The aim of the proposed study is to evaluate the safety and efficacy of the PDT for the diagnostics and treatment of CIN I and II. The equipment and the photosensitizer are produced in Brazil with a representative low cost. It is possible to visualize the fluorescence of the cervix and to treat the lesions, without side effects. The proposed clinical protocol shows great potential to become a public health technique.

  16. Second generation photodynamic agents: a review.

    PubMed

    Sternberg, E D; Dolphin, D

    1993-10-01

    Over the last decade, laser treatment of neoplastic diseases has become routine. The ability of these light-induced therapies to effect positive results is increased with the utilization of photosensitizing dyes. The approval of Photofrin in Canada as a first generation photodynamic therapeutic agent for the treatment of some forms of bladder cancer is being followed by the development of other agents with improved properties. At this time a number of second generation photosensitizing dyes are under study in phase I/II clinical trials. A review of the status of these trials along with mechanistic aspects is reviewed in this article. In addition, a review of the status of lasers to be utilized for photodynamic therapy gives some indication of which instruments could be considered for this therapy in the future.

  17. Mechanism of photodynamic activity of pheophorbides.

    PubMed

    Tanielian, C; Kobayashi, M; Wolff, C

    2001-04-01

    Plasmid DNA is efficiently photocleaved by sodium pheophorbides (Na-Phdes) a and b in the absence of oxygen as well as in the presence of oxygen. Fluorescence microscopic observation shows a rapid incorporation of Na-Phde a into nuclei, mitochondria, and lysosome of human oral mucosa cells. In contrast Na-Phde b is incorporated only into the plasma membrane. The photodynamic activity of these pigments in living tissues is probably determined by the monomeric pigment molecules formed in hydrophobic cellular structures and involves two types of reactions: (i) direct electron transfer between DNA bases (especially guanine) and pheophorbide singlet excited state, and (ii) indirect reactions mediated by reactive oxygen species, including singlet oxygen whose production from molecular oxygen is sensitized by the Na-Phdes triplet state. A preliminary report has appeared in "Photodynamic Therapy of Cancer II," Proc. SPIE 2325, 416-424 (1994).

  18. Photodynamic therapy for pododermatitis in penguins.

    PubMed

    Sellera, Fábio Parra; Sabino, Caetano Padial; Ribeiro, Martha Simões; Fernandes, Loriê Tukamoto; Pogliani, Fabio Celidonio; Teixeira, Carlos Roberto; Dutra, Gustavo Henrique Pereira; Nascimento, Cristiane Lassálvia

    2014-01-01

    Pododermatitis is currently one of most frequent and important clinical complications in seabirds kept in captivity or in rehabilitation centers. In this study, five Magellanic penguins with previous pododermatitis lesions on their footpad were treated with photodynamic therapy (PDT). All PDT treated lesions successfully regressed and no recurrence was observed during the 6-month follow-up period. PDT seems to be an inexpensive and effective alternative treatment for pododermatitis in Magellanic penguins encouraging further research on this topic.

  19. Retinoblastoma: might photodynamic therapy be an option?

    PubMed

    Teixo, Ricardo; Laranjo, Mafalda; Abrantes, Ana Margarida; Brites, Gonçalo; Serra, Arménio; Proença, Rui; Botelho, Maria Filomena

    2015-12-01

    Retinoblastoma is a tumor that mainly affects children under 5 years, all over the world. The origin of these tumors is related with mutations in the RB1 gene, which may result from genetic alterations in cells of the germ line or in retinal somatic cells. In developing countries, the number of retinoblastoma-related deaths is higher due to less access to treatment, unlike what happens in developed countries where survival rates are higher. However, treatments such as chemotherapy and radiotherapy, although quite effective in treating this type of cancer, do not avoid high indices of mortality due to secondary malignances which are quite frequent in these patients. Additionally, treatments such as cryotherapy, thermotherapy, thermochemotherapy, or brachytherapy represent other options for retinoblastoma. When all these approaches fail, enucleation is the last option. Photodynamic therapy might be considered as an alternative, particularly because of its non-mutagenic character. Photodynamic therapy is a treatment modality based on the administration of photosensitizing molecules that only upon irradiation of the tumor with a light source of appropriate wavelength are activated, triggering its antitumor action. This activity may be not only due to direct damage to tumor cells but also due to damage caused to the blood vessels responsible for the vascular supply of the tumor. Over the past decades, several in vitro and in vivo studies were conducted to assess the effectiveness of photodynamic therapy in the treatment of retinoblastoma, and very promising results were achieved.

  20. Combined surgery and photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Douplik, Alexandre

    According to the recent guidelines, the gold standard is resecting an extra 0.5-3 cm beyond the lesion margins that are visually detected and/or biopsy confirmed depending on type of malignancy and its localisation to avoid missing the residuals of the tumour. Often, such a large resection leads to dysfunctions of the organ or tissues, which underwent the surgery. In some cases, an extra tumour-free margin cannot be achieved because of tumour proximity to vital sites such as major vascular or nerve structures. Photodynamic Therapy (PDT) is an emerging clinical modality to locally destroy cancer lesions selectively. The limitation of photodynamic therapy is the curable depth of an order of one centimetre or less. A combination of cancer surgery following by PDT can bring a benefit to reduce the resection and minimise the impact on the organ or tissue functionality. Combination of cancer surgery and photodynamic therapy provides another opportunity-fluorescence image guidance of cancer removal. Most of the photosensitizers intensively fluoresce and hence facilitate a strong fluorescence contrast versus healthy adjacent tissues.

  1. Milestones in the development of photodynamic therapy and fluorescence diagnosis.

    PubMed

    Juzeniene, Asta; Peng, Qian; Moan, Johan

    2007-12-01

    Many reviews on PDT have been published. This field is now so large, and embraces so many sub-specialties, from laser technology and optical penetration through diffusing media to a number of medical fields including dermatology, gastroenterology, ophthalmology, blood sterilization and treatment of microbial-viral diseases, that it is impossible to cover all aspects in a single review. Here, we will concentrate on a few basic aspects, all important for the route of development leading PDT to its present state: early work on hematoporphyrin and hematoporphyrin derivative, second and third generation photosensitizers, 5-aminolevulinic acid and its derivatives, oxygen and singlet oxygen, PDT effects on cell organelles, mutagenic potential, the basis for tumour selectivity, cell cooperativity, photochemical internalization, light penetration into tissue and the significance of oxygen depletion, photobleaching of photosensitizers, optimal light sources, effects on the immune system, and, finally, future trends.

  2. A Direct, Biomass-Based Synthesis of Benzoic Acid: Formic Acid-Mediated Deoxygenation of the Glucose-Derived Materials Quinic Acid and Shikimic Acid

    SciTech Connect

    Arceo, Elena; Ellman, Jonathan; Bergman, Robert

    2010-05-03

    An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.

  3. Pulse mode of laser photodynamic treatment induced cell apoptosis.

    PubMed

    Klimenko, Vladimir V; Knyazev, Nickolay A; Moiseenko, Fedor V; Rusanov, Anatoliy A; Bogdanov, Alexey A; Dubina, Michael V

    2016-03-01

    One of the factors limiting photodynamic therapy (PDT) is hypoxia in tumor cells during photodynamic action. PDT with pulse mode irradiation and appropriate irradiation parameters could be more effective in the singlet oxygen generation and tissue re-oxygenation than continuous wave (CW) mode. We theoretically demonstrate differences between the cumulative singlet oxygen concentration in PDT using pulse mode and CW mode of laser irradiation. In vitro experimental results show that photodynamic treatment with pulse mode irradiation has similar cytotoxicity to CW mode and induces mainly cell apoptosis, whereas CW mode induces necrotic cell death. We assume that the cumulative singlet oxygen concentration and the temporal distribution of singlet oxygen are important in photodynamic cytotoxicity and apoptosis initiation. We expect our research may improve irradiation protocols and photodynamic therapy efficiency.

  4. In-office Painless Aminolevulinic Acid Photodynamic Therapy

    PubMed Central

    2016-01-01

    Objective: To evaluate the efficacy, safety, and pain of in-office “painless” aminolevulinic acid photodynamic therapy aimed at decreasing treatment-associated pain in patients undergoing removal of actinic keratoses. Design: Prospective split-face study comparing short aminolevulinic acid incubation times of 15 minutes followed by extended exposure (60 minutes) of continuous blue light versus conventional aminolevulinic acid photodynamic therapy. Prospective assessment of pain in patients undergoing in-office “painless” aminolevulinic acid photodynamic therapy. Setting: Clinical practice office. Participants: Three patients with actinic keratoses participated in the split-face study and 101 in the pain assessment study. Measurements: Evaluations in the split-face study included removal of actinic keratoses, skin temperature, and pain measured on a 10-point visual analog scale. Pain was assessed using the visual analog scale in the pain assessment study. Results: In the split-face study, in-office “painless” aminolevulinic acid photodynamic therapy resulted in a 52-percent reduction in lesions versus 44 percent for conventional aminolevulinic acid photodynamic therapy. Maximum pain scores of in-office “painless” aminolevulinic acid photodynamic therapy were all 0 at each time point, and the average score for conventional aminolevulinic acid photodynamic therapy was 7. Baseline skin temperatures increased from a baseline of 29 to 32°C to 34 to 35°C by minute 10 of blue light activation on both sides of the face. Results from the pain assessment study indicated no or minimal (scores 0-2) pain in nearly all patients who received in-office “painless” aminolevulinic acid photodynamic therapy as monotherapy or in combination with 5-fluoruacil or imiquimod used as pretreatments. Conclusions: In-office “painless” aminolevulinic acid photodynamic therapy appears to be effective for removing actinic keratoses and is associated with little or no pain

  5. Hormonal component of tumor photodynamic therapy response

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Merchant, Soroush

    2008-02-01

    The involvement of adrenal glucocorticoid hormones in the response of the treatment of solid tumors by photodynamic therapy (PDT) comes from the induction of acute phase response by this modality. This adrenal gland activity is orchestrated through the engagement of the hypothalamic-pituitary-adrenal hormonal axis incited by stress signals emanating from the PDT-treated tumor. Glucocorticoid hormone activity engendered within the context of PDT-induced acute phase response performs multiple important functions; among other involvements they beget acute phase reactant production, systemic neutrophil mobilization, and control the production of inflammation-modulating and immunoregulatory proteins.

  6. Flexible textile light diffuser for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Selm, Barbel; Camenzind, Martin

    2005-03-01

    In this article a new medical application is introduced using textile production techniques to deliver a defined radiation dose. The advantage for photodynamic therapy (PDT) is that a flat luminous textile structure can homogeneously illuminate unequal body surfaces. The optical properties of this two-dimensional luminous pad are characterized with a set of bench-scale tests. In vitro investigations on petri dishes with cultivated cells and first clinical tests on animal patients are promising. In addition first measurement results are presented together with an outlook to future developments.

  7. Acceleration Of Wound Healing Ny Photodynamic Therapy

    SciTech Connect

    Hasan, Tayyaba; Hamblin, Michael R.; Trauner, Kenneth

    2000-08-22

    Disclosed is a method for accelerating wound healing in a mammal. The method includes identifying an unhealed wound site or partially-healed wound site in a mammal; administering a photosensitizer to the mammal; waiting for a time period wherein the photosensitizer reaches an effective tissue concentration at the wound site; and photoactivating the photosensitizer at the wound site. The dose of photodynamic therapy is selected to stimulate the production of one or more growth factor by cells at the wound site, without causing tissue destruction.

  8. Photodynamic therapy and anti-tumour immunity

    PubMed Central

    Castano, Ana P.; Mroz, Pawel; Hamblin, Michael R.

    2010-01-01

    Photodynamic therapy (PDT) uses non-toxic photosensitizers and harmless visible light in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumour microvasculature and stimulate the host immune system. In contrast to surgery, radiotherapy and chemotherapy that are mostly immunosuppressive, PDT causes acute inflammation, expression of heat-shock proteins, invasion and infiltration of the tumour by leukocytes, and might increase the presentation of tumour-derived antigens to T cells. PMID:16794636

  9. Photodynamic dosimetry in the treatment of periodontitis

    NASA Astrophysics Data System (ADS)

    Andersen, Roger C.; Loebel, Nicolas G.; Andersen, Dane M.

    2009-06-01

    Photodynamic therapy has been demonstrated to effectively kill human periopathogens in vitro. However, the translation of in vitro work to in vivo clinical efficacy has been difficult due to the number of variables present in any given patient. Parameters such as photosensitizer concentration, duration of light therapy and amount of light delivered to the target tissue all play a role in the dose response of PDT in vivo. In this 121 patient study we kept all parameters the same except for light dose which was delivered at either 150 mW or 220 mW. This clearly demonstrated the clinical benefits of a higher light dose in the treatment of periodontitis.

  10. Photodynamic Therapy Treatment to Enhance Fracture Healing

    DTIC Science & Technology

    2013-06-01

    Military  Health  System Research Symposium (MHSRS);    13.‐ 16. August 2012 in Fort Lauderdale, FL, USA       The  Effect  of Photodynamic Therapy (PDT...ORGANIZATION: Sunnybrook Health Sciences Centre Toronto, ON, Canada M4N 3M5 REPORT DATE...Sunnybrook Health Sciences Centre 8. PERFORMING ORGANIZATION REPORT NUMBER Toronto, ON, Canada M4N 3M5

  11. Semiconductor quantum dots for photodynamic therapy.

    PubMed

    Samia, Anna C S; Chen, Xiaobo; Burda, Clemens

    2003-12-24

    The applicability of semiconductor QDs in photodynamic therapy (PDT) was evaluated by studying the interaction between CdSe QDs with a known silicon phthalocyanine PDT photosensitizer, Pc4. The study revealed that the QDs could be used to sensitize the PDT agent through a fluorescence resonance energy transfer (FRET) mechanism, or interact directly with molecular oxygen via a triplet energy-transfer process (TET). Both mechanisms result in the generation of reactive singlet oxygen species that can be used for PDT cancer therapy.

  12. Photosensitizer and light diffusion through dentin in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Nogueira, Ana C.; Graciano, Ariane X.; Nagata, Juliana Y.; Fujimaki, Mitsue; Terada, Raquel S. S.; Bento, Antonio C.; Astrath, Nelson G. C.; Baesso, Mauro L.

    2013-05-01

    Photodynamic therapy has been considered a potential antimicrobial modality against oral infections, including dental caries. A model to estimate the penetration of both photosensitizers and light through human dentin, a factor of interest in photodynamic therapy, is proposed. The photoacoustic spectroscopy technique was used to evaluate in vitro dentin permeability of three different photosensitizers. Using the dentin optical absorption and scattering coefficients, it was possible to propose a semi-quantitative model predicting both photosensitizer and light doses within dentin. The graphic illustrations obtained provided guidelines that may be useful in photodynamic therapy protocols used as antimicrobial tools in caries lesions.

  13. Photodynamic impact on the epiphyseal plates.

    PubMed

    Kurchenko, S; Shashko, A; Dudin, M; Mikhailov, V; Netylko, G; Ashmarov, V

    2012-01-01

    This study was carried out to prove the possibility of inhibition of long bones epiphyseal plates activity with photodynamic impact. Comparative analysis of the Chlorin E6 accumulation with transcutaneous and intraperitoneal administration mode, carried out on 175 laboratory mice showed the drug accumulates selectively in the epiphyseal plates of long bones, regardless of the mode of administration. 15 mice (males and females) at the age of active grownig were subjected to the single laser radiation impact on the knee joints area: 5 ones with transcutaneous Chlorine E6 administration, another 5 ones with intraperitoneal administration and the rest 5 without the drug. Histological samples of 15 experimental mice epiphyseal plates were examined by light microscopy, compared with 10 intact control mice. Influence of the laser radiation without administration of Chlorin E6 leads to intracellular swelling of epiphyseal plates chondrocytes. Influence of the laser radiation after transcutaneous or intraperitoneal injection of Chlorine E6 reduces significantly the total number of epiphyseal plates chondrocytes, without reducing the proportion of terminally-differentiated chondrocytes. Thus, the photodynamic impact inhibits the activity of epiphyseal plates of the mice.

  14. Photonic metallic nanostructures in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Ion, Rodica-Mariana; Fierascu, R. C.; Dumitriu, Irina

    2009-01-01

    Plasmons are resonant modes that involve the interaction between free charges and light. Nanoparticle-based photonic explorers have been developed for photodynamic therapy (PDT). PDT has been widely used in both oncological (e.g., tumors) and nononcological (e.g., age-related macular degeneration, localized infection, and nonmalignant skin conditions) applications. Three primary components are involved in PDT: light, a photosensitizing drug, and oxygen. The photosensitizer adsorbs light energy, which it then transfers to molecular oxygen to create an activated form of oxygen called singlet oxygen. The singlet oxygen is a cytotoxic agent and reacts rapidly with cellular components to cause damage that ultimately leads to cell death and tumor destruction. The changed topography of the film surface after deposition is caused by a local material transport and a material separation between formed particles (probably AgNO3) and an embedding polymer matrix as chitosan. This paper focuses on the current use of injectable in situ Au/(Ag)/chitosan hydrogels in cancer photodynamic treatment. Formulation protocols for their cytotoxic properties, their effect on cell growth in vitro and inhibition of tumor growth in vivo using mouse models, are discussed.

  15. Photodynamic inactivation of oropharyngeal Candida strains.

    PubMed

    Postigo, Agustina; Bulacio, Lucía; Sortino, Maximiliano

    2014-09-25

    Oropharyngeal candidiasis (OPC) is an infection frequent in immunocompromised patients. Photodynamic therapy is an alternative to conventional treatments, based on the utilization of compounds that inhibit or kill microorganisms only under the effect of light, process known as Photodynamic Inactivation (PDI). In the present study, PDI of Candida spp. by the natural product α-terthienyl (α-T) was investigated following the guidelines of CLSI M27-A3, under UV-A light irradiation. The optimal values of two variables, exposure irradiation time (ET) and distance to the irradiation source (DIS) were established by employing Design Expert Software (DES). For this purpose, a panel of Candida strains isolated from OPC (C. albicans, C. tropicalis, C. parapsilosis and C. krusei) was employed and optimal values were 5 min (ET) and between 6.06 and 6.43 cm (DIS) with a desirability factor of 0.989. α-T plus UV-A light in the optimal conditions caused a complete reduction in viable cells in 5 min which was demonstrated by viable cells reduction assays and confocal microscopy after vital staining (propidium iodide/fluorescein diacetate). The germ tube formation of C. albicans was inhibited by α-T at sub-inhibitory concentrations. Results showed that α-T plus UV-A light could constitute an alternative for OPC treatments at the optimal conditions determined here.

  16. Role of multidrug resistance in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Diddens, Heyke C.

    1992-06-01

    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  17. Treatment of ichthyophthiriasis with photodynamically active chlorophyllin.

    PubMed

    Häder, D-P; Schmidl, J; Hilbig, R; Oberle, M; Wedekind, H; Richter, P R

    2016-04-01

    Water-soluble chlorophyll (chlorophyllin) exerts pronounced photodynamic activity on fish parasites. In order to determine its potential as a remedy against ectoparasites in fish carps were incubated in water with defined concentrations of chlorophyllin. The main focus of the experiments was on the ciliate Ichthyophthirius multifiliis (Fouquet) which is responsible for considerable losses in livestock in aquaculture. As malachite green, which in the past efficiently cured infected fishes, is banned because of its possible carcinogenicity; no effective remedy is presently available in aquaculture to treat ichthyophthiriasis. Using chlorophyllin, the number of trophonts was significantly reduced (more than 50 %) after 3 h incubation of infested fish at 2 and 4 mg/L and subsequent irradiation with simulated solar radiation. The lack of reinfection after light treatment indicates that also the remaining parasites have lost their multiplication capacity. In the controls (no chlorophyllin and no light, light but no chlorophyllin, or chlorophyllin but no light), no reduction of the I. multifiliis infection was observed. We propose that chlorophyllin (or other photodynamic substances) is a possible effective countermeasure against I. multifiliis and other ectoparasites in aquaculture.

  18. Fighting fish parasites with photodynamically active chlorophyllin.

    PubMed

    Häder, D-P; Schmidl, J; Hilbig, R; Oberle, M; Wedekind, H; Richter, P

    2016-06-01

    Water-soluble chlorophyll (chlorophyllin) was used in a phototoxic reaction against a number of fish ectoparasites such as Ichtyobodo, Dactylogyrus, Trichodina, and Argulus. Chlorophyllin is applied to the water at concentrations of several micrograms per milliliter for a predefined incubation time, and afterwards, the parasites are exposed to simulated solar radiation. Application in the dark caused only little damage to the parasites; likewise, light exposure without the addition of the photosensitizer was ineffective. In Ichthyobodo, 2 μg/mL proved sufficient with subsequent simulated solar radiation to almost quantitatively kill the parasites, while in Dactylogyrus, a concentration of about 6 μg/mL was necessary. The LD50 value for this parasite was 1.02 μg/mL. Trichodina could be almost completely eliminated at 2 μg/mL. Only in the parasitic crustacean Argulus, no killing could be achieved by a photodynamic reaction using chlorophyllin. Chlorophyllin is non-toxic, biodegradable, and can be produced at low cost. Therefore, we propose that chlorophyllin (or other photodynamic substances) are a possible effective countermeasure against several ectoparasites in ponds and aquaculture since chemical remedies are either forbidden and/or ineffective.

  19. Photodynamic-induced inactivation of Propionibacterium acnes

    NASA Astrophysics Data System (ADS)

    Koenig, Karsten; Teschke, M.; Eick, Stephen G.; Pfister, W.; Meyer, Herbert; Halbhuber, Karl-Juergen

    1998-05-01

    We report on photodynamically induced inactivation of the skin bacterium Propionibacterium acnes (P. acnes) using endogenous as well as exogenous photosensitizers and red light sources. P. acnes is involved in the pathogenesis of the skin disease acne vulgaris. The skin bacterium is able to synthesize the metal-free fluorescent porphyrins protoporphyrin IX (PP) and coproporphyrin (CP) as shown by in situ spectrally-resolved detection of natural autofluorescence of human skin and bacteria colonies. These naturally occurring intracellular porphyrins act as efficient endogenous photosensitizers. Inactivation of P. acnes suspensions was achieved by irradiation with He-Ne laser light in the red spectral region (632.8 nm). We monitored the photodynamically-induced death of single bacteria using a fluorescent viability kit in combination with confocal laser scanning microscopy. In addition, the photo-induced inactivation was calculated by CFU (colony forming units) determination. We found 633 nm-induced inactivation (60 mW, 0.12 cm2 exposure area, 1 hour irradiation) of 72% in the case of non-incubated bacteria based on the destructive effect of singlet oxygen produced by red light excited endogenous porphyrins and subsequent energy transfer to molecular oxygen. In order to achieve a nearly complete inactivation within one exposure procedure, the exogenous photosensitizer Methylene Blue (Mb) was added. Far red exposure of Mb-labeled bacteria using a krypton ion laser at 647 nm and 676 nm resulted in 99% inactivation.

  20. Potential new photosensitizers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Ho, Yau-Kwan; Pandey, Ravindra K.; Sumlin, Adam B.; Missert, Joseph R.; Bellnier, David A.; Dougherty, Thomas J.

    1990-07-01

    In continuation of the effort to search for an ideal photosensitizer, two groups of potential new photosensitizers were synthesized and investigated for their photodynamic actions against tumors in mice. These were derivatives of methyl pheophorbide-a and of silicon naphthalocyanine. Of the former group, the 2 (1-0--hexyl) ethyl-desvinyl--methyl pheophorbide-a, or }IEDP, was the most active sensitizer. HEDP could be readily produced in large quantities and showed an optimum photodynamic action at 665 mu where it absorbs strongly. Also HEDP was cleared from the mouse skin within 4 days after administration, thus possibly alleviating the long-term phototoxic side-effects observed in Photofrin-based therapy. Of the second group of photosensitizers, the bis (dimethyl hydroxypropylsiloxy) silicon naphthalocyanine (HPSiNc) , and the corresponding acetoxy derivative (APSiNc) were of particular interest. At a drug-light dose of 1.0 mg/kg-135 J/cm2 (delivered by a laser at 772 nm), they showed antitumor activities comparable to that of PhotofrinTM. Further studies on these photosensitizers are warranted.

  1. Nanoparticle Based Photodynamic Therapy for Cancer

    NASA Astrophysics Data System (ADS)

    Chen, Wei

    2006-10-01

    This presentation describes research into a new approach to cancer treatment through a combination of radiation and photodynamic therapy. Under this concept, scintillation or persistent luminescence nanoparticles with attached photosensitizers, such as porphyrins, are used as an in vivo agent for photodynamic therapy. The nanoparticle PDT agents are delivered to the treatment site. Upon exposure to ionizing radiation such as X-rays, the nanoparticles emit scintillation or luminescence, which in turn activates the photosensitizers; as a consequence, singlet oxygen (^1O2) is produced. Studies have shown that ^1O2 can be effective in killing cancer cells. The innovation described in this study involves the use of in vivo luminescent nanoparticles so that an external light source is not required to support PDT. Consequently, application of the therapy can be more localized and the potential of damage to healthy cells is reduced. This new modality will provide an efficient, low-cost approach to PDT while still offering the benefits of augmented radiation therapy at lower doses.

  2. Drug Carrier for Photodynamic Cancer Therapy

    PubMed Central

    Debele, Tilahun Ayane; Peng, Sydney; Tsai, Hsieh-Chih

    2015-01-01

    Photodynamic therapy (PDT) is a non-invasive combinatorial therapeutic modality using light, photosensitizer (PS), and oxygen used for the treatment of cancer and other diseases. When PSs in cells are exposed to specific wavelengths of light, they are transformed from the singlet ground state (S0) to an excited singlet state (S1–Sn), followed by intersystem crossing to an excited triplet state (T1). The energy transferred from T1 to biological substrates and molecular oxygen, via type I and II reactions, generates reactive oxygen species, (1O2, H2O2, O2*, HO*), which causes cellular damage that leads to tumor cell death through necrosis or apoptosis. The solubility, selectivity, and targeting of photosensitizers are important factors that must be considered in PDT. Nano-formulating PSs with organic and inorganic nanoparticles poses as potential strategy to satisfy the requirements of an ideal PDT system. In this review, we summarize several organic and inorganic PS carriers that have been studied to enhance the efficacy of photodynamic therapy against cancer. PMID:26389879

  3. Nicotinamide augments the survival and incidence of apoptosis in glioma cells following photodynamic therapy in vitro

    NASA Astrophysics Data System (ADS)

    Bisland, Stuart K.; Modi, Nayan; Wilson, Brian C.

    2004-10-01

    The ability to customize photodynamic therapy (PDT) parameters with regards to timing and dosing of administered drug and light can be beneficial in determining target specificity and mode of cell death. Sustained, low level PDT or metronomic PDT (mPDT) may afford enhanced apoptotic cell death. This is of particular importance when considering PDT for the treatment of brain tumors as unlike apoptosis, necrotic cell death often leads to inflammation with increased intracranial pressure. The ability, therefore, to 'fine tune' PDT in favour of apoptosis is paramount. We have studied both acute (one time treatment) PDT (aPDT) and mPDT delivery strategies in combination with nicotinamide (NA) in an attempt to maximize the number of tumor cells dieing by apoptosis. Using several different glioma cell lines (9L, U87-MG and CNS-1) we now confirm that NA provides a dose-dependent (0.1-0.5 mM) increase in apoptotic cells following d-aminolevulinic acid-mediated aPDT or mPDT. Furthermore, using the 9L cell line stably transfected with the luciferase gene, NA was shown to delay the depletion of bioluminscence signal in aPDT and mPDT treated cells, inferring that adenosine triphosphate levels are maintained for longer following NA treatment. NA has previously been reported as promoting neuronal and vascular cell survival in normal brain following a number of neurological insults in which reactive oxygen species are implicated including, stroke, Alzheimer's disease and toxin-induced lesions. It is likely that the effects of NA reflect its capacity as an antioxidant as well as its ability to inhibit poly (adenosine diphosphate-ribose) polymerase-mediated depletion of ATP. Our results indicate that NA may prove therapeutically advantageous when used in combination with PDT treatment of brain tumors.

  4. Photodynamic Therapy in Non-Gastrointestinal Thoracic Malignancies.

    PubMed

    Kidane, Biniam; Hirpara, Dhruvin; Yasufuku, Kazuhiro

    2016-01-21

    Photodynamic therapy has a role in the management of early and late thoracic malignancies. It can be used to facilitate minimally-invasive treatment of early endobronchial tumours and also to palliate obstructive and bleeding effects of advanced endobronchial tumours. Photodynamic therapy has been used as a means of downsizing tumours to allow for resection, as well as reducing the extent of resection necessary. It has also been used successfully for minimally-invasive management of local recurrences, which is especially valuable for patients who are not eligible for radiation therapy. Photodynamic therapy has also shown promising results in mesothelioma and pleural-based metastatic disease. As new generation photosensitizers are being developed and tested and methodological issues continue to be addressed, the role of photodynamic therapy in thoracic malignancies continues to evolve.

  5. Photodynamic action of protoporphyrin IX derivatives on Trichophyton rubrum*

    PubMed Central

    Ramos, Rogério Rodrigo; Kozusny-Andreani, Dora Inês; Fernandes, Adjaci Uchôa; Baptista, Mauricio da Silva

    2016-01-01

    BACKGROUND Dermatophytes are filamentous keratinophilic fungi. Trichophyton rubrum is a prevalent infectious agent in tineas and other skin diseases. Drug therapy is considered to be limited in the treatment of such infections, mainly due to low accessibility of the drug to the tissue attacked and development of antifungal resistance in these microorganisms. In this context, Photodynamic Therapy is presented as an alternative. OBJECTIVE Evaluate, in vitro, the photodynamic activity of four derivatives of Protoporphyrin IX by irradiation with LED 400 nm in T. rubrum. METHOD Assays were subjected to irradiation by twelve cycles of ten minutes at five minute intervals. RESULT Photodynamic action appeared as effective with total elimination of UFCs from the second irradiation cycle. CONCLUSION Studies show that the photodynamic activity on Trichophyton rubrum relates to a suitable embodiment of the photosensitizer, which can be maximized by functionalization of peripheral groups of the porphyrinic ring. PMID:27192510

  6. Chlorophyll mediated photodynamic inactivation of blue laser on Streptococcus mutans

    NASA Astrophysics Data System (ADS)

    Astuti, Suryani Dyah; Zaidan, A.; Setiawati, Ernie Maduratna; Suhariningsih

    2016-03-01

    Photodynamic inactivation is an inactivation method in microbial pathogens that utilize light and photosensitizer. This study was conducted to investigate photodynamic inactivation effects of low intensity laser exposure with various dose energy on Streptococcus mutans bacteria. The photodynamic inactivation was achieved with the addition of chlorophyll as photosensitizers. To determine the survival percentage of Streptococcus mutans bacteria after laser exposure, the total plate count method was used. For this study, the wavelength of the laser is 405 nm and variables of energy doses are 1.44, 2.87, 4.31, 5.74, 7.18, and 8.61 in J/cm2. The results show that exposure to laser with energy dose of 7.18 J/cm2 has the best photodynamic inactivation with a decrease of 78% in Streptococcus

  7. Photodynamic Therapy in Non-Gastrointestinal Thoracic Malignancies

    PubMed Central

    Kidane, Biniam; Hirpara, Dhruvin; Yasufuku, Kazuhiro

    2016-01-01

    Photodynamic therapy has a role in the management of early and late thoracic malignancies. It can be used to facilitate minimally-invasive treatment of early endobronchial tumours and also to palliate obstructive and bleeding effects of advanced endobronchial tumours. Photodynamic therapy has been used as a means of downsizing tumours to allow for resection, as well as reducing the extent of resection necessary. It has also been used successfully for minimally-invasive management of local recurrences, which is especially valuable for patients who are not eligible for radiation therapy. Photodynamic therapy has also shown promising results in mesothelioma and pleural-based metastatic disease. As new generation photosensitizers are being developed and tested and methodological issues continue to be addressed, the role of photodynamic therapy in thoracic malignancies continues to evolve. PMID:26805818

  8. Photodynamic Cancer Therapy—Recent Advances

    NASA Astrophysics Data System (ADS)

    Abrahamse, Heidi

    2011-09-01

    The basic principle of the photodynamic effect was discovered over a hundred years ago leading to the pioneering work on PDT in Europe. It was only during the 1980s, however, when "photoradiation therapy" was investigated as a possible treatment modality for cancer. Photodynamic therapy (PDT) is a photochemotherapeutic process which requires the use of a photosensitizer (PS) that, upon entry into a cancer cell is targeted by laser irradiation to initiate a series of events that contribute to cell death. PSs are light-sensitive dyes activated by a light source at a specific wavelength and can be classified as first or second generation PSs based on its origin and synthetic pathway. The principle of PS activation lies in a photochemical reaction resulting from excitation of the PS producing singlet oxygen which in turn reacts and damages cell organelles and biomolecules required for cell function and ultimately leading to cell destruction. Several first and second generation PSs have been studied in several different cancer types in the quest to optimize treatment. PSs including haematoporphyrin derivative (HpD), aminolevulinic acid (ALA), chlorins, bacteriochlorins, phthalocyanines, naphthalocyanines, pheophorbiedes and purpurins all require selective uptake and retention by cancer cells prior to activation by a light source and subsequent cell death induction. Photodynamic diagnosis (PDD) is based on the fluorescence effect exhibited by PSs upon irradiation and is often used concurrently with PDT to detect and locate tumours. Both laser and light emitting diodes (LED) have been used for PDT depending on the location of the tumour. Internal cancers more often require the use of laser light delivery using fibre optics as delivery system while external PDT often make use of LEDs. Normal cells have a lower uptake of the PS in comparison to tumour cells, however the acute cytotoxic effect of the compound on the recovery rate of normal cells is not known. Subcellular

  9. A comprehensive tutorial on in vitro characterization of new photosensitizers for photodynamic antitumor therapy and photodynamic inactivation of microorganisms.

    PubMed

    Kiesslich, Tobias; Gollmer, Anita; Maisch, Tim; Berneburg, Mark; Plaetzer, Kristjan

    2013-01-01

    In vitro research performed on eukaryotic or prokaryotic cell cultures usually represents the initial step for characterization of a novel photosensitizer (PS) intended for application in photodynamic therapy (PDT) of cancer or photodynamic inactivation (PDI) of microorganisms. Although many experimental steps of PS testing make use of the wide spectrum of methods readily employed in cell biology, special aspects of working with photoactive substances, such as the autofluorescence of the PS molecule or the requirement of light protection, need to be considered when performing in vitro experiments in PDT/PDI. This tutorial represents a comprehensive collection of operative instructions, by which, based on photochemical and photophysical properties of a PS, its uptake into cells, the intracellular localization and photodynamic action in both tumor cells and microorganisms novel photoactive molecules may be characterized for their suitability for PDT/PDI. Furthermore, it shall stimulate the efforts to expand the convincing benefits of photodynamic therapy and photodynamic inactivation within both established and new fields of applications and motivate scientists of all disciplines to get involved in photodynamic research.

  10. A Comprehensive Tutorial on In Vitro Characterization of New Photosensitizers for Photodynamic Antitumor Therapy and Photodynamic Inactivation of Microorganisms

    PubMed Central

    Maisch, Tim; Berneburg, Mark; Plaetzer, Kristjan

    2013-01-01

    In vitro research performed on eukaryotic or prokaryotic cell cultures usually represents the initial step for characterization of a novel photosensitizer (PS) intended for application in photodynamic therapy (PDT) of cancer or photodynamic inactivation (PDI) of microorganisms. Although many experimental steps of PS testing make use of the wide spectrum of methods readily employed in cell biology, special aspects of working with photoactive substances, such as the autofluorescence of the PS molecule or the requirement of light protection, need to be considered when performing in vitro experiments in PDT/PDI. This tutorial represents a comprehensive collection of operative instructions, by which, based on photochemical and photophysical properties of a PS, its uptake into cells, the intracellular localization and photodynamic action in both tumor cells and microorganisms novel photoactive molecules may be characterized for their suitability for PDT/PDI. Furthermore, it shall stimulate the efforts to expand the convincing benefits of photodynamic therapy and photodynamic inactivation within both established and new fields of applications and motivate scientists of all disciplines to get involved in photodynamic research. PMID:23762860

  11. [New light on skin photodynamic therapy].

    PubMed

    Kuonen, François; Gaide, Olivier

    2014-04-02

    Photodynamic therapy (PDT) relies on the cellular toxicity of an exogenous porphyrin that is activated by light rays. Its specificity depends on its cellular uptake, which is typically high in cells with a high metabolism, such as cancer cells and several microbial pathogens. Both the diffusion of the substrate and the penetration of the light in the tissue limit its efficiency to the first few millimeters of the skin. This explains why this technique is used for the treatment of superficial skin cancers (actinic keratosis and basal cell carcinomas), but also for selected skin inflammatory diseases (psoriasis) or infections (leishmaniosis). However, at the bedside, the limitations of PDT are rather the complexity and the pain associated with the treatment. Herein, we present the new developments, in particular concerning the new light sources, which make PDT a better option for our patients.

  12. Photodynamic therapy: superficial and interstitial illumination

    NASA Astrophysics Data System (ADS)

    Svanberg, Katarina; Bendsoe, Niels; Axelsson, Johan; Andersson-Engels, Stefan; Svanberg, Sune

    2010-07-01

    Photodynamic therapy (PDT) is reviewed using the treatment of skin tumors as an example of superficial lesions and prostate cancer as an example of deep-lying lesions requiring interstitial intervention. These two applications are among the most commonly studied in oncological PDT, and illustrate well the different challenges facing the two modalities of PDT-superficial and interstitial. They thus serve as good examples to illustrate the entire field of PDT in oncology. PDT is discussed based on the Lund University group's over 20 yr of experience in the field. In particular, the interplay between optical diagnostics and dosimetry and the delivery of the therapeutic light dose are highlighted. An interactive multiple-fiber interstitial procedure to deliver the required therapeutic dose based on the assessment of light fluence rate and sensitizer concentration and oxygen level throughout the tumor is presented.

  13. Interstitial Photodynamic Therapy—A Focused Review

    PubMed Central

    Shafirstein, Gal; Bellnier, David; Oakley, Emily; Hamilton, Sasheen; Potasek, Mary; Beeson, Karl; Parilov, Evgueni

    2017-01-01

    Multiple clinical studies have shown that interstitial photodynamic therapy (I-PDT) is a promising modality in the treatment of locally-advanced cancerous tumors. However, the utilization of I-PDT has been limited to several centers. The objective of this focused review is to highlight the different approaches employed to administer I-PDT with photosensitizers that are either approved or in clinical studies for the treatment of prostate cancer, pancreatic cancer, head and neck cancer, and brain cancer. Our review suggests that I-PDT is a promising treatment in patients with large-volume or thick tumors. Image-based treatment planning and real-time dosimetry are required to optimize and further advance the utilization of I-PDT. In addition, pre- and post-imaging using computed tomography (CT) with contrast may be utilized to assess the response. PMID:28125024

  14. The role of photodynamic therapy (PDT) physics

    PubMed Central

    Zhu, Timothy C.; Finlay, Jarod C.

    2008-01-01

    Photodynamic therapy (PDT) is an emerging treatment modality that employs the photochemical interaction of three components: light, photosensitizer, and oxygen. Tremendous progress has been made in the last 2 decades in new technical development of all components as well as understanding of the biophysical mechanism of PDT. The authors will review the current state of art in PDT research, with an emphasis in PDT physics. They foresee a merge of current separate areas of research in light production and delivery, PDT dosimetry, multimodality imaging, new photosensitizer development, and PDT biology into interdisciplinary combination of two to three areas. Ultimately, they strongly believe that all these categories of research will be linked to develop an integrated model for real-time dosimetry and treatment planning based on biological response. PMID:18697538

  15. Monitoring photodynamic therapy with photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Shao, Peng; Chapman, David W.; Moore, Ronald B.; Zemp, Roger J.

    2015-10-01

    We present our work on examining the feasibility of monitoring photodynamic therapy (PDT)-induced vasculature change with acoustic-resolution photoacoustic microscopy (PAM). Verteporfin, an FDA-approved photosensitizer for clinical PDT, was utilized. With a 60-μm-resolution PAM system, we demonstrated the capability of PAM to monitor PDT-induced vasculature variations in a chick chorioallantoic membrane model with topical application and in a rat ear with intravenous injection of the photosensitizer. We also showed oxygen saturation change in target blood vessels due to PDT. Success of the present approach may potentially lead to the application of PAM imaging in evaluating PDT efficacy, guiding treatment, and predicting responders from nonresponders.

  16. Photodynamic therapy as an antifungal treatment

    PubMed Central

    LIANG, YI; LU, LI-MING; CHEN, YONG; LIN, YOU-KUN

    2016-01-01

    Photodynamic therapy (PDT) involves the systemic or topical application of a photosensitizer (PS), alongside the selective illumination of the target lesion with light of an appropriate wavelength, in order to promote localized oxidative photodamage and subsequent cell death. Numerous studies have demonstrated that PDT is highly effective in the destruction of fungi in vitro. The mechanism underlying the effects of PDT results from the photons of visible light of an appropriate wavelength interacting with the intracellular molecules of the PS. Reactive species are produced as a result of the oxidative stress caused by the interaction between the visible light and the biological tissue. At present, no antifungal treatment based on PDT has been licensed. However, antifungal PDT is emerging as an area of interest for research. PMID:27347012

  17. PHOTODYNAMIC THERAPY OF CANCER: AN UPDATE

    PubMed Central

    Agostinis, Patrizia; Berg, Kristian; Cengel, Keith A.; Foster, Thomas H.; Girotti, Albert W.; Gollnick, Sandra O.; Hahn, Stephen M.; Hamblin, Michael R.; Juzeniene, Asta; Kessel, David; Korbelik, Mladen; Moan, Johan; Mroz, Pawel; Nowis, Dominika; Piette, Jacques; Wilson, Brian C.; Golab, Jakub

    2011-01-01

    Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative particularly in early-stage tumors. It can prolong survival in inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. PMID:21617154

  18. Scope of photodynamic therapy in periodontics.

    PubMed

    Kumar, Vivek; Sinha, Jolly; Verma, Neelu; Nayan, Kamal; Saimbi, C S; Tripathi, Amitandra K

    2015-01-01

    Periodontal disease results from inflammation of the supporting structure of the teeth and in response to chronic infection caused by various periodontopathic bacteria. The mechanical removal of this biofilm and adjunctive use of antibacterial disinfectants and antibiotics have been the conventional methods of periodontal therapy. However, the removal of plaque and the reduction in the number of infectious organisms can be impaired in sites with difficult access. Photodynamic therapy (PDT) is a powerful laser-initiated photochemical reaction, involving the use of a photoactive dye (photosensitizer) activated by light of a specific wavelength in the presence of oxygen. Application of PDT in periodontics such as pocket debridement, gingivitis, and aggressive periodontitis continue to evolve into a mature clinical treatment modality and is considered as a promising novel approach for eradicating pathogenic bacteria in periodontitis.

  19. Photosensitizers mediated photodynamic inactivation against virus particles.

    PubMed

    Sobotta, Lukasz; Skupin-Mrugalska, Paulina; Mielcarek, Jadwiga; Goslinski, Tomasz; Balzarini, Jan

    2015-01-01

    Viruses cause many diseases in humans from the rather innocent common cold to more serious or chronic, life-threatening infections. The long-term side effects, sometimes low effectiveness of standard pharmacotherapy and the emergence of drug resistance require a search for new alternative or complementary antiviral therapeutic approaches. One new approach to inactivate microorganisms is photodynamic antimicrobial chemotherapy (PACT). PACT has evolved as a potential method to inactivate viruses. The great challenge for PACT is to develop a methodology enabling the effective inactivation of viruses while leaving the host cells as untouched as possible. This review aims to provide some main directions of antiviral PACT, taking into account different photosensitizers, which have been widely investigated as potential antiviral agents. In addition, several aspects concerning PACT as a tool to assure viral inactivation in human blood products will be addressed.

  20. Photodynamic therapy in dermatology: history and horizons.

    PubMed

    Taub, Amy Forman

    2004-01-01

    Photodynamic therapy (PDT) uses a photosensitizer, light, and molecular oxygen to selectively kill cells. When localized in the target tissue, the photosensitizer is activated by light to produce oxygen intermediates that destroy target tissue cells. The easy access of skin to light-based therapy has led dermatologists to apply PDT to cutaneous disorders. In dermatology, PDT has been most successful in treating actinic keratoses, basal cell carcinoma, and Bowen's disease. The introduction of aminolevulinic acid, which does not make patients susceptible to phototoxicity for extended periods, has reduced morbidity associated with PDT. This has led to new interest in PDT not only for nonmelanoma skin cancer and premalignant lesions but also in the treatment of acne and as an adjuvant to photorejuvenation procedures. This review examines the historical roots of PDT and the research evaluating different light and laser sources as well as reports on new horizons for PDT in dermatology.

  1. Photodynamic therapy for malignant pleural mesothelioma.

    PubMed

    Friedberg, Joseph S

    2012-10-01

    Surgery is the treatment option most likely to be associated with prolonged remission in patients with malignant pleural mesothelioma. However, it remains investigational and must always be combined with other modalities to treat the microscopic disease that remains after the most aggressive operations. Improvements in quality of life for appropriate patients with this rare yet incurable cancer may be obtained with less drastic lung-sparing surgical procedures along with intraoperative use of photodynamic therapy (PDT). Very encouraging survival results have been obtained with the combination of surgery and PDT, which requires the well-orchestrated collaborative effort of an extensive team of professionals, from thoracic surgeons and radiation oncologists to basic science researchers. Multi-institutional trials are necessary to duplicate these early findings and shed more light on the tumor-directed immune response of this surgically based multimodal treatment.

  2. Intraoperative photodynamic therapy for larynx carcinomas

    NASA Astrophysics Data System (ADS)

    Loukatch, Erwin V.; Latyshevska, Galina; Fekeshgazi, Ishtvan V.

    1995-05-01

    We made an experimental and clinical researches to examine Intraoperative Photodynamic Therapy (IPT) as a method to prevent the recidives of tumors. In experimental researches on models with radio-inducated fibrosarcomas and Erlich carcinomas of mice the best method of IPT was worked out. The therapeutic effect was studied also on patients with laryngeal cancer. In researches on C3H mice the antirecidive effect of IPT established with local administration of methylene blue and Ar-laser. We found that IPT (He-Ne laser combined with methylene blue administration) was endured by patients with laryngeal cancers without problems. We got good results of treatment 42 patients with laryngeal cancers with middle localization during three years with using IPT method. This can show the perspectives of using this method in treatment of other ENT-oncological diseases.

  3. Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.

    PubMed

    Reddan, J C; Anderson, C Y; Xu, H; Hrabovsky, S; Freye, K; Fairchild, R; Tubesing, K A; Elmets, C A

    1999-07-01

    The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

  4. Feasibility of chemiluminescence as photodynamic therapy dosimetor

    NASA Astrophysics Data System (ADS)

    Qin, Yanfang; Xing, Da; Zhong, Xueyun; Zhou, Jin; Luo, Shiming; Chen, Qun

    2006-09-01

    Photodynamic therapy (PDT) utilizes light energy of a proper wavelength to activate a pre-administered photosensitizer in a target tissue to achieve a localized treatment effect. Current treatment protocol of photodynamic therapy (PDT) is defined by empirical values such as irradiation light fluence, fluence rate and the amount of administered photosensitizer. It is well known that Singlet oxygen is the most important cytotoxic agent responsible for PDT biological effects. An in situ monitoring of singlet oxygen production during PDT would provide a more accurate dosimeter for PDT. The presented study has investigated the feasibility of using Fhioresceinyl Cypridina Luciferin Analog (FCLA), a singlet oxygen specific chemiluminescence (CL) probe, as a dosimetric tool for PDT. Raji lymphoma cell suspensions were sensitized with Photofrin (R) of various concentrations and irradiated with 635 nm laser light at different fluence rates. FCLA-CL from singlet oxygen produced by the treatment was measured, in real time, with a photon multiplier tube (PMT) system, and linked to the cytotoxicity resulting from the treatment. We have observed that the CL intensity of FCLA is dependent on the PDT treatment parameters. After each PDT treatment and CL measurement, the irradiated cells were evaluated by MIT assay for their Viability. The results show that the cell viability is highly related to the accumulated CL. With 10 II quencher, we confirmed that the CL was mainly related to PDT produced 10 II The results suggest that the FCLA-CL system can be an effective means in measuring PDT 1O II production and may provide an alternative dosimetry technique for PDT.

  5. Mitochondria-targeting for improved photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Ngen, Ethel J.

    Photodynamic therapy (PDT) is an emerging cancer therapeutic modality, with great potential to selectively treat surface cancers, thus minimizing systemic side effects. In this dissertation, two approaches to deliver photosensitizers to mitochondria were investigated: 1) Reducing photosensitizer sizes to improve endocytosis and lysosomal localization. Upon irradiation the photosensitizers would then produce singlet oxygen which could rupture the lysosomal membrane releasing the lysosomally trapped photosensitizers to the cytosol, from where they could relocalize to mitochondria by passive diffusion (photochemical internalization). 2) Using delocalized lipophilic cationic dyes (DLCs) to exploit membrane potential differences between the cytoplasm and mitochondria in delivering photosensitizers to mitochondria. To investigate the effects of steric hindrance on mitochondrial localization and photodynamic response, a series of eight thiaporphyrins were studied. Two new thiaporphyrin analogues 6 and 8 with reduced steric hindrance at the 10- and 15- meso positions were studied in comparison to 5,20-diphenyl-10,15-bis[4 (carboxymethyleneoxy)-phenyl]-21,23-dithiaporphyrin 1, previously validated as a potential second generation photosensitizer. Although 6 showed an extraordinarily high uptake (7.6 times higher than 1), it was less potent than 1 (IC 50 = 0.18 muM versus 0.13 muM) even though they both showed similar sub-cellular localization patterns. This low potency was attributed to its high aggregation tendency in aqueous media (4 times higher than 1), which might have affected its ability to generate singlet oxygen in vitro . 8 on the other hand showed an even lower potency than 6 (2.28 vs 0.18 muM). However this was attributed to its low cellular uptake (20 times less than 6) and inefficient generation of singlet oxygen. Overall, although the structural modifications did improve the cellular uptake of 6, 6 was still less potent than the lead photosensitizers 1. Thus

  6. Comparison microbial killing efficacy between sonodynamic therapy and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Drantantiyas, Nike Dwi Grevika; Astuti, Suryani Dyah; Nasution, Aulia M. T.

    2016-11-01

    Biofilm is a way used by bacteria to survive from their environmental conditions by forming colony of bacteria. Specific characteristic in biofilm formation is the availability of matrix layer, known as extracellular polymer substance. Treatment using antibiotics may lead bacteria to be to resistant. Other treatments to reduce microbial, like biofilm, can be performed by using photodynamic therapy. Successful of this kind of therapy is induced by penetration of light and photosensitizer into target cells. The sonodynamic therapy offers greater penetrating capability into tissues. This research aimed to use sonodynamic therapy in reducing biofilm. Moreover, it compares also the killing efficacy of photodynamic therapy, sonodynamic therapy, and the combination of both therapeutic schemes (known as sono-photodynamic) to achieve higher microbial killing efficacy. Samples used are Staphylococcus aureus biofilm. Treatments were divided into 4 groups, i.e. group under ultrasound treatment with variation of 5 power levels, group of light treatment with exposure of 75s, group of combined ultrasound-light with variation of ultrasound power levels, and group of combined lightultrasound with variation of ultrasound power levels. Results obtained for each treatment, expressed in % efficacy of log CFU/mL, showed that the treatment of photo-sonodynamic provides greater killing efficacy in comparison to either sonodynamic and sono-photodynamic. The photo-sonodynamic shows also greater efficacy to photodynamic. So combination of light-ultrasound (photo-sonodynamic) can effectively kill microbial biofilm. The combined therapy will provide even better efficacy using exogenous photosensitizer.

  7. Graphene-based nanovehicles for photodynamic medical therapy

    PubMed Central

    Li, Yan; Dong, Haiqing; Li, Yongyong; Shi, Donglu

    2015-01-01

    Graphene and its derivatives such as graphene oxide (GO) have been widely explored as promising drug delivery vehicles for improved cancer treatment. In this review, we focus on their applications in photodynamic therapy. The large specific surface area of GO facilitates efficient loading of the photosensitizers and biological molecules via various surface functional groups. By incorporation of targeting ligands or activatable agents responsive to specific biological stimulations, smart nanovehicles are established, enabling tumor-triggering release or tumor-selective accumulation of photosensitizer for effective therapy with minimum side effects. Graphene-based nanosystems have been shown to improve the stability, bioavailability, and photodynamic efficiency of organic photosensitizer molecules. They have also been shown to behave as electron sinks for enhanced visible-light photodynamic activities. Owing to its intrinsic near infrared absorption properties, GO can be designed to combine both photodynamic and photothermal hyperthermia for optimum therapeutic efficiency. Critical issues and future aspects of photodynamic therapy research are addressed in this review. PMID:25848263

  8. Charge dependent photodynamic activity of alanine based zinc phthalocyanines.

    PubMed

    Wang, Ao; Li, Yejing; Zhou, Lin; Yuan, Linxin; Lu, Shan; Lin, Yun; Zhou, Jiahong; Wei, Shaohua

    2014-12-01

    In this paper, to minimize the effects of different structure, three alanine-based zinc phthalocyanines (Pcs) of differing charges were engineered and synthesized with the same basic structure. On this premise, the relationship between nature of charge and photodynamic activity was studied. Besides, further verification and explanation of some inconsistent results were also carried out. The results showed that charge can influence the aggregation state, singlet oxygen generation ability and cellular uptake of Pcs, thereby affecting their photodynamic activity. In addition, the biomolecules inside cells may interact with Pcs of differing charges, which can also influence the aggregation state and singlet oxygen generation of the Pcs, and then influence the relationship between nature of charge and photodynamic activity.

  9. Optical delivery and monitoring of photodynamic therapy of prostate cancer

    NASA Astrophysics Data System (ADS)

    Weersink, Robert A.; Bogaards, Arjun; Gertner, Mark; Davidson, Sean; Zhang, Kai; Netchev, George; Giewercer, David J.; Trachtenberg, John; Wilson, Brian C.

    2004-10-01

    Photodynamic therapy of recurrent prostate cancer is currently undergoing Phase II clinical trials with the vascular targeting drug TOOKAD. Proper PDT dosage requires sound estimates of the light fluence and drug concentration throughout the organ. The treatment requires multiple diffusing light delivery fibers placed in position according to a light dose treatment plan under ultrasound guidance. Fluence rate is monitored by multiple sensor fibers placed throughout the organ and in sensitive organs near the prostate. The combination of multiple light delivery and fluence sensor fibers is used to estimate the optical properties of the tissue and to provide a general fluence map throughout the organ. This fluence map is then used to estimate extent of photodynamic dose. Optical spectroscopy is used to monitor drug pharmacokinetics in the organ and blood hemodynamics within the organ. Further development of these delivery and monitoring techniques will permit full online monitoring of the treatment that will enable real-time patient-specific delivery of photodynamic therapy.

  10. Influence of bacterial interactions on the susceptibility to photodynamic inactivation

    NASA Astrophysics Data System (ADS)

    Upadya, M. H.; Tegos, G.; Hamblin, M.; Kishen, A.

    2009-06-01

    Photodynamic therapy has emerged as a possible supplement to the existing protocols for endodontic disinfection. Microbes are known to gain significant ecological advantage when they survive as coaggregates and biofilms in an infected tissue. Such microbial coaggregates and biofilms have been confirmed to play a key role in the pathogenicity of many infections. So far, not many studies have correlated the efficacy of antimicrobial photodynamic inactivation (APDI) to the different modes of bacterial growth. This study aims to evaluate the APDI of 3 strains of Enterococcus faecalis in planktonic phase, in a co-aggregated suspension and in a 4-day old biofilm. The results showed that the biofilm mode of growth offered the greatest resistance to APDI and the inclusion of an efflux pump inhibitor significantly increased the APDI of biofilm bacteria. From this study, we conclude that APDI of bacteria in biofilms is the most challenging and that the use of bacterial efflux pump inhibitors enhances its photodynamic antibiofilm efficacy.

  11. [Photophysical properties and photodynamic activity of nanostructured aluminium phthalocyanines].

    PubMed

    Udartseva, O O; Lobanov, A V; Andeeva, E R; Dmitrieva, G S; Mel'nikov, M Ia; Buravkova, L B

    2014-01-01

    We developed water-soluble supramolecular complexes of aluminium phthalocyanine based on mesoporous silica nanoparticles and polyvinylpirrolidone containing rare photoactive nanoaggregates. Radiative lifetimes, extinction coefficients and energy of electronic transitions of isolated and associated metal phthalocyanine complexes were calculated. Nontoxic concentrations of synthesized nanocomposite photosensibilizers were in vitro determined. In present study we compared photodynamic treatment efficacy using different modifications of aluminium phthalocyanine (Photosens®, AlPc-nSiO2 and AlPc-PVP). Mesenchymal stromal cells were used as a model for photodynamic treatment. Intracellular accumulation of aluminium phthalocyanine based on mesoporous silica nanoparticles AlPc-nSiO2 was the most efficient. Illumination of phthalocyanine-loaded cells led to reactive oxygen species generation and subsequent apoptotic cell death. Silica nanoparticles provided a significant decrease of effective phthalocyanine concentration and enhanced cytotoxicity of photodynamic treatment.

  12. Photodynamic therapy for malignant pleural mesothelioma: the future of treatment?

    PubMed

    Friedberg, Joseph S

    2011-02-01

    Malignant pleural mesothelioma is a deadly incurable cancer, with a median survival of approximately 9 months. The best available chemotherapy, arguably the standard of care, only yields a 40% response rate and an 11-week extension in median survival. Surgery, the modality most likely to be associated with prolonged remission, remains investigational and must always be combined with other modalities in an effort to treat the microscopic disease that will remain even after the most aggressive operations. One such modality, photodynamic therapy, is a light-based cancer treatment that has features making it particularly well suited as a component of a surgery-based multimodal treatment plan. Utilizing intraoperative photodynamic therapy has enabled development of a less drastic surgical procedure that is also yielding some encouraging survival results. A unique aspect of photodynamic therapy is its stimulation of a tumor-directed immune response, a feature that offers promise for designing future treatments.

  13. X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy

    PubMed Central

    Wang, Geoffrey D.; Nguyen, Ha T.; Chen, Hongmin; Cox, Phillip B.; Wang, Lianchun; Nagata, Koichi; Hao, Zhonglin; Wang, Andrew; Li, Zibo; Xie, Jin

    2016-01-01

    Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer. PMID:27877235

  14. Mreg Activity in Tumor Response to Photodynamic Therapy and Photodynamic Therapy-Generated Cancer Vaccines

    PubMed Central

    Korbelik, Mladen; Banáth, Judith; Zhang, Wei

    2016-01-01

    Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction is closely dependent on the associated antitumor immune response. The present study investigated whether the immunodepletion of granulocytic Mregs in host mice by anti-GR1 antibody would improve the response of tumors to PDT or PDT vaccines in these animals. Anti-GR1 administration immediately after Temoporfin-PDT of mouse SCCVII tumors abrogated curative effect of PDT. The opposite effect, increasing PDT-mediated tumor cure-rates was attained by delaying anti-GR1 treatment to 1 h post PDT. With PDT vaccines, multiple anti-GR1 administrations (days 0, 4, and 8 post vaccination) improved the therapy response with SCCVII tumors. The results with PDT suggest that neutrophils (boosting antitumor effect of this therapy) that are engaged immediately after photodynamic light treatment are within one hour replaced with a different myeloid population, presumably Mregs that hampers the therapy-mediated antitumor effect. Anti-GR1 antibody, when used with optimal timing, can improve the efficacy of both PDT of tumors in situ and PDT-generated cancer vaccines. PMID:27754452

  15. Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro

    PubMed Central

    Shin, Seung Kyun; Kim, Ji Hyeon; Lee, Jung Hoon; Son, Young Hoon; Lee, Min Wook; Kim, Hak Joong; Noh, Sue Ah; Kim, Kwang Pyo; Kim, In-Gyu; Lee, Min Jae

    2017-01-01

    Proteasomes are the primary degradation machinery for oxidatively damaged proteins that compose a class of misfolded protein substrates. Cellular levels of reactive oxygen species increase with age and this cellular propensity is particularly harmful when combined with the age-associated development of various human disorders including cancer, neurodegenerative disease and muscle atrophy. Proteasome activity is reportedly downregulated in these disease conditions. Herein, we report that docosahexaenoic acid (DHA), a major dietary omega-3 polyunsaturated fatty acid, mediates intermolecular protein cross-linkages through oxidation, and the resulting protein aggregates potently reduce proteasomal activity both in vitro and in cultured cells. Cellular models overexpressing aggregation-prone proteins such as tau showed significantly elevated levels of tau aggregates and total ubiquitin conjugates in the presence of DHA, thereby reflecting suppressed proteasome activity. Strong synergetic cytotoxicity was observed when the cells overexpressing tau were simultaneously treated with DHA. Antioxidant N-acetyl cysteine significantly desensitized the cells to DHA-induced oxidative stress. DHA significantly delayed the proteasomal degradation of muscle proteins in a cellular atrophy model. Thus, the results of our study identified DHA as a potent inducer of cellular protein aggregates that inhibit proteasome activity and potentially delay systemic muscle protein degradation in certain pathologic conditions. PMID:28104914

  16. Photodynamic therapy of cervical intraepithelial neoplasia using hexaminolevulinate and methylaminolevulinate

    NASA Astrophysics Data System (ADS)

    Soergel, Philipp; Staboulidou, Ismini; Hertel, Herrmann; Schippert, Cordula; Hillemanns, Peter

    2009-06-01

    Cervical intraepithelial neoplasia (CIN) is the precursor of invasive cervical cancer. Previous studies indicated that photodynamic therapy (PDT) represents an effective treatment modality in CIN. In 28 patients with CIN 1 - 3, 1 - 2 cycles of PDT were conducted using hexaminolevulinate (HAL) or methylaminolevulinate (MAL) and a special light delivery system. After 6 months, biopsies were obtained to assess response. The overall response rate for complete or partial response was 65%. Photodynamic therapy using new ALA esters is effective and may offer unique advantages in the therapy of CIN.

  17. Photodynamic therapy for polypoidal choroidal vasculopathy secondary to choroidal nevus

    PubMed Central

    Wong, James G; Lai, Xin Jie; Sarafian, Richard Y; Wong, Hon Seng; Smith, Jeremy B

    2017-01-01

    We report a case of a Caucasian female who developed active polypoidal choroidal vasculopathy (PCV) at the edge of a stable choroidal nevus and was successfully treated with verteporfin photodynamic therapy. No active polyp was detectable on indocyanine green angiography 2 years after treatment, and good vision was maintained. Indocyanine green angiography is a useful investigation to diagnose PCV and may be underutilized. Unlike treatment of choroidal neovascularization secondary to choroidal nevus, management of PCV secondary to nevus may not require intravitreal anti-vascular endothelial growth factor therapy. Photodynamic monotherapy may be an effective treatment of secondary PCV. PMID:28243154

  18. Combination immunotherapy and photodynamic therapy for cancer

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel

    2006-02-01

    Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.

  19. Photodynamic therapy of breast cancer with photosense

    NASA Astrophysics Data System (ADS)

    Vakoulovskaya, Elena G.; Shental, Victor V.; Oumnova, Loubov V.; Vorozhcsov, Georgiu N.

    2003-06-01

    Photodynamic Therapy (PDT) using photosensitizer Photosense (PS) in dose 0.5 mg per kg of body weight have been provided in 24 patients with breast cancer. In 22 patients with T1-T2N0M0 primary tumor was treated as the preoperative treatment, radical mastectomy has been fulfilled 7-10 days after PDT with subsequent histological examination. 2 patients had recurrencies of breast cancer with lymph node metastases after radiotherapy. Fluorescent diagnostics of tumor, accumulation of PS in tumor, adjacent tissue, skin before and during PDT was fulfilled with spectranalyzer LESA-01. We used semiconductive laser for PDT - λ = 672+2nm, P=1,5 W, interstitial irradiation 2-24 hours after PS injection has been done in light dose 150-200 J/cm3, 1-3 irradiations with interval 24-48 hours and total light dose 400-600 J/cm3 depending mostly of size and fluorescent data. Partial regression of tumor with pathomorphosis of 2-4 degrees has been found in 19 cases. Our experience shows pronounced efficacy of PDT for treating breast cancer as preoperative modality and as palliation in cases of recurrencies.

  20. Photodynamic therapy of malignant mesothelioma of pleura

    NASA Astrophysics Data System (ADS)

    Warloe, Trond; Heyerdahl, Helen; Peng, Qian; Hoie, J.; Normann, E.; Solheim, O.; Moan, Johan; Giercksky, Karl-Erik

    1995-03-01

    Nine patients with malignant pleural mesothelioma underwent extensive surgery followed by intra-operative photodynamic therapy. Two mg/kg Photofrin was given 48 hours prior to surgery. The thoracic cavity and eventual remaining lung were exposed to 15 - 30 Joules/cm2 of 630 nm laser light. Tumor tissue was analyzed by microscopic photometrical techniques. Five patients with mixed or epithelioid tumors with fluorescence intensity > 100 gray level/pixel seemed to benefit from the given therapy. One patient was free of disease 18 months after treatment. Two patients were treated for metastasis after 12 months with no sign of intrathoracic recurrence. Both are still alive, one without further sign of disease 32 months after initial treatment. Two patients presented generalized disease after 9 and 13 months and intrathoracic recurrence several months later. Two patients with poorly differentiated tumors and 2 patients with moderate to highly differentiated tumors, but with fluorescence intensity < 100 gray level/pixel, presented recurrences after 4 months. PDT-efficiency seems to be predicted by the intensity and distribution of drug-induced fluorescence in tumor tissue. PDT may enhance the possibility to achieve complete local tumor control after excision. Multimodal therapeutic approach of local and systemic disease seems mandatory to further improve survival.

  1. Corneal endothelial glutathione after photodynamic change

    SciTech Connect

    Hull, D.S.; Riley, M.V.; Csukas, S.; Green, K.

    1982-03-01

    Rabbit corneal endothelial cells perfused with 5 X 10(-6)M rose bengal and exposed to incandescent light demonstrated no alteration of either total of or percent oxidized glutathione after 1 hr. Addition of 5400 U/ml catalase to the perfusing solution had no effect on total glutathione levels but caused a marked reduction in percent oxidized glutathione in corneas exposed to light as well as in those not exposed to light. Substitution of sucrose for glucose in the perfusing solution had no effect on total or percent oxidized glutathione. Perfusion of rabbit corneal endothelium with 0.5 mM chlorpromazine and exposure to ultraviolet (UV) light resulted in no change in total glutathione content. A marked reduction in percent oxidized glutathione occurred, however, in corneas perfused with 0.5 mM chlorpromazine both in the presence and absence of UV light. It is concluded that photodynamically induced swelling of corneas is not the result of a failure of the glutathione redox system.

  2. Photodynamic therapy monitoring with optical coherence angiography

    NASA Astrophysics Data System (ADS)

    Sirotkina, M. A.; Matveev, L. A.; Shirmanova, M. V.; Zaitsev, V. Y.; Buyanova, N. L.; Elagin, V. V.; Gelikonov, G. V.; Kuznetsov, S. S.; Kiseleva, E. B.; Moiseev, A. A.; Gamayunov, S. V.; Zagaynova, E. V.; Feldchtein, F. I.; Vitkin, A.; Gladkova, N. D.

    2017-02-01

    Photodynamic therapy (PDT) is a promising modern approach for cancer therapy with low normal tissue toxicity. This study was focused on a vascular-targeting Chlorine E6 mediated PDT. A new angiographic imaging approach known as M-mode-like optical coherence angiography (MML-OCA) was able to sensitively detect PDT-induced microvascular alterations in the mouse ear tumour model CT26. Histological analysis showed that the main mechanisms of vascular PDT was thrombosis of blood vessels and hemorrhage, which agrees with angiographic imaging by MML-OCA. Relationship between MML-OCA-detected early microvascular damage post PDT (within 24 hours) and tumour regression/regrowth was confirmed by histology. The advantages of MML-OCA such as direct image acquisition, fast processing, robust and affordable system opto-electronics, and label-free high contrast 3D visualization of the microvasculature suggest attractive possibilities of this method in practical clinical monitoring of cancer therapies with microvascular involvement.

  3. PDT Dose Dosimeter for Pleural Photodynamic Therapy

    PubMed Central

    Kim, Michele M.; Darafsheh, Arash; Ahmad, Mahmoud; Finlay, Jarod C.; Zhu, Timothy C.

    2016-01-01

    PDT dose is the product of the photosensitizer concentration and the light fluence in the target tissue. For improved dosimetry during plural photodynamic therapy (PDT), a PDT dose dosimeter was developed to measure both the light fluence and the photosensitizer concentration simultaneously in the same treatment location. Light fluence and spectral data were rigorously compared to other methods of measurement (e.g. photodiode, multi-fiber spectroscopy contact probe) to assess the accuracy of the measurements as well as their uncertainty. Photosensitizer concentration was obtained by measuring the fluorescence of the sensitizer excited by the treatment light. Fluence rate based on the intensity of the laser spectrum was compared to the data obtained by direct measurement of fluence rate by a fiber-coupled photodiode. Phantom studies were done to obtain an optical property correction for the fluorescence signal. Measurements were performed in patients treated Photofrin for different locations in the pleural cavity. Multiple sites were measured to investigate the heterogeneity of the cavity and to provide cross-validation via relative dosimetry. This novel method will allow for accurate real-time determination of delivered PDT dose and improved PDT dosimetry. PMID:27053825

  4. Photodynamic antibacterial effect of graphene quantum dots.

    PubMed

    Ristic, Biljana Z; Milenkovic, Marina M; Dakic, Ivana R; Todorovic-Markovic, Biljana M; Milosavljevic, Momir S; Budimir, Milica D; Paunovic, Verica G; Dramicanin, Miroslav D; Markovic, Zoran M; Trajkovic, Vladimir S

    2014-05-01

    Synthesis of new antibacterial agents is becoming increasingly important in light of the emerging antibiotic resistance. In the present study we report that electrochemically produced graphene quantum dots (GQD), a new class of carbon nanoparticles, generate reactive oxygen species when photoexcited (470 nm, 1 W), and kill two strains of pathogenic bacteria, methicillin-resistant Staphylococcus aureus and Escherichia coli. Bacterial killing was demonstrated by the reduction in number of bacterial colonies in a standard plate count method, the increase in propidium iodide uptake confirming the cell membrane damage, as well as by morphological defects visualized by atomic force microscopy. The induction of oxidative stress in bacteria exposed to photoexcited GQD was confirmed by staining with a redox-sensitive fluorochrome dihydrorhodamine 123. Neither GQD nor light exposure alone were able to cause oxidative stress and reduce the viability of bacteria. Importantly, mouse spleen cells were markedly less sensitive in the same experimental conditions, thus indicating a fairly selective antibacterial photodynamic action of GQD.

  5. Advances in photodynamic therapy assisted by electroporation.

    PubMed

    Kotulska, Malgorzata; Kulbacka, Julita; Saczko, Jolanta

    2013-03-01

    Low invasive therapies of cancer are directed toward the methods that target selectively on carcinoma cells. Photodynamic therapy (PDT) is a therapeutic modality in which combination of a photosensitizer, light, and oxygen renders reactive oxygen species (ROS) which cause damage to a tumor tissue. Each of these factors is not toxic in itself and the effect of therapy results from high uptake of a photosensitizer by carcinoma cells and directed tumor irradiation by light. Realization of the therapy depends on efficient transport of the photosensitizer across the membrane and intracellular accumulation of the drug. Depending on the treatment conditions and the uptake mechanism, sensitizers can potentially reach different intracellular concentrations and different cellular effects can be triggered. Transport efficacy can be significantly augmented by applying electric pulses to plasma membrane, which opens transient non-selective hydrophilic nanopores as additional pathways across lipid membranes. Electroporation (EP) has been utilized to facilitate drug uptake in electrochemotherapy (ECT) and has been tested in combination with PDT. In the review, we described effects of PDT and electrophotodynamic therapy (EPDT) on carcinoma and healthy cells, studied in vitro and vivo. The comparison of different drugs has been applied to tests considering the enhancement of their cytotoxicity, selectivity, and additional effects caused by electroporation.

  6. Optical dosimetry for interstitial photodynamic therapy

    SciTech Connect

    Arnfield, M.R.; Tulip, J.; Chetner, M.; McPhee, M.S. )

    1989-07-01

    An approach to photodynamic treatment of tumors is the interstitial implantation of fiber optic light sources. Dosimetry is critical in identifying regions of low light intensity in the tumor which may prevent tumor cure. We describe a numerical technique for calculating light distributions within tumors, from multiple fiber optic sources. The method was tested using four translucent plastic needles, which were placed in a 0.94 X 0.94 cm grid pattern within excised Dunning R3327-AT rat prostate tumors. A cylindrical diffusing fiber tip, illuminated by 630 nm dye laser light was placed within one needle and a miniature light detector was placed within another. The average penetration depth in the tumor region between the two needles was calculated from the optical power measured by the detector, using a modified diffusion theory. Repeating the procedure for each pair of needles revealed significant variations in penetration depth within individual tumors. Average values of penetration depth, absorption coefficient, scattering coefficient, and mean scattering cosine were 0.282 cm, 0.469 cm-1, 250 cm-1 and 0.964, respectively. Calculated light distributions from four cylindrical sources in tumors gave reasonable agreement with direct light measurements using fiber optic probes.

  7. Guidelines for topical photodynamic therapy: update.

    PubMed

    Morton, C A; McKenna, K E; Rhodes, L E

    2008-12-01

    Multicentre randomized controlled studies now demonstrate high efficacy of topical photodynamic therapy (PDT) for actinic keratoses, Bowen's disease (BD) and superficial basal cell carcinoma (BCC), and efficacy in thin nodular BCC, while confirming the superiority of cosmetic outcome over standard therapies. Long-term follow-up studies are also now available, indicating that PDT has recurrence rates equivalent to other standard therapies in BD and superficial BCC, but with lower sustained efficacy than surgery in nodular BCC. In contrast, current evidence does not support the use of topical PDT for squamous cell carcinoma. PDT can reduce the number of new lesions developing in patients at high risk of skin cancer and may have a role as a preventive therapy. Case reports and small series attest to the potential of PDT in a wide range of inflammatory/infective dermatoses, although recent studies indicate insufficient evidence to support its use in psoriasis. There is an accumulating evidence base for the use of PDT in acne, while detailed study of an optimized protocol is still required. In addition to high-quality treatment site cosmesis, several studies observe improvements in aspects of photoageing. Management of treatment-related pain/discomfort is a challenge in a minority of patients, and the modality is otherwise well tolerated. Long-term studies provide reassurance over the safety of repeated use of PDT.

  8. Photodynamic therapy (PDT) as a biological modifier

    NASA Astrophysics Data System (ADS)

    Obochi, Modestus; Tao, Jing-Song; Hunt, David W. C.; Levy, Julia G.

    1996-04-01

    The capacity of photosensitizers and light to ablate cancerous tissues and unwanted neovasculature constitutes the classical application of photodynamic therapy (PDT). Cell death results from either necrotic or apoptotic processes. The use of photosensitizers and light at doses which do not cause death has been found to affect changes in certain cell populations which profoundly effect their expression of cell surface molecules and secretion of cytokines, thereby altering the functional attributes of the treated cells. Cells of the immune system and the skin may be sensitive to modulation by 'sub-lethal PDT.' Ongoing studies have been conducted to assess, at the molecular level, changes in both lymphocytes and epidermal cells (EC) caused by treatment with low levels of benzoporphyrin derivative monoacid ring A (BPD) (a photosensitizer currently in clinical trials for cancer, psoriasis, endometriosis and age-related macular degeneration) and light. Treatment of skin with BPD and light, at levels which significantly enhanced the length of murine skin allograft acceptance, have been found to down-regulate the expression of Langerhans cell (LC) surface antigen molecules [major histocompatibility complex (MHC) class II and intracellular adhesion molecule (ICAM)-1] and the formation of some cytokines (tumor necrosis factor-alpha (TNF- (alpha) ).

  9. Photodynamic inactivation of pathogens causing infectious keratitis

    NASA Astrophysics Data System (ADS)

    Simon, Carole; Wolf, G.; Walther, M.; Winkler, K.; Finke, M.; Hüttenberger, D.; Bischoff, Markus; Seitz, B.; Cullum, J.; Foth, H.-J.

    2014-03-01

    The increasing prevalence of antibiotic resistance requires new approaches also for the treatment of infectious keratitis. Photodynamic Inactivation (PDI) using the photosensitizer (PS) Chlorin e6 (Ce6) was investigated as an alternative to antibiotic treatment. An in-vitro cornea model was established using porcine eyes. The uptake of Ce6 by bacteria and the diffusion of the PS in the individual layers of corneal tissue were investigated by fluorescence. After removal of the cornea's epithelium Ce6-concentrations < 1 mM were sufficient to reach a penetration depth of 500 μm. Liquid cultures of microorganisms were irradiated using a specially constructed illumination chamber made of Spectralon(R) (reflectance: 99 %), which was equipped with high power light emitting diodes (λ = 670 nm). Clinical isolates of Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) from keratitis patients were tested in liquid culture against different concentrations of Ce6 (1 - 512 μM) using 10 minutes irradiation (E = 18 J/cm2 ). This demonstrated that a complete inactivation of the pathogen strains were feasible whereby SA was slightly more susceptible than PA. 3909 mutants of the Keio collection of Escherichia coli (E.coli) were screened for potential resistance factors. The sensitive mutants can be grouped into three categories: transport mutants, mutants in lipopolysaccharide synthesis and mutants in the bacterial SOS-response. In conclusion PDI is seen as a promising therapy concept for infectious keratitis.

  10. Integrating spheres for improved skin photodynamic therapy.

    PubMed

    Glennie, Diana L; Farrell, Thomas J; Hayward, Joseph E; Patterson, Michael S

    2010-01-01

    The prescribed radiant exposures for photodynamic therapy (PDT) of superficial skin cancers are chosen empirically to maximize the success of the treatment while minimizing adverse reactions for the majority of patients. They do not take into account the wide range of tissue optical properties for human skin, contributing to relatively low treatment success rates. Additionally, treatment times can be unnecessarily long for large treatment areas if the laser power is not sufficient. Both of these concerns can be addressed by the incorporation of an integrating sphere into the irradiation apparatus. The light fluence rate can be increased by as much as 100%, depending on the tissue optical properties. This improvement can be determined in advance of treatment by measuring the reflectance from the tissue through a side port on the integrating sphere, allowing for patient-specific treatment times. The sphere is also effective at improving beam flatness, and reducing the penumbra, creating a more uniform light field. The side port reflectance measurements are also related to the tissue transport albedo, enabling an approximation of the penetration depth, which is useful for real-time light dosimetry.

  11. Tissue temperature monitoring during interstitial photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Svensson, Jenny; Johansson, Ann; Svanberg, Katarina; Andersson-Engels, Stefan

    2005-04-01

    During δ-aminolevulinic acid (ALA) based Interstitial Photodynamic Therapy (IPDT) a high light fluence rate is present close to the source fibers. This might induce an unintentional tissue temperature increase of importance for the treatment outcome. In a previous study, we have observed, that the absorption in the tissue increases during the treatment. A system to measure the local tissue temperature at the source fibers during IPDT on tissue phantoms is presented. The temperature was measured by acquiring the fluorescence from small Cr3+-doped crystals attached to the tip of the illumination fiber used in an IPDT-system. The fluorescence of the Alexandrite crystal used is temperature dependent. A ratio of the intensity of the fluorescence was formed between two different wavelength bands in the red region. The system was calibrated by immersing the fibers in an Intralipid solution placed in a temperature controlled oven. Measurements were then performed by placing the fibers interstitially in a pork chop as a tissue phantom. Measurements were also performed superficially on skin on a volunteer. A treatment was conducted for 10 minutes, and the fluorescence was measured each minute during the illumination. The fluorescence yielded the temperature at the fiber tip through the calibration curve. The measurements indicate a temperature increase of a few degrees during the simulated treatment.

  12. Photodynamic therapy monitoring with optical coherence angiography

    PubMed Central

    Sirotkina, M. A.; Matveev, L. A.; Shirmanova, M. V.; Zaitsev, V. Y.; Buyanova, N. L.; Elagin, V. V.; Gelikonov, G. V.; Kuznetsov, S. S.; Kiseleva, E. B.; Moiseev, A. A.; Gamayunov, S. V.; Zagaynova, E. V.; Feldchtein, F. I.; Vitkin, A.; Gladkova, N. D.

    2017-01-01

    Photodynamic therapy (PDT) is a promising modern approach for cancer therapy with low normal tissue toxicity. This study was focused on a vascular-targeting Chlorine E6 mediated PDT. A new angiographic imaging approach known as M-mode-like optical coherence angiography (MML-OCA) was able to sensitively detect PDT-induced microvascular alterations in the mouse ear tumour model CT26. Histological analysis showed that the main mechanisms of vascular PDT was thrombosis of blood vessels and hemorrhage, which agrees with angiographic imaging by MML-OCA. Relationship between MML-OCA-detected early microvascular damage post PDT (within 24 hours) and tumour regression/regrowth was confirmed by histology. The advantages of MML-OCA such as direct image acquisition, fast processing, robust and affordable system opto-electronics, and label-free high contrast 3D visualization of the microvasculature suggest attractive possibilities of this method in practical clinical monitoring of cancer therapies with microvascular involvement. PMID:28148963

  13. Photodynamic inactivation of verrucae vulgares. II.

    PubMed

    Veien, N K; Genner, J; Brodthagen, H; Wettermark, G

    1977-01-01

    Photodynamic inactivation therapy, consisting of a double-blind, paired comparison treatment schedule, was used in treating 56 patients for recalcitrant, symmetrical verrucae vulgares. 0.1% proflavine in 100% dimethylsulphoxide (DMSO) and 0.1% neutral red in 100% DMSO were used as active dyes, and 1% picric acid in 100% DMSO and 1% color ruber in 100% DMSO and 1% color ruber in 100% DMSO served as corresponding placebos. A Westinghouse sunlamp and black light were used to irradiate the warts dyed with proflavine and its placebo, and the warts dyed with neutral red and its placebo were irradiated with an ordinary light bulb (Osram 588597). 50 patients completed the treatment. 10 of the 27 patients treated with proflavine and 10 of the 23 patients treated with neutral red were cured by the end of an 8 week period, with the warts disappearing simultaneously from the actively as well as the placebo-treated side. Complement fixing antibodies against wart virus were detected in one of the cured patients and 2 who were treatment failures.

  14. Pecularities of clinical photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Stranadko, Eugeny P.; Skobelkin, Oleg K.; Litvin, Grigory D.; Astrakhankina, Tamara A.

    1996-01-01

    The analysis of the results of photodynamic therapy (PDT) for treating malignant neoplasms of the skin, mammary glands, tongue, oral mucous, lower lip, larynx, lungs, urinary bladder rectum and other locations has been made. During 1992 - 1995 478 tumoral foci in 125 patients have been treated with PDT. All patients were previously treated with conventional techniques without effect or they were not treated due to contraindications either because of severe accompanying diseases or because of old age. A part of the patients had PDT because of recurrences or intradermal metastases in 1 - 2 years after surgical, radial or combined treatment. Two home-made preparations were used as photosensitizers: Photohem (hematoporphyrine derivative) and Photosense (aluminum sulfonated phthalocyanine). Light sources were: the argon pumped dye laser (`Innova-200', `Coherent') and home-made laser devices: copper-vapor laser-pumped dye laser (`Yakhroma-2', Frjazino), gas-discharge unit `Ksenon' (wavelength 630 nm), gold-vapor laser (wavelength 627.8 nm) for Photohem; while for Photosense sessions we used solid-state laser on ittrium aluminate `Poljus-1' (wavelength 670 nm). Up to now we have follow-up control data within 2 months and 3 years. Positive effect of PDT was seen in 92% of patients including complete regression of tumors in 66.4% and partial in 25.6%. Currently, this new perspective technique of treating malignant neoplasms is successfully being used in Russia; new photosensitizers and light sources for PDT and fluorescent tumor diagnostics are being developed as well.

  15. Variables in photodynamic therapy for Barrett's esophagus

    NASA Astrophysics Data System (ADS)

    Jones, Linda R.; Preyer, Norris W.; Buchanan, Jane; Reynolds, Daryl M.; Wolfsen, Herbert C.; Wallace, Michael B.; Gill, Kanwar R. S.

    2009-06-01

    Photodynamic therapy with porfimer sodium (PS) is a treatment option for high grade dysplasia associated with Barrett's esophagus. This study sought to investigate the optical properties of Barrett's dysplasia that may be useful in light dosimetry planning and to determine the effect of PS on tissue absorption and scattering. Fiber optic reflectance spectra were collected before and 48 hours after administration of 2 mg/kg PS. Mucosal biopsies were collected at the same locations. According to Monte Carlo analysis, the fiber optic probe sampled only the mucosal layer. A mathematical fit of the reflectance spectra was performed as a function of blood volume fraction, oxygen saturation and scattering. The average calculated blood volume was 100% higher in Barrett's tissue than normal esophageal tissue. The average scattering slope from 620 to 750 nm was 26% higher for Barrett's dysplasia than normal esophageal tissue, indicating an increase in the size of scattering particles. The difference in the scattering amplitude was not statistically significant, suggesting no significant increase in the number of scattering particles. PS tissue content was determined with extraction methods. Changes in the scattering slope due to PS sensitization were observed; however they were not proportional to the extracted PS concentration.

  16. Photodynamic therapy: a promising alternative in oncology

    NASA Astrophysics Data System (ADS)

    Nelius, Thomas; de Riese, Werner T. W.; Filleur, Stephanie

    2004-07-01

    Photodynamic Therapy (PDT) is a treatment modality that is based on the administration of a photosensitizer and the following application of light in a wavelength range matching the absorption spectrum of the photosensitizer. Ideally the photosensitizer retains in the tumor tissue more than in normal tissue and thus allows targeted destruction of cancerous tissue. The use of PDT is slowly being accepted as a standard treatment for certain types of cancer. This includes mainly treatment strategies with only palliative intentions (obstructive esophageal cancer and advanced lung cancer) while for certain malignant conditions new applications exists that are already intended for cure (e.g. early stage of lung cancer). The main advantage of PDT is that the treatment can be repeated multiple times safely without major side effects. PDT can be safely combined with already established treatment options like surgery, chemotherapy or radiotherapy. A disadvantage of PDT is the only localized effect of the therapy, which usually cannot significantly alter the outcome of a systemic disease. In this paper we review the history of PDT as well as current clinical applications in oncology and future directions.

  17. Photodynamic Antimicrobial Polymers for Infection Control

    PubMed Central

    McCoy, Colin P.; O’Neil, Edward J.; Cowley, John F.; Carson, Louise; De Baróid, Áine T.; Gdowski, Greg T.; Gorman, Sean P.; Jones, David S.

    2014-01-01

    Hospital-acquired infections pose both a major risk to patient wellbeing and an economic burden on global healthcare systems, with the problem compounded by the emergence of multidrug resistant and biocide tolerant bacterial pathogens. Many inanimate surfaces can act as a reservoir for infection, and adequate disinfection is difficult to achieve and requires direct intervention. In this study we demonstrate the preparation and performance of materials with inherent photodynamic, surface-active, persistent antimicrobial properties through the incorporation of photosensitizers into high density poly(ethylene) (HDPE) using hot-melt extrusion, which require no external intervention except a source of visible light. Our aim is to prevent bacterial adherence to these surfaces and eliminate them as reservoirs of nosocomial pathogens, thus presenting a valuable advance in infection control. A two-layer system with one layer comprising photosensitizer-incorporated HDPE, and one layer comprising HDPE alone is also described to demonstrate the versatility of our approach. The photosensitizer-incorporated materials are capable of reducing the adherence of viable bacteria by up to 3.62 Log colony forming units (CFU) per square centimeter of material surface for methicillin resistant Staphylococcus aureus (MRSA), and by up to 1.51 Log CFU/cm2 for Escherichia coli. Potential applications for the technology are in antimicrobial coatings for, or materials comprising objects, such as tubing, collection bags, handrails, finger-plates on hospital doors, or medical equipment found in the healthcare setting. PMID:25250740

  18. Photodynamic Therapy for Infections: Clinical Applications

    PubMed Central

    Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; Dai, Tianhong; Hamblin, Michael R.

    2012-01-01

    Background and Objective Photodynamic therapy (PDT) was discovered over 100 years ago by its ability to kill various microorganisms when the appropriate dye and light were combined in the presence of oxygen. However it is only in relatively recent times that PDT has been studied as a treatment for various types of localized infections. This resurgence of interest has been partly motivated by the alarming increase in drug resistance amongst bacteria and other pathogens. This review will focus on the clinical applications of antimicrobial PDT. Study Design/Materials and Methods The published peer-reviewed literature was reviewed between 1960 and 2011. Results The basics of antimicrobial PDT are discussed. Clinical applications of antimicrobial PDT to localized viral infections caused by herpes and papilloma viruses, and nonviral dermatological infections such as acne and other yeast, fungal and bacterial skin infections are covered. PDT has been used to treat bacterial infections in brain abscesses and non-healing ulcers. PDT for dental infections including periodontitis and endodontics has been well studied. PDT has also been used for cutaneous Leishmaniasis. Clinical trials of PDT and blue light alone therapy for gastric Helicobacter pylori infection are also covered. Conclusion As yet clinical PDT for infections has been mainly in the field of dermatology using 5-aminolevulanic acid and in dentistry using phenothiazinium dyes. We expect more to see applications of PDT to more challenging infections using advanced antimicrobial photosensitizers targeted to microbial cells in the years to come. PMID:22057503

  19. Photodynamic therapy of recurrent cerebral glioma

    NASA Astrophysics Data System (ADS)

    Zhu, Shu-Gan; Wu, Si-En; Chen, Zong-Qian; Sun, Wei

    1993-03-01

    Photodynamic therapy (PDT) was performed on 11 cases of recurrent cerebral glioma, including 3 cases of recurrent glioblastoma, 7 of recurrent anaplastic astrocytoma, and 1 recurrent ependymoma. Hematoporphyrin derivative (HPD) was administered intravenously at a dose of 4 - 7 mg/kg 5 - 24 hours before the operation. All patients underwent a craniotomy with a nearly radical excision of the tumor following which the tumor bed was irradiated with 630 nm laser light emitting either an argon pumped dye laser or frequency double YAG pumped dye laser for 30 to 80 minutes with a total dose of 50 J/cm2 (n equals 1), 100 J/cm2 (n equals 2), 200 J/cm2 (n equals 7), and 300 J/cm2 (n equals 1). The temperature was kept below 37 degree(s)C by irrigation. Two patients underwent postoperative radiotherapy. There was no evidence of increased cerebral edema, and no other toxicity by the therapy. All patients were discharged from the hospital within 15 days after surgery. We conclude that PDT using 4 - 7 mg/kg of HPD and 630 nm light with a dose of up to 300 J/cm2 can be used as an adjuvant therapy with no additional complications. Adjuvant PDT in the treatment of recurrent glioma is better than simple surgery.

  20. Suppression of cucurbit scab on cucumber leaves by photodynamic dyes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of this study was to test the ability of the photodynamic dyes bengal rose, toluidine blue, and methylene blue, to protect systemically cucumber plants from cucurbit scab. At the stage of one true leaf, water or aqueous solutions of the dyes were applied to the leaf as droplets. When the se...

  1. Photodynamic therapy by in situ nonlinear photon conversion

    NASA Astrophysics Data System (ADS)

    Kachynski, A. V.; Pliss, A.; Kuzmin, A. N.; Ohulchanskyy, T. Y.; Baev, A.; Qu, J.; Prasad, P. N.

    2014-06-01

    In photodynamic therapy, light is absorbed by a therapy agent (photosensitizer) to generate reactive oxygen, which then locally kills diseased cells. Here, we report a new form of photodynamic therapy in which nonlinear optical interactions of near-infrared laser radiation with a biological medium in situ produce light that falls within the absorption band of the photosensitizer. The use of near-infrared radiation, followed by upconversion to visible or ultraviolet light, provides deep tissue penetration, thus overcoming a major hurdle in treatment. By modelling and experiment, we demonstrate activation of a known photosensitizer, chlorin e6, by in situ nonlinear optical upconversion of near-infrared laser radiation using second-harmonic generation in collagen and four-wave mixing, including coherent anti-Stokes Raman scattering, produced by cellular biomolecules. The introduction of coherent anti-Stokes Raman scattering/four-wave mixing to photodynamic therapy in vitro increases the efficiency by a factor of two compared to two-photon photodynamic therapy alone, while second-harmonic generation provides a fivefold increase.

  2. Laser effect in photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Ion, Rodica-Mariana; Brezoi, Dragos-Viorel; Neagu, Monica; Manda, Gina; Constantin, Carolina

    2007-03-01

    Photodynamic therapy is a method that provides a reasonable alternative to other treatment modalities for patients with certain cancers, and in some cases may be the preferred treatment. The therapy implies the intravenous administration of a light-sensitive substance, the photosensitizer. The used sensitizer must absorb at long wavelength. For these purposes, the carbon dioxide laser, He-Ne and the argon laser are particularly suitable. In this study we evaluate in vitro the cytotoxic activity of three synthesized metallo-phthalocyanines with absorption bands in the red part of the spectrum: zinc-di-sulphonated phthalocyanine (ZnS IIPc), zinc-tri-sulphonated phthalocyanine (ZnS 3Pc) and zinc-tetrasulphonated phthalocyanine (ZnS 4Pc). Some cellular models have been used in this paper, in order to optimize the conditions of this method, as we are presenting in this paper (LSR-SF(SR) - transplantable sarcoma in rat induced by Rous sarcoma virus strain Schmidt-Ruppin; LSCC-SF(Mc29) - transplantable chicken hepatoma induced by the myelocytomatosis virus Mc29, MCF-7 cell line (human breast adenocarcinoma) derived from a patient with metastatic breast cancer, 8-MG-BA - glioblastoma multiforme 8-MG-BA, K562 - lymphoblastic human cell line, LLC-WRC 256 - Walker epithelial carcinoma. Activation of these photosensitizers retained in the cancerous cells, by red light emitted from a He-Ne laser at λ= 632.8 nm laser system, or by a diode laser emitting at 672 nm, produces a photochemical reaction that results in the selective destruction of tumor cells.

  3. Photodynamic Therapy for Malignant Brain Tumors.

    PubMed

    Akimoto, Jiro

    2016-01-01

    Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women's Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area.

  4. Important cellular targets for antimicrobial photodynamic therapy.

    PubMed

    Awad, Mariam M; Tovmasyan, Artak; Craik, James D; Batinic-Haberle, Ines; Benov, Ludmil T

    2016-09-01

    The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic-resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram-negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets.

  5. Animal models for photodynamic therapy (PDT)

    PubMed Central

    Silva, Zenildo Santos; Bussadori, Sandra Kalil; Fernandes, Kristianne Porta Santos; Huang, Ying-Ying; Hamblin, Michael R.

    2015-01-01

    Photodynamic therapy (PDT) employs non-toxic dyes called photosensitizers (PSs), which absorb visible light to give the excited singlet state, followed by the long-lived triplet state that can undergo photochemistry. In the presence of ambient oxygen, reactive oxygen species (ROS), such as singlet oxygen and hydroxyl radicals are formed that are able to kill cancer cells, inactivate microbial pathogens and destroy unwanted tissue. Although there are already several clinically approved PSs for various disease indications, many studies around the world are using animal models to investigate the further utility of PDT. The present review will cover the main groups of animal models that have been described in the literature. Cancer comprises the single biggest group of models including syngeneic mouse/rat tumours that can either be subcutaneous or orthotopic and allow the study of anti-tumour immune response; human tumours that need to be implanted in immunosuppressed hosts; carcinogen-induced tumours; and mice that have been genetically engineered to develop cancer (often by pathways similar to those in patients). Infections are the second biggest class of animal models and the anatomical sites include wounds, burns, oral cavity, ears, eyes, nose etc. Responsible pathogens can include Gram-positive and Gram-negative bacteria, fungi, viruses and parasites. A smaller and diverse group of miscellaneous animal models have been reported that allow PDT to be tested in ophthalmology, atherosclerosis, atrial fibrillation, dermatology and wound healing. Successful studies using animal models of PDT are blazing the trail for tomorrow's clinical approvals. PMID:26415497

  6. Photodynamic diagnosis of ovarian cancer using hexaminolaevulinate: a preclinical study.

    PubMed

    Lüdicke, F; Gabrecht, T; Lange, N; Wagnières, G; Van Den Bergh, H; Berclaz, L; Major, A L

    2003-06-02

    The unfailing detection of micrometastases during surgery of patients suffering from ovarian cancer is mandatory for the optimal management of this disease. Thus, the present study aimed at determining the feasibility of detecting micrometastases in an ovarian cancer model using the intraperitoneal administration of the photosensitiser precursor hexaminolaevulinate (HAL). For this purpose, HAL was applied intraperitoneally at different concentrations (4-12 mM) to immunocompetent Fischer 344 rats bearing a syngeneic epithelial ovarian carcinoma. The tumours were visualised laparoscopically using both white and blue light (D-light, Karl Storz, Tuttlingen, Germany), and the number of peritoneal micrometastases detected through HAL-induced photodiagnosis (PD) was compared to standard white light visualisation. Fluorescence spectra were recorded with an optical fibre-based spectrofluorometer and the fluorescence intensities were compared to the protoporphyrin IX (PpIX) fluorescence induced by 5-aminolevulinic acid under similar conditions. The number of metastases detected by the PD blue light mode was higher than when using standard white light abdominal inspection for all applied concentrations. Twice as many cancer lesions were detected by fluorescence than by white light inspection. The hexyl-ester derivative produced higher PpIX fluorescence than its parent substance aminolevulinic acid at the same concentration and application time. Fluorescence contrast between healthy and cancerous tissue was excellent for both compounds. To overcome poor diagnostic efficiency and to detect peritoneal ovarian carcinoma foci in the large surface area of the human peritoneal cavity, HAL fluorescence-based visualisation techniques may acquire importance in future and lead to a more correct staging of early ovarian cancer.

  7. Photodynamic therapy for the treatment of non-small cell lung cancer

    PubMed Central

    Simone, Charles B; Friedberg, Joseph S; Glatstein, Eli; Stevenson, James P; Sterman, Daniel H; Hahn, Stephen M; Cengel, Keith A

    2012-01-01

    Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described. PMID:22295169

  8. Photodynamic therapy for the treatment of non-small cell lung cancer.

    PubMed

    Simone, Charles B; Friedberg, Joseph S; Glatstein, Eli; Stevenson, James P; Sterman, Daniel H; Hahn, Stephen M; Cengel, Keith A

    2012-02-01

    Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described.

  9. Photons for Therapy: Targeted Photodynamic Therapy for Infected and Contaminated Wounds

    DTIC Science & Technology

    2004-09-01

    RTO-MP-HFM-109 30 - 1 Photons for Therapy : Targeted Photodynamic Therapy for Infected and Contaminated Wounds Michael R Hamblin Faten Gad...unknown antibiotic susceptibility. Rationale: Previously workers have used photodynamic therapy to kill bacteria in vitro, but the use of this approach...play in preventing and treating infection in combat wounds. 1.0 INTRODUCTION Photodynamic therapy (PDT) is a therapy for cancer and other diseases

  10. Enhancement of selectivity for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Bedwell, Joanne

    Photodynamic Therapy (PDT) is a technique for producing localised tissue damage with low power light following prior administration of a photosensitising drug. The promise of PDT has been based on the selective retention of photosensitisers by tumours, but this aspect has been over-emphasised with a maximum ratio of photosensitiser concentration of 3:1, tumour to normal, for extracranial tumours and current drugs. This makes selective tumour necrosis difficult to achieve. This thesis explores ways in which selectivity may be improved. Aluminium sulphonated phthalocyanine (AlSPc) has better photochemical properties than the widely used HpD and Photofrin II, but has the same tumour selectivity, although the ratio was improved marginally using its disulphonated component. However, when used in conjunction with the radioprotective drug W7, in a rat colon cancer model, tumour necrosis was the same as without W7 while there was no damage to adjacent normal colon. A radical new approach is to give 5-aminolaevulinic acid (ALA) which induces endogenous production of the photosensitiser protoporphyrin IX. This improves selectivity in the rat colon cancer to 6:1 (tumour to normal mucosa), but also sensitises the mucosa selectively compared with the underlying muscle (10:1), giving a tumour to muscle ratio of 60:1. This has enormous potential for treating small tumours or areas of dysplasia in a range of hollow organs. ALA also has the major advantages of a short optimum drug to light time (typically 4-6 hours), short duration of skin sensitivity (approximately 24 hours) and it can be given orally with minimal systemic toxicity. This work has also shown in vitro that PDT with AlSPc sensitisation can kill helicohacter pylori at doses unlikely to affect gastric mucosa. In conclusion, by careful choice of photosensitising agents and treatment regimes, it is possible to limit PDT effects to abnormal tissues, and even if there is some normal tissue damage, in most cases, this heals

  11. [Intraoperative fluorescence diagnosis using 5-aminolevulinic acid in surgical treatment of children with recurrent neuroepithelial tumors].

    PubMed

    Kim, A V; Khachatryan, V A

    2017-01-01

    Цель работы — анализ эффективности и безопасности применения 5-аминолевулиновой кислоты (5-ALA) для интраоперационной флуоресцентной диагностики (ФД) при повторных операциях по поводу рецидивов нейроэпителиальных опухолей (НЭО) у детей. Материал и методы. Проведен ретроспективный анализ результатов удаления рецидивирующих НЭО у 13 детей в возрасте от 3 до 17 лет за период с декабря 2013 г. по май 2015 г. Источником 5-ALA являлся препарат Аласенс, который принимался больным из расчета 20 мг на 1 кг массы тела за 4 ч до начала удаления опухоли. Степень флуоресценции оценивали по визуальной шкале. Препарат применялся при информированном согласии родителей ребенка и с одобрения этического комитета РНХИ им. проф. А.Л. Поленова. Всем пациентам проведено комплексное клинико-интроскопическое обследование в до- и послеоперационном периоде, повторное гистологическое исследование опухоли. Результаты. Флуоресценция отсутствовала в 4 наблюдениях (2 — Grade I; 2 — Grade II). В 1 случае отмечена флуоресценция 1-й степени (Grade II), у остальных 8 больных — II—III степени. Тотальная и субтотальная резекция опухоли достигнута у 11 (84,6%) из 13 больных. Клинически значимые побочные эффекты не зарегистрированы. Отмечалось транзиторное увеличение трансаминаз у 2 больных. У 2 девочек в течение 2 сут сохранялась повышенная фотосенсибилизация к свету. Заключение. ФД является безопасным методом в детском возрасте и позволяет улучшить интраоперационную детекцию НЭО при ее повторном росте, в том числе дифференцировать ее с патологическими тканями неопухолевой природы, что позволяет увеличить тотальность удаления бластоматозной ткани. Возможно, изменение характера и степени флуоресценции при повторном росте НЭО. Необходимо дальнейшее изучение эффективности ФД у больных разного возраста с опухолями разной гистоструктуры и степени анаплазии при первичном и повторном росте новообразования.

  12. Fractionated PDT with 5-aminolevulinic acid: effective, cost effective, and patient friendly

    NASA Astrophysics Data System (ADS)

    de Vijlder, Hannah C.; Middelburg, Tom A.; de Bruijn, Henriette S.; Robinson, Dominic J.; Neumann, H. A. Martino; de Haas, Ellen R. M.

    2009-06-01

    PDT with ALA and MAL is established as a relatively effective treatment for non-melanoma skin cancer and premalignancies. PDT is often repeated, because a single treatment gives poor long term results. Preclinical studies showed that ALA-PDT applying a fractionated illumination scheme with a small first light fraction and a second larger light fraction separated by a dark interval of two hours resulted in a significant increase in efficacy. Whereas the efficacy was not enhanced by fractionating MAL-PDT, indicating that ALA-PDT mechanism is not the same as MAL-PDT mechanism. The increase in efficacy using fractionated PDT was confirmed clinically. A randomized comparative clinical study comparing fractionated ALA-PDT versus non-fractionated ALA-PDT in the treatment of superficial basal cell carcinoma showed a significant higher response rate in the lesions treated with fractionated ALA-PDT after a follow-up of one year ( p<0.002, log-rank test). The five year follow-up is studied at moment. So far the complete response in the group treated with fractionated ALA-PDT seems to be only a few percentages lower compared to the one year follow-up. Besides the gain in response rate, fractionated ALA PDT is cost effective. ALA gel is less expensive than the commercially available MAL (Metvix) and moreover fractionated ALA-PDT takes one treatment day, instead of two treatment days using the Metvix treatment protocol (two MAL-PDT treatments separated by one week), both reducing direct and indirect costs and the burden to the patient.

  13. Immune Response Following Photodynamic Therapy For Bladder Cancer

    NASA Astrophysics Data System (ADS)

    Raymond K.

    1989-06-01

    This study was undertaken to determine if photodynamic therapy (PDT) produces an immunologic response in patients treated for bladder cancer. Gamma interferon, interleukin 1-beta, interleukin 2 and tumor necrosis factor-alpha were assayed in the urine of four patients treated with photodynamic therapy for bladder cancer, in seven patients undergoing transurethral procedures, and in five healthy control subjects. Quantifiable concentrations of all cytokines, except gamma interferon, were measured in urine samples from the PDT patients treated with the highest light energies, while no urinary cytokines were found in the PDT patient who received the lowest light energy or in the control subjects. These findings suggest that a local immunologic response may occur following PDT for bladder cancer. Such an immunologic response activated by PDT may be an additional mechanism involved in bladder tumor destruction.

  14. Anticancer photodynamic therapy based on the use of a microsystem

    NASA Astrophysics Data System (ADS)

    Jastrzebska, E.; Bulka, N.; Zukowski, K.; Chudy, M.; Brzozka, Z.; Dybko, A.

    2015-07-01

    The paper presents the evaluation of photodynamic therapy (PDT) procedures with an application of a microsystem. Two cell lines were used in the experiments, i.e. human lung carcinoma - A549 and normal human fetal lung fibroblast MRC5. Mono-, coculture and mixed cultures were performed in a microsystem at the same time. The microsystem consisted of a concentration gradient generator (CGG) which generates different concentrations of a photosensitizer, and a set of microchambers for cells. The microchambers were linked by microchannels of various length in order to allow cells migration and in this way cocultures were created. Transparent materials were used for the chip manufacture, i.e. glass and poly(dimethylsiloxane). A high power LED was used to test photodynamic therapy effectiveness in the microsystem.

  15. Towards image-guided photodynamic therapy of Glioblastoma

    NASA Astrophysics Data System (ADS)

    Mallidi, Srivalleesha; Huang, Huang-Chiao; Liu, Joyce; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    Glioblastoma (GBM) is an aggressive cancer with dismal survival rates and few new treatment options. Fluorescence guided resection of GBM followed by photodynamic therapy (PDT) has shown promise in several chemo- or radiotherapy non-responsive GBM treatments clinically. PDT is an emerging light and photosensitizer (PS) mediated cytotoxic method. However, as with other therapeutic modalities, the outcomes are variable largely due to the nonpersonalization of dose parameters. The variability can be attributed to the differences in heterogeneous photosensitizer accumulation in tumors. Building upon our previous findings on utilizing PS fluorescence for designing tumor-specific PDT dose, we explore the use of photoacoustic imaging, a technique that provides contrast based on the tissue optical absorption properties, to obtain 3D information on the tumoral photosensitizer accumulation. The findings of this study will form the basis for customized photodynamic therapy for glioblastoma and have the potential to serve as a platform for treatment of other cancers.

  16. Photodynamic therapy: novel third-generation photosensitizers one step closer?

    PubMed

    Josefsen, L B; Boyle, R W

    2008-05-01

    Photodynamic sensitizers are drugs activated by light of a specific wavelength and are used in the photodynamic therapy (PDT) of certain diseases. Second- and third-generation photosensitizers with improved PDT properties are now under investigation. In this issue of the British Journal of Pharmacology, Leung et al. have described the synthesis and investigation of a second-generation photosensitizer (BAM-SiPc) targeted towards the cells of HepG2 and HT29 tumours. BAM-SiPc is selectively functionalized with bis-amino groups and has demonstrated potent PDT activity in a small animal model. However, it also exhibited non-selective distribution and accumulation in multiple animal (small mouse) organs and tissue. These issues highlight the importance and need for good biodistribution and localization properties for an efficacious photosensitizer. The lack of tumour specificity may have a significant impact on the potential BAM-SiPc has in clinical PDT.

  17. First experience of application of photodynamic therapy in keratoplasty

    NASA Astrophysics Data System (ADS)

    Fyodorov, Svyatoslav N.; Kopayeva, V. G.; Andreev, Yu. V.; Stranadko, Eugeny P.; Ponomariov, G. V.

    1996-12-01

    Vascular effect of photodynamic therapy has been studied in patients with corneal neovascularized transplant in 10 cases. THe injection of photoheme intravenously were made with subsequent irradiation by light of argon-pumped dye laser with light density of 150-300 mW/cm2 for 10-15 minutes. Energy density consisted 150-300 J/cm2. In all the cases at the time of irradiation the aggregated blood flow was appeared followed by blood flow stasis. In post- operative period the vessels disintegrated into separate fragments which disappeared completely after 10-15 days. Taking into account the data of light microscope, the disappearance of the vessels took place as a result of the vascular endothelium lysis along the vascular walls. The vessel alteration study presented in this paper, may also serve to specify the mechanism of photodynamic destruction of neovascularized stroma of tumor.

  18. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.

    PubMed

    Zhen, Zipeng; Tang, Wei; Chuang, Yen-Jun; Todd, Trever; Zhang, Weizhong; Lin, Xin; Niu, Gang; Liu, Gang; Wang, Lianchun; Pan, Zhengwei; Chen, Xiaoyuan; Xie, Jin

    2014-06-24

    Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.

  19. New sensitizers and rapid monitoring of their photodynamic activity

    NASA Astrophysics Data System (ADS)

    Torshina, Nadezgda L.; Posypanova, Anna M.; Volkova, Anna I.

    1996-04-01

    At present, there are lots and lots of chemical compounds that are, to a certain extent, photodynamically active. Therefore, the task of carrying out the expressive screening of such compounds has been raised sharply enough. The primary screening in vitro of compounds, with the help of biological liquids, is notable for quickness and cheapness at the same time, it is possible to determine the comparative characteristics of compounds by their photodynamical activity. Decomposition of albumins of a mixture of photosensitizer and biological liquid when irradiating with light is the basis of this method. Efficiency of decomposition of components of biological liquids is determined using biochemical reactions (e.g., those for determining the total albumins or blood hemoglobin). Subsequently, with a sufficient efficiency of a photosensitizer, it will be possible to carry out a study in vivo, with the purpose of establishing accumulation of preparations in tumor.

  20. Simultaneous two-photon excitation of photodynamic therapy agents

    SciTech Connect

    Wachter, E.A.; Fisher, W.G. |; Partridge, W.P.; Dees, H.C.; Petersen, M.G.

    1998-01-01

    The spectroscopic and photochemical properties of several photosensitive compounds are compared using conventional single-photon excitation (SPE) and simultaneous two-photon excitation (TPE). TPE is achieved using a mode-locked titanium:sapphire laser, the near infrared output of which allows direct promotion of non-resonant TPE. Excitation spectra and excited state properties of both type 1 and type 2 photodynamic therapy (PDT) agents are examined.

  1. Photodynamic action on some pathogenic microorganisms of oral cavity

    NASA Astrophysics Data System (ADS)

    Ovchinnikov, Ilya S.; Tuchin, Valery V.

    2001-10-01

    The work is devoted to an analysis of pre-clinical and clinical experiments on photodynamic action of HeNe laser radiation in aggregate with a cation thiazinium dye Methylene Blue (MB) on a mix of pathogenic and conditionally pathogenic aerobic bacteria being activators of pyoinflammatory diseases of oral cavity. Concentration of photosensitizes at which there is no own bactericidal influence on dying microflora, and parameters of influence at which the efficiency of irradiated microflora defeat reaches 99 % are determined.

  2. Photodynamic action on some pathogenic microorganisms of oral cavity

    NASA Astrophysics Data System (ADS)

    Ovchinnikov, Ilya S.; Tuchin, Valery V.; Ivanov, Krill I.; Shoub, Gennady M.

    2001-04-01

    We have studied photodynamic action of He-Ne laser radiation on cultures of Staphylococcus (strain 209 P), Streptococcus anhaemolyticus, and total microflora of dental deposit been sensitized by methylene blue. The concentration of the dye was varied from 0.001% to 0.1%, radiation power density was 100 divided by 2300 mW/cm2. Irradiated strain was put into thermostat for 48 hours and the number of colonies was counted and analyzed.

  3. A Photosensitizer-Loaded DNA Origami Nanosystem for Photodynamic Therapy.

    PubMed

    Zhuang, Xiaoxi; Ma, Xiaowei; Xue, Xiangdong; Jiang, Qiao; Song, Linlin; Dai, Luru; Zhang, Chunqiu; Jin, Shubin; Yang, Keni; Ding, Baoquan; Wang, Paul C; Liang, Xing-Jie

    2016-03-22

    Photodynamic therapy (PDT) offers an alternative for cancer treatment by using ultraviolet or visible light in the presence of a photosensitizer and molecular oxygen, which can produce highly reactive oxygen species that ultimately leading to the ablation of tumor cells by multifactorial mechanisms. However, this technique is limited by the penetration depth of incident light, the hypoxic environment of solid tumors, and the vulnerability of photobleaching reduces the efficiency of many imaging agents. In this work, we reported a cellular level dual-functional imaging and PDT nanosystem BMEPC-loaded DNA origami for photodynamic therapy with high efficiency and stable photoreactive property. The carbazole derivative BMEPC is a one- and two-photon imaging agent and photosensitizer with large two-photon absorption cross section, which can be fully excited by near-infrared light, and is also capable of destroying targets under anaerobic condition by generating reactive intermediates of Type I photodynamic reactions. However, the application of BMEPC was restricted by its poor solubility in aqueous environment and its aggregation caused quenching. We observed BMEPC-loaded DNA origami effectively reduced the photobleaching of BMEPC within cells. Upon binding to DNA origami, the intramolecular rotation of BMEPC became proper restricted, which intensify fluorescence emission and radicals production when being excited. After the BMEPC-loaded DNA origami are taken up by tumor cells, upon irradiation, BMEPC could generate free radicals and be released due to DNA photocleavage as well as the following partially degradation. Apoptosis was then induced by the generation of free radicals. This functional nanosystem provides an insight into the design of photosensitizer-loaded DNA origami for effective intracellular imaging and photodynamic therapy.

  4. Improvement of photodynamic activity of aluminium sulphophthalocyanine due to biotinylation

    NASA Astrophysics Data System (ADS)

    Meerovich, Irina G.; Jerdeva, Victoria V.; Derkacheva, Valentina M.; Meerovich, Gennadii A.; Lukyanets, Eugeny A.; Kogan, Eugenia A.; Savitsky, Alexander P.

    2003-09-01

    The photodynamic activity of dibiotinylated aluminium sulphophthalocyanine in vitro and in vivo were studied. It was obtained that in vitro dibiotinylated aluminium sulphophthalocyanine provides the effective damage of small cell lung carcinoma OAT-75. In vivo dibiotinylated aluminium sulphophthalocyanine causes destruction of tumor (Erlich carcinoma), results in total necrosis of tumor tissue and expresses vascular damage (trombosis and destruction of vascular walls) even in concentration 0.25 mg/kg of a body weight.

  5. Structure-photodynamic activity relationships of substituted zinc trisulfophthalocyanines.

    PubMed

    Cauchon, Nicole; Tian, Hongjian; Langlois, Réjean; La Madeleine, Carole; Martin, Stephane; Ali, Hasrat; Hunting, Darel; van Lier, Johan E

    2005-01-01

    To identify optimal features of metalated sulfophthalocyanine dyes for their use as photosensitizers in the photodynamic therapy of cancer, we synthesized a series of alkynyl-substituted trisulfonated phthalocyanines and compared their amphiphilic properties to a number of parameters related to their photodynamic potency. Varying the length of the substituted alkynyl side-chain modulates the hydrophobic/hydrophilic properties of the dyes providing a linear relationship between their n-octanol/water partition coefficients and retention times on reversed-phase HPLC. Aggregate formation of the dyes in aqueous solution increased with increasing hydrophobicity while monomer formation was favored by the addition of serum proteins or organic solvent. Trisulfonated zinc phthalocyanines bearing hexynyl and nonynyl substituents exhibited high cellular uptake with strong localization at the mitochondrial membranes, which coincided with effective photocytotoxicity toward EMT-6 murine mammary tumor cells. Further increase in the length of the alkynyl chains (dodecynyl, hexadecynyl) did not improve their phototoxicity, likely resulting from extensive aggregation of the dyes in aqueous medium and reduced cell uptake. Aggregation was evident from shifts in the electronic spectra and reduced capacity to generate singlet oxygen. When monomerized through the addition of Cremophor EL all sulfonated zinc phthalocyanines gave similar singlet oxygen yields. Accordingly, differences in the tendency of the dyes to aggregate do not appear to be a determining factor in their photodynamic potency. Our results confirm that the latter in particular relates to their amphiphilic properties, which facilitate cell uptake and intracellular localization at photosensitive sites such as the mitochondria. Combined, these factors play a significant role in the overall photodynamic potency of the dyes.

  6. The impact of absorbed photons on antimicrobial photodynamic efficacy

    PubMed Central

    Cieplik, Fabian; Pummer, Andreas; Regensburger, Johannes; Hiller, Karl-Anton; Späth, Andreas; Tabenski, Laura; Buchalla, Wolfgang; Maisch, Tim

    2015-01-01

    Due to increasing resistance of pathogens toward standard antimicrobial procedures, alternative approaches that are capable of inactivating pathogens are necessary in support of regular modalities. In this instance, the photodynamic inactivation of bacteria (PIB) may be a promising alternative. For clinical application of PIB it is essential to ensure appropriate comparison of given photosensitizer (PS)-light source systems, which is complicated by distinct absorption and emission characteristics of given PS and their corresponding light sources, respectively. Consequently, in the present study two strategies for adjustment of irradiation parameters were evaluated: (i) matching energy doses applied by respective light sources (common practice) and (ii) by development and application of a formula for adjusting the numbers of photons absorbed by PS upon irradiation by their corresponding light sources. Since according to the photodynamic principle one PS molecule is excited by the absorption of one photon, this formula allows comparison of photodynamic efficacy of distinct PS per excited molecule. In light of this, the antimicrobial photodynamic efficacy of recently developed PS SAPYR was compared to that of clinical standard PS Methylene Blue (MB) regarding inactivation of monospecies biofilms formed by Enterococcus faecalis and Actinomyces naeslundii whereby evaluating both adjustment strategies. PIB with SAPYR exhibited CFU-reductions of 5.1 log10 and 6.5 log10 against E. faecalis and A. naeslundii, respectively, which is declared as a disinfectant efficacy. In contrast, the effect of PIB with MB was smaller when the applied energy dose was adjusted compared to SAPYR (CFU-reductions of 3.4 log10 and 4.2 log10 against E. faecalis and A. naeslundii), or there was even no effect at all when the number of absorbed photons was adjusted compared to SAPYR. Since adjusting the numbers of absorbed photons is the more precise and adequate method from a photophysical point

  7. Influence of human serum albumin on the bile acid-mediated inhibition of liver microsomal type 1 11β-hydroxysteroid dehydrogenase.

    PubMed

    Maeda, Yorio; Funagayama, Mayumi; Shinohara, Akio; Koshimoto, Chihiro; Furusawa, Hidemi; Nakahara, Hiroshi; Yamaguchi, Yukiko; Saitoh, Tomokazu; Yamamoto, Takashi; Komaki, Kansei

    2014-09-01

    The influence of human serum albumin (HSA) on the bile acid-mediated inhibition of liver microsomal type 1 11β-hydroxysteroid dehydrogenase (11β-HSD1) was studied in vitro. A rat liver microsomal fraction was prepared, and the 11β-HSD1 enzyme activity in the presence of various concentrations of bile acids and HSA was determined using hydrocortisone as the substrate. The products of the reaction were extracted and analyzed using high-performance liquid chromatography. The magnitude of the inhibition decreased with the addition of HSA in a dose-dependent manner. Four percent human albumin decreased the inhibitory effects of 100 μM chenodeoxycholic acid and lithocholic acid from 89.9 ± 5.6 to 54.5 ± 6.1% and from 83.8 ± 4.8 to 20.8 ± 4.2%, respectively. In contrast, ursodeoxycholic acid and deoxycholic acid showed no inhibitory effect on the enzyme activity in the presence of 4% human serum albumin, and the addition of 1% γ-globulin to the assay mixture in the presence of bile acids did not affect the enzyme activity. Our in vitro study showed that the addition of HSA ameliorated the inhibition of 11β-HSD1 and that the magnitude of the change is dependent on the species of bile acid, presumably based on the numbers of hydroxyl groups. These results suggest that HSA seems to protect the bile acid-mediated inhibition of 11β-HSD1 in the healthy subject. On the other hand, in the patients with obstructive biliary diseases, not only elevated serum bile acid but also the accompanying hypoalbuminemia is important to evaluate the pathophysiology of the bile acid-mediated inhibition of 11β-HSD1 of the disease.

  8. Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma

    PubMed Central

    Wentrup, Robert; Winkelmann, Nicola; Mitroshkin, Andrey; Prager, Matthias; Voderholzer, Winfried; Schachschal, Guido; Jürgensen, Christian; Büning, Carsten

    2016-01-01

    Background/Aims Standard treatments are not available for hilar nonresectable cholangiocarcinoma (NCC). It is unknown whether combination therapy of photodynamic therapy (PDT) plus systemic chemotherapy is superior to PDT alone. Methods We retrospectively reviewed 68 patients with hilar NCC treated with either PDT plus chemotherapy (PTD-C) or PDT monotherapy (PDT-M). The primary endpoint was the mean overall survival rate. Secondary endpoints included the 1-year survival rate, risk of cholangitic complications, and outcomes, which were evaluated according to the chemotherapy protocol. Results More than 90% of the study population had advanced hilar NCC Bismuth type III or IV. In the PDT-M group (n=35), the mean survival time was 374 days compared with 520 days in the PDT-C group (n=33, p=0.021). The 1-year survival rate was significantly higher in the PDT-C group compared with the PDT-M group (88% vs 58%, p=0.001) with a significant reduction of mortality (hazard ratio, 0.20; 95% confidence interval, 0.07 to 0.58; p=0.003). Gemcitabine monotherapy resulted in a shorter survival time compared with the gemcitabine combination therapy (mean, 395 days vs 566 days; p=0.09). Cholangitic complications were observed at a similar frequency in the PDT-C and PDT-M groups. Conclusions Combining repeated PDT with a gemcitabine-based combination therapy might offer a significant survival benefit in patients with hilar NCC. PMID:26814610

  9. Photodynamic control of human pathogenic parasites in aquatic ecosystems using chlorophyllin and pheophorbid as photodynamic substances.

    PubMed

    Wohllebe, S; Richter, R; Richter, P; Häder, D P

    2009-02-01

    When used at low concentrations and added to the water body, water-soluble chlorophyllin (resulting from chlorophyll after removal of the phytol) and pheophorbid (produced from chlorophyllin by acidification) are able to kill mosquito larvae and other small animals within a few hours under exposure of solar radiation. Under laboratory conditions, the use of chlorophyllin/pheophorbid as photodynamic substances for pest control in water bodies promises to be not only effective and ecologically beneficial but also cheap. The LD50 (50% of mortality in the tested organisms) value in Culex sp. larvae was about 6.88 mg/l, in Chaoborus sp. larvae about 24.18 mg/l, and in Daphnia 0.55 mg/l. The LD50 values determined for pheophorbid were 8.44 mg/l in Culex, 1.05 mg/l in Chaoborus, and 0.45 mg/l in Daphnia, respectively. In some cases, chlorophyllin and pheophorbid were also found to be (less) active in darkness. The results presented in this paper show that chlorophyllin is about a factor of 100 more effective than methylene blue or hematoporphyrine, which were tested earlier for the same purpose. It is also much cheaper and, as a substance found in every green plant, it is 100% biodegradable.

  10. Photodynamic therapy for the treatment of buccal candidiasis in rats.

    PubMed

    Junqueira, Juliana Campos; Martins, Joyce da Silva; Faria, Raquel Lourdes; Colombo, Carlos Eduardo Dias; Jorge, Antonio Olavo Cardoso

    2009-11-01

    The study objective was to evaluate the effects of photodynamic therapy on buccal candidiasis in rats. After experimental candidiasis had been induced on the tongue dorsum, 72 rats were distributed into four groups according to treatment: treated with laser and methylene blue photosensitizer (L+P+); treated only with laser (L+P-); treated only with photosensitizer (L--P+); not treated with laser or photosensitizer (L-P-). The rats were killed immediately, 1 day, or 5 days after treatment, for microscopic analysis of the tongue dorsum. Observation verified that the photodynamic therapy group (L+P+) exhibited fewer epithelial alterations and a lower chronic inflammatory response than the L-P- group. The group L+P- presented more intense epithelial alterations and chronic inflammatory response than the remaining groups. The L-P+ group showed tissue lesions similar to those of the L-P- group. In conclusion, rats treated with photodynamic therapy developed more discrete candidiasis lesions than did the remaining groups.

  11. Nanotechnology-Based Photodynamic Therapy: Concepts, Advances, and Perspectives.

    PubMed

    Garg, Tarun; Jain, Nitin K; Rath, Goutam; Goyal, Amit Kumar

    2015-01-01

    Photodynamic therapy (PDT) is a photoactive process that uses the combination of photosensitizers (PSs) and specific wavelengths of light for the treatment of solid tumors and other diseases. PDT received increased attention after regulatory approval of several photosensitizing drugs and light applicators worldwide. With the advent of newer PSs, the role of PDT in the treatment of cancer and other diseases has been revolutionized. In addition, various targeting strategies developed for site-specific delivery of PSs will be helpful for avoiding phototoxicity to normal tissues. Receptor-mediated targeted PDT approaches using nanocarriers offer the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. At present, clinical application of PDT is well established in medicine and surgery. Successfully used in dermatology, urology, gastroenterology, and neurosurgery, PDT has also seen much progress in basic sciences and clinical photodynamics in recent years. Currently, the use of PDT is just beginning, and more research must be performed to prove its therapeutic efficacy. However, nontoxic compounds involved in PDT provide a certain hope that it will evolve to be an effective mechanism for combating chronic diseases.

  12. Effects of telomerase expression on photodynamic therapy of Barrett's esophagus

    NASA Astrophysics Data System (ADS)

    Wang, Kenneth K.; Anderson, Marlys; Buttar, Navtej; WongKeeSong, Louis-Michel; Borkenhagen, Lynn; Lutzke, Lori

    2003-06-01

    Photodynamic therapy has been applied to Barrett's esophagus and has been shown in prospective randomized studies to eliminate dysplasia as well as decrease the occurrence of cancer. However, the therapy isnot always effective and there are issues with residual areas of Barrett's mucosa despite therapy. There has not been a good explanation for these residual areas and they seem to imply that there may exist a biological mechanisms by which these cells may be resistant to photodynamic therapy. It was our aim to determine if known abnormalities in Barrett's mucosa could be correlated with the lack of response of some of these tissues. We examined the tissue from mulitpel patients who had resonse to therapy as well as those who did not respond. We assessed the tissue for p53 mutations, inactivatino of p16, ploidy status, cell proliferation, telomerase activity, and degree of dysplasia. Interestingly, the only genetic marker than was found to be correlated with lack of reonse was p53 and telomerase activity. This suggests that cells that have lost mechanisms for cell death such as apoptosis or telomere shortengin may be more resistant to photodynamic therapy. In this study, we examined patients before and after PDT for telomerase activity.

  13. Protoporphyrin IX fluorescence for enhanced photodynamic diagnosis and photodynamic therapy in murine models of skin and breast cancer

    NASA Astrophysics Data System (ADS)

    Rollakanti, Kishore Reddy

    Protoporphyrin IX (PpIX) is a photosensitizing agent derived from aminolevulinic acid. PpIX accumulates specifically within target cancer cells, where it fluoresces and produces cytotoxic reactive oxygen species. Our aims were to employ PpIX fluorescence to detect squamous cell carcinoma (SCC) of the skin (Photodynamic diagnosis, PDD), and to improve treatment efficacy (Photodynamic therapy, PDT) for basal cell carcinoma (BCC) and cutaneous breast cancer. Hyperspectral imaging and a spectrometer based dosimeter system were used to detect very early SCC in UVB-irradiated murine skin, using PpIX fluorescence. Regarding PDT, we showed that low non-toxic doses of vitamin D, given before ALA application, increase tumor specific PpIX accumulation and sensitize BCC and breast cancer cells to ALA-PDT. These optical imaging methods and the combination therapy regimen (vitamin D and ALA-PDT) are promising tools for effective management of skin and breast cancer.

  14. Studies of lipid peroxidation of rat blood after in vivo photodynamic treatment

    NASA Astrophysics Data System (ADS)

    Yanina, Irina Yu.; Navolokin, Nikita A.; Nikitina, Victoria V.; Bucharskaya, Alla B.; Maslyakova, Galina N.; Tuchin, Valery V.

    2011-10-01

    Lipid peroxidation (LP) of blood serum of laboratory animals after in vivo photodynamic treatment was investigated. To determine changes in LP the standard colorimetric test OXYSTAT was used. The results indicate an increase in the intensity of free radical generation in tissues induced by photodynamic treatment.

  15. Studies of lipid peroxidation of rat blood after in vivo photodynamic treatment

    NASA Astrophysics Data System (ADS)

    Yanina, Irina Yu.; Navolokin, Nikita A.; Nikitina, Victoria V.; Bucharskaya, Alla B.; Maslyakova, Galina N.; Tuchin, Valery V.

    2012-03-01

    Lipid peroxidation (LP) of blood serum of laboratory animals after in vivo photodynamic treatment was investigated. To determine changes in LP the standard colorimetric test OXYSTAT was used. The results indicate an increase in the intensity of free radical generation in tissues induced by photodynamic treatment.

  16. Efficient Photodynamic Therapy on Human Retinoblastoma Cell Lines

    PubMed Central

    Walther, Jan; Schastak, Stanislas; Dukic-Stefanovic, Sladjana; Wiedemann, Peter; Neuhaus, Jochen; Claudepierre, Thomas

    2014-01-01

    Photodynamic therapy (PDT) has shown to be a promising technique to treat various forms of malignant neoplasia. The photodynamic eradication of the tumor cells is achieved by applying a photosensitizer either locally or systemically and following local activation through irradiation of the tumor mass with light of a specific wavelength after a certain time of incubation. Due to preferential accumulation of the photosensitizer in tumor cells, this procedure allows a selective inactivation of the malignant tumor while sparing the surrounding tissue to the greatest extent. These features and requirements make the PDT an attractive therapeutic option for the treatment of retinoblastoma, especially when surgical enucleation is a curative option. This extreme solution is still in use in case of tumours that are resistant to conventional chemotherapy or handled too late due to poor access to medical care in less advanced country. In this study we initially conducted in-vitro investigations of the new cationic water-soluble photo sensitizer tetrahydroporphyrin-tetratosylat (THPTS) regarding its photodynamic effect on human Rb-1 and Y79 retinoblastoma cells. We were able to show, that neither the incubation with THPTS without following illumination, nor the sole illumination showed a considerable effect on the proliferation of the retinoblastoma cells, whereas the incubation with THPTS combined with following illumination led to a maximal cytotoxic effect on the tumor cells. Moreover the phototoxicity was lower in normal primary cells from retinal pigmented epithelium demonstrating a higher phototoxic effect of THPTS in cancer cells than in this normal retinal cell type. The results at hand form an encouraging foundation for further in-vivo studies on the therapeutic potential of this promising photosensitizer for the eyeball and vision preserving as well as potentially curative therapy of retinoblastoma. PMID:24498108

  17. Aminophthalocyanine-Mediated Photodynamic Inactivation of Leishmania tropica.

    PubMed

    Al-Qahtani, Ahmed; Alkahtani, Saad; Kolli, Bala; Tripathi, Pankaj; Dutta, Sujoy; Al-Kahtane, Abdullah A; Jiang, Xiong-Jie; Ng, Dennis K P; Chang, Kwang Poo

    2016-04-01

    Photodynamic inactivation ofLeishmaniaspp. requires the cellular uptake of photosensitizers, e.g., endocytosis of silicon(IV)-phthalocyanines (PC) axially substituted with bulky ligands. We report here that when substituted with amino-containing ligands, the PCs (PC1 and PC2) were endocytosed and displayed improved potency againstLeishmania tropicapromastigotes and axenic amastigotesin vitro The uptake of these PCs by bothLeishmaniastages followed saturation kinetics, as expected. Sensitive assays were developed for assessing the photodynamic inactivation ofLeishmaniaspp. by rendering them fluorescent in two ways: transfecting promastigotes to express green fluorescent protein (GFP) and loading them with carboxyfluorescein succinimidyl ester (CFSE). PC-sensitizedLeishmania tropicastrains were seen microscopically to lose their motility, structural integrity, and GFP/CFSE fluorescence after exposure to red light (wavelength, ∼650 nm) at a fluence of 1 to 2 J cm(-2) Quantitative fluorescence assays based on the loss of GFP/CFSE from liveLeishmania tropicashowed that PC1 and PC2 dose dependently sensitized both stages for photoinactivation, consistent with the results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay.Leishmania tropicastrains are >100 times more sensitive than their host cells or macrophages to PC1- and PC2-mediated photoinactivation, judging from the estimated 50% effective concentrations (EC50s) of these cells. Axial substitution of the PC with amino groups instead of other ligands appears to increase its leishmanial photolytic activity by up to 40-fold. PC1 and PC2 are thus potentially useful for photodynamic therapy of leishmaniasis and for oxidative photoinactivation ofLeishmaniaspp. for use as vaccines or vaccine carriers.

  18. Aminophthalocyanine-Mediated Photodynamic Inactivation of Leishmania tropica

    PubMed Central

    Al-Qahtani, Ahmed; Alkahtani, Saad; Kolli, Bala; Tripathi, Pankaj; Dutta, Sujoy; Al-Kahtane, Abdullah A.; Jiang, Xiong-Jie; Ng, Dennis K. P.

    2016-01-01

    Photodynamic inactivation of Leishmania spp. requires the cellular uptake of photosensitizers, e.g., endocytosis of silicon(IV)-phthalocyanines (PC) axially substituted with bulky ligands. We report here that when substituted with amino-containing ligands, the PCs (PC1 and PC2) were endocytosed and displayed improved potency against Leishmania tropica promastigotes and axenic amastigotes in vitro. The uptake of these PCs by both Leishmania stages followed saturation kinetics, as expected. Sensitive assays were developed for assessing the photodynamic inactivation of Leishmania spp. by rendering them fluorescent in two ways: transfecting promastigotes to express green fluorescent protein (GFP) and loading them with carboxyfluorescein succinimidyl ester (CFSE). PC-sensitized Leishmania tropica strains were seen microscopically to lose their motility, structural integrity, and GFP/CFSE fluorescence after exposure to red light (wavelength, ∼650 nm) at a fluence of 1 to 2 J cm−2. Quantitative fluorescence assays based on the loss of GFP/CFSE from live Leishmania tropica showed that PC1 and PC2 dose dependently sensitized both stages for photoinactivation, consistent with the results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay. Leishmania tropica strains are >100 times more sensitive than their host cells or macrophages to PC1- and PC2-mediated photoinactivation, judging from the estimated 50% effective concentrations (EC50s) of these cells. Axial substitution of the PC with amino groups instead of other ligands appears to increase its leishmanial photolytic activity by up to 40-fold. PC1 and PC2 are thus potentially useful for photodynamic therapy of leishmaniasis and for oxidative photoinactivation of Leishmania spp. for use as vaccines or vaccine carriers. PMID:26824938

  19. Three-dimensional illumination procedure for photodynamic therapy of dermatology

    NASA Astrophysics Data System (ADS)

    Hu, Xiao-ming; Zhang, Feng-juan; Dong, Fei; Zhou, Ya

    2014-09-01

    Light dosimetry is an important parameter that affects the efficacy of photodynamic therapy (PDT). However, the irregular morphologies of lesions complicate lesion segmentation and light irradiance adjustment. Therefore, this study developed an illumination demo system comprising a camera, a digital projector, and a computing unit to solve these problems. A three-dimensional model of a lesion was reconstructed using the developed system. Hierarchical segmentation was achieved with the superpixel algorithm. The expected light dosimetry on the targeted lesion was achieved with the proposed illumination procedure. Accurate control and optimization of light delivery can improve the efficacy of PDT.

  20. Photodynamic therapy with laser scanning mode of tumor irradiation

    NASA Astrophysics Data System (ADS)

    Chepurna, Oksana; Shton, Irina; Kholin, Vladimir; Voytsehovich, Valerii; Popov, Viacheslav; Pavlov, Sergii; Gamaleia, Nikolai; Wójcik, Waldemar; Zhassandykyzy, Maral

    2015-12-01

    In this study we propose a new version of photodynamic therapy performed by laser scanning. The method consists in tumor treatment by a light beam of a small cross section which incrementally moves through the chosen area with a defined delay at each point and repetitively re-scans a zone starting from the initial position. Experimental evaluation of the method in vitro on murine tumor model showed that despite the dose, applied by scanning irradiation mode, was 400 times lower, the tumor inhibition rate conceded to attained with continuous irradiation mode by only 20%.

  1. THE PHOTODYNAMIC ACTION OF EOSIN AND ERYTHROSIN UPON SNAKE VENOM

    PubMed Central

    Noguchi, Hideyo

    1906-01-01

    Since the hæmolysins of the several venoms respond differently to photodynamic action, they may be regarded as possessing different chemical constitutions. As regards stability, cobra hæmolysin ranks first, daboia second, and Crotalus third. The toxicity of all the venoms is more or less diminished by eosin and erythrosin in sunlight. This reduction in toxicity depends upon chemical changes, of more or less profound nature, taking place in certain of the active principles of the venom. The more stabile the predominant active principles the less the reduction in toxicity, and vice versa. Venom-neurotoxins are highly resistant to photodynamic action, venom-hæmolysins are less resistant, while the hæmorrhagin and thrombokinase of Crotalus and daboia venoms exhibit weak powers of resistance to their action. Hence it follows that while cobra venom remained almost unaltered, rattlesnake and daboia venoms were greatly reduced in toxicity when mixed with the fluorescent dyes and exposed to sunlight. There is an interesting parallel between the action of eosin and erythrosin upon the different venoms and their reactions to other injurious agencies. For example, the hæmolysins of cobra and daboia venoms are more heat resistant than the hæmolysin of Crotalus venom, and the former are less injured by the dyes than the latter. The neurotoxin of the former venoms is also more heat stabile than that of the rattlesnake, and the same relative degree of resistance holds for this substance and the anilines. Just as the hæmorrhagin of rattlesnake venom and the thrombokinase of daboia venom are destroyed by a temperature of 75° C., so are they readily inactivated by the photo dynamic substances employed. The globulin-precipitating and blood corpuscle-protecting principle of cobra venom is relatively thermostabile and in contradistinction to the immunity-precipitins it is also unaffected by eosin and erythrosin. This study of the action of photodynamic substances upon snake

  2. Synthesis, bioanalysis and biodistribution of photosensitizer conjugates for photodynamic therapy

    PubMed Central

    Denis, Tyler GSt; Hamblin, Michael R

    2013-01-01

    Photodynamic therapy (PDT) was discovered in 1900 by Raab, and has since emerged as a promising tool for treating diseases characterized by unwanted cells or hyperproliferating tissue (e.g., cancer or infectious disease). PDT consists of the light excitation of a photosensitizer (PS) in the presence of O2 to yield highly reactive oxygen species. In recent years, PDT has been improved by the synthesis of targeted bioconjugates between monoclonal antibodies and PS, and by investigating PS biodistribution and PD. Here, we provide a comprehensive review of major developments in PS-immunoconjugate-based PDT and the bioanalysis of these agents, with a specific emphasis on anticancer and antimicrobial PDT. PMID:23641699

  3. 3D Monte Carlo radiation transfer modelling of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Campbell, C. Louise; Christison, Craig; Brown, C. Tom A.; Wood, Kenneth; Valentine, Ronan M.; Moseley, Harry

    2015-06-01

    The effects of ageing and skin type on Photodynamic Therapy (PDT) for different treatment methods have been theoretically investigated. A multilayered Monte Carlo Radiation Transfer model is presented where both daylight activated PDT and conventional PDT are compared. It was found that light penetrates deeper through older skin with a lighter complexion, which translates into a deeper effective treatment depth. The effect of ageing was found to be larger for darker skin types. The investigation further strengthens the usage of daylight as a potential light source for PDT where effective treatment depths of about 2 mm can be achieved.

  4. Photodynamic therapy (PDT) of cancer: from local to systemic treatment.

    PubMed

    Dąbrowski, Janusz M; Arnaut, Luis G

    2015-10-01

    Photodynamic therapy (PDT) requires a medical device, a photosensitizing drug and adequate use of both to trigger biological mechanisms that can rapidly destroy the primary tumour and provide long-lasting protection against metastasis. We present a multidisciplinary view of the issues raised by the development of PDT. We show how spectroscopy, photophysics, photochemistry and pharmacokinetics of photosensitizers determine the mechanism of cell death and clinical protocols. Various examples of combinations with chemotherapies and immunotherapies illustrate the opportunities to potentiate the outcome of PDT. Particular emphasis is given to the mechanisms that can be exploited to establish PDT as a systemic treatment of solid tumours and metastatic disease.

  5. Photodynamic Therapy Using Endogenous Photosensitization for Gastrointestinal Tumors

    PubMed Central

    Webber, John; Kessel, David; Fromm, David

    1997-01-01

    Photodynamic therapy (PDT) is a novel approach in the treatment of carcinomas of the gastrointestinal tract. This review defines PDT, discusses means of photosensitization and considers the mechanisms by which PDT causes cell death of the target tissue while at the same time avoid damage to normal tissues. Additional considerations include the time of PDT application, activation of the photosensitizer, effectiveness and toxicity of PDT, potential need for additional modalities of treatment and concludes with application of PDT principals to the early detection of malignancy. Data regarding the long term effectiveness of PDT for digestive tract adenocarcinomas are lacking because this field is still in its infancy.

  6. Spectroscopic evaluation of photodynamic therapy of the intraperitoneal cavity

    NASA Astrophysics Data System (ADS)

    Finlay, Jarod C.; Sandell, Julia L.; Zhu, Timothy C.; Lewis, Robert; Cengel, Keith A.; Hahn, Stephen M.

    2010-02-01

    We present the results of spectroscopic measurements of diffuse reflectance and fluorescence before and after photodynamic therapy of healthy canine peritoneal cavity. Animals were treated intra-operatively after iv injection of the benzoporphyrin derivative (BPD). The small bowel was treated using a uniform light field projected by a microlens-tipped fiber. The cavity was then filled with scattering medium and the remaining organs were treated using a moving diffuser. Diffuse reflectance and fluorescence measurements were made using a multi-fiber optical probe positioned on the surface of various tissues within the cavity before and after illumination. The measured data were analyzed to quantify hemoglobin concentration and oxygenation and sensitizer concentration.

  7. Spectroscopic evaluation of photodynamic therapy of the intraperitoneal cavity

    PubMed Central

    Finlay, Jarod C.; Sandell, Julia L.; Zhu, Timothy C.; Lewis, Robert; Cengel, Keith A.; Hahn, Stephen M.

    2015-01-01

    We present the results of spectroscopic measurements of diffuse reflectance and fluorescence before and after photodynamic therapy of healthy canine peritoneal cavity. Animals were treated intra-operatively after iv injection of the benzoporphyrin derivative (BPD). The small bowel was treated using a uniform light field projected by a microlenstipped fiber. The cavity was then filled with scattering medium and the remaining organs were treated using a moving diffuser. Diffuse reflectance and fluorescence measurements were made using a multi-fiber optical probe positioned on the surface of various tissues within the cavity before and after illumination. The measured data were analyzed to quantify hemoglobin concentration and oxygenation and sensitizer concentration. PMID:26028798

  8. On molecular mechanism of the photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Mostovnikov, Vasili A.; Mostovnikova, Galina R.; Plavski, Vitali Y.; Tretjakov, S. A.

    1995-01-01

    In this work we present the experimental results indicating that the photodestruction (inactivation) of glycolysis enzymes located in mitochondria and responsible for the energy providing of malignant tumors, could serve as a possible molecular mechanism of a photodynamic therapy of cancer. The formation of complexes between the glycolysis enzymes and sensitizer favors can lead to an effective photodestruction of the former [in the experiments lactate dehydrogenase (LDH), pyruvate kinase (PK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and water-soluble tetra(carboxiphenyl)porphyrine [T(CP)P] (the analogue of coprorphyrin) were used as photosensitizer.

  9. HpD Photobiology And Photodynamic Therapy Of Bladder Carcinoma

    NASA Astrophysics Data System (ADS)

    Lin, Chi-Wei

    1988-02-01

    Bladder carcinoma is considered one of the most favorable targets for the application of photodynamic therapy (PDT) due to the accessibility of the bladder for light delivery. Examination of the bladder and surgical procedures are routinely performed by the insertion of an optical instrument called cystoscope through the urethra. Thus, the treatment of bladder cancer by PDT can be conducted through the cystoscope with minimal invasion. However, to achieve optimal results from this treatment, one must consider both the structure of the bladder and the nature of the carcinoma.

  10. [Gorlin syndrome: photodynamic therapy, as a useful adjunct to surgery].

    PubMed

    Huguier, V; Wierzbicka-Hainaut, E; Fray, J; Guillet, G; Dagrégorio, G

    2012-04-01

    Gorlin syndrome, also called nevoid basal cell carcinoma syndrome, is well known by dermatologists. Since its onset, 10 years ago, photodynamic therapy has found new applications and is now currently used to cure single or multiple basal cell carcinomas, with good results and without residual scars. We recall some of the basic principles of this technique, as well as its indications in Gorlin syndrome, which we illustrate with one case. Plastic surgeons must consider this relatively new technique, developed by dermatologists, as a useful adjunct to surgery in the management of Gorlin syndrome.

  11. Upconversion nanoparticles for photodynamic therapy and other cancer therapeutics.

    PubMed

    Wang, Chao; Cheng, Liang; Liu, Zhuang

    2013-01-01

    Photodynamic therapy (PDT) is a non-invasive treatment modality for a variety of diseases including cancer. PDT based on upconversion nanoparticles (UCNPs) has received much attention in recent years. Under near-infrared (NIR) light excitation, UCNPs are able to emit high-energy visible light, which can activate surrounding photosensitizer (PS) molecules to produce singlet oxygen and kill cancer cells. Owing to the high tissue penetration ability of NIR light, NIR-excited UCNPs can be used to activate PS molecules in much deeper tissues compared to traditional PDT induced by visible or ultraviolet (UV) light. In addition to the application of UCNPs as an energy donor in PDT, via similar mechanisms, they could also be used for the NIR light-triggered drug release or activation of 'caged' imaging or therapeutic molecules. In this review, we will summarize the latest progresses regarding the applications of UCNPs for photodynamic therapy, NIR triggered drug and gene delivery, as well as several other UCNP-based cancer therapeutic approaches. The future prospects and challenges in this emerging field will be also discussed.

  12. Complexing Methylene Blue with Phosphorus Dendrimers to Increase Photodynamic Activity.

    PubMed

    Dabrzalska, Monika; Janaszewska, Anna; Zablocka, Maria; Mignani, Serge; Majoral, Jean Pierre; Klajnert-Maculewicz, Barbara

    2017-02-23

    The efficiency of photodynamic therapy is limited mainly due to low selectivity, unfavorable biodistribution of photosensitizers, and long-lasting skin sensitivity to light. However, drug delivery systems based on nanoparticles may overcome the limitations mentioned above. Among others, dendrimers are particularly attractive as carriers, because of their globular architecture and high loading capacity. The goal of the study was to check whether an anionic phosphorus dendrimer is suitable as a carrier of a photosensitizer-methylene blue (MB). As a biological model, basal cell carcinoma cell lines were used. We checked the influence of the MB complexation on its singlet oxygen production ability using a commercial fluorescence probe. Next, cellular uptake, phototoxicity, reactive oxygen species (ROS) generation, and cell death were investigated. The MB-anionic dendrimer complex (MB-1an) was found to generate less singlet oxygen; however, the complex showed higher cellular uptake and phototoxicity against basal cell carcinoma cell lines, which was accompanied with enhanced ROS production. Owing to the obtained results, we conclude that the photodynamic activity of MB complexed with an anionic dendrimer is higher than free MB against basal cell carcinoma cell lines.

  13. Metal nanoparticles amplify photodynamic effect on skin cells in vitro

    NASA Astrophysics Data System (ADS)

    Bauer, Brigitte; Chen, Si; Käll, Mikael; Gunnarsson, Linda; Ericson, Marica B.

    2011-03-01

    We report on an investigation aimed to increase the efficiency of photodynamic therapy (PDT) through the influence of localized surface plasmon resonances (LSPR's) in metal nanoparticles. PDT is based on photosensitizers that generate singlet oxygen at the tumour site upon exposure to visible light. Although PDT is a well-established treatment for skin cancer, a major drawback is the low quantum yield for singlet-oxygen production. This motivates the development of novel methods that enhance singlet oxygen generation during treatment. In this context, we study the photodynamic effect on cultured human skin cells in the presence or absence of gold nanoparticles with well established LSPR and field-enhancement properties. The cultured skin cells were exposed to protoporphyrin IX and gold nanoparticles and subsequently illuminated with red light. We investigated the differences in cell viability by tuning different parameters, such as incubation time and light dose. In order to find optimal parameters for specific targeting of tumour cells, we compared normal human epidermal keratinocytes with a human squamous skin cancer cell line. The study indicates significantly enhanced cell death in the presence of nanoparticles and important differences in treatment efficiency between normal and tumour cells. These results are thus promising and clearly motivate further development of nanoparticle enhanced clinical PDT treatment.

  14. Merocyanine-540 mediated photodynamic effects on Staphylococcus epidermidis biofilms

    NASA Astrophysics Data System (ADS)

    Sbarra, Maria Sonia; Di Poto, Antonella; Saino, Enrica; Visai, Livia; Minzioni, Paolo; Bragheri, Francesca; Cristiani, Ilaria

    2009-07-01

    Staphylococci are important causes of nosocomial and medical-device-related infections. Their virulence is attributed to the elaboration of biofilms that protect the organisms from immune system clearance and to increased resistance to phagocytosis and antibiotics. Photodynamic treatment (PDT) has been proposed as an alternative approach for the inactivation of bacteria in biofilms. In this study, we evaluated the antimicrobial activity of merocyanine 540 (MC 540), a photosensitizing dye that is used for purging malignant cells from autologous bone marrow grafts, against Staphylococcus epidermidis biofilms. We evaluated the effect of the combined photodynamic action of MC 540 and 532 nm laser on the viability and structure of biofilms of two Staphylococcus epidermidis strains. Significant inactivation of cells was observed in the biofilms treated with MC-540 and then exposed to laser radiation. Furthermore we found that the PDT effect, on both types of cells, was significantly dependent on both the light-dose and on the impinging lightintensity. Disruption of PDT-treated biofilm was confirmed by scanning electron microscopy (SEM).

  15. Pulmonary decontamination for photodynamic inactivation with extracorporeal illumination

    NASA Astrophysics Data System (ADS)

    Geralde, Mariana C.; Leite, Ilaiáli S.; Inada, Natalia M.; Grecco, Clóvis; Medeiros, Alexandra I.; Kurachi, Cristina; Bagnato, Vanderlei S.

    2014-03-01

    Infectious pneumonia is a major cause of morbidity and mortality, despite advances in diagnostics and therapeutics in pulmonary infections. One of the major difficulties associated with the infection comes from the high rate of antibiotic resistant microorganisms, claiming for the use of alternative techniques with high efficiency and low cost. The photodynamic inactivation (PDI) is emerging as one of the great possibilities in this area, once its action is oxidative, not allowing microorganism develops resistance against the treatment. PDI for decontamination pulmonary has potential for treatment or creating better conditions for the action of antibiotics. In this study, we are developing a device to implement PDI for the treatment of lung diseases with extracorporeal illumination. To validate our theory, we performed measurements in liquid phantom to simulate light penetration in biological tissues at various fluency rates, the temperature was monitored in a body of hairless mice and the measurements of light transmittance in this same animal model. A diode laser emitting at 810 nm in continuous mode was used. Our results show 70% of leakage at 0.5 mm of thickness in phantom model. The mouse body temperature variation was 5.4 °C and was observed light transmittance through its chest. These results are suggesting the possible application of the extracorporeal illumination using infrared light source. Based on these findings, further studies about photodynamic inactivation will be performed in animal model using indocyanine green and bacteriochlorin as photosensitizers. The pulmonary infection will be induced with Streptococcus pneumoniae and Klebsiella pneumoniae.

  16. Targeted photodynamic therapy for infected wounds in mice

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; O'Donnell, David A.; Zahra, Touqir; Contag, Christopher H.; McManus, Albert T.; Hasan, Tayyaba

    2002-06-01

    Although many workers have used photodynamic therapy to kill bacteria in vitro, the use of this approach has seldom been reported in vivo in animal models of infection. We report on the use of a targeted polycationic photosensitizer conjugate between poly-L-lysine and chlorin(e6) that can penetrate the Gram (-) outer membrane together with red laser light to kill Escherichia coli and Pseudomonas aeruginosa infecting excisional wounds in mice. We used genetically engineered luminescent bacteria that allowed the infection to be imaged in mouse wounds using a sensitive CCD camera. Wounds were infected with 5x106 bacteria, followed by application of the conjugate in solution and illumination. There was a light-dose dependent loss of luminescence as measured by image analysis in the wound treated with conjugate and light, not seen in control wounds. This strain of E coli is non-invasive and the infection in untreated wounds spontaneously resolved in a few days and all wounds healed equally well showing the photodynamic treatment did not damage the host tissue. P aeruginosa is highly invasive and mice with untreated or control wounds all died while 90% of PDT treated mice survived. PDT may have a role to play in the rapid treatment of infected wounds in view of the worldwide rise in antibiotic resistance.

  17. Upconversion Nanoparticles for Photodynamic Therapy and Other Cancer Therapeutics

    PubMed Central

    Wang, Chao; Cheng, Liang; Liu, Zhuang

    2013-01-01

    Photodynamic therapy (PDT) is a non-invasive treatment modality for a variety of diseases including cancer. PDT based on upconversion nanoparticles (UCNPs) has received much attention in recent years. Under near-infrared (NIR) light excitation, UCNPs are able to emit high-energy visible light, which can activate surrounding photosensitizer (PS) molecules to produce singlet oxygen and kill cancer cells. Owing to the high tissue penetration ability of NIR light, NIR-excited UCNPs can be used to activate PS molecules in much deeper tissues compared to traditional PDT induced by visible or ultraviolet (UV) light. In addition to the application of UCNPs as an energy donor in PDT, via similar mechanisms, they could also be used for the NIR light-triggered drug release or activation of 'caged' imaging or therapeutic molecules. In this review, we will summarize the latest progresses regarding the applications of UCNPs for photodynamic therapy, NIR triggered drug and gene delivery, as well as several other UCNP-based cancer therapeutic approaches. The future prospects and challenges in this emerging field will be also discussed. PMID:23650479

  18. Fluorescence Imaging and Photodynamic Therapy of Skin Cancer

    NASA Astrophysics Data System (ADS)

    Rosen, Arne; Ericsson, Marica; Grapengiesser, Sofia; Gudmundson, Fredrik; Larko, Olle; Mölne, Lena; Stenquist, Bo; Ternesten, Annika; Wennberg, Ann-Marie

    2000-03-01

    Fluorescence Imaging and Photodynamic Therapy of Skin Cancer Photodynamic therapy has become an interesting alternative to conventional therapy of skin cancer as basal cell carcinoma, BCC. Delta-aminolevulinic acid, ALA, is a precursor in the biosynthesis of protoporphyrin IX, Ph IX, which accumulates to a large extent in tumor tissue. We have compared in vivo Ph IX, fluorescence with the extent of BCC on the face, trunk and thigh etc determined by histological mapping in a number of lesions. A non-laser-based set-up (1) was used to record the fluorescence images. The time for application of ALA was varied to optimize the uptake and the contrast in fluorescence between tumor attached and healthy skin. In more than 50 correlation between the fluorescence imaging and histological pattern. The contrast in fluorescence between tumor and healthy skin seems to be highr for older patients. Work is in progress to develope routines for optimization of the contrast. 1. A-M Wennberg et al, Acta Derm Venereol(Stockh) 1999, 79:54-61.

  19. Photodynamic research at Baylor University Medical Center Dallas, Texas

    NASA Astrophysics Data System (ADS)

    Gulliya, Kirpal S.; Matthews, James Lester; Sogandares-Bernal, Franklin M.; Aronoff, Billie L.; Judy, Millard M.

    1993-03-01

    We received our first CO2 laser at Baylor University Medical Center in December 1974, following a trip to Israel in January of that year. Discussion with the customs office of the propriety of charging an 18% import tax lasted for nine months. We lost that argument. Baylor has been using lasers of many types for many procedures since that time. About ten years ago, through the kindness of Tom Dougherty and Roswell Park, we started working with photodynamic therapy, first with hematoporphyrin I and later with dihematoporphyrin ether (II). In February 1984, we were invited to a conference at Los Alamos, New Mexico, U.S.A. on medical applications of the free electron laser as part of the Star Wars Program. A grant application from Baylor was approved that November, but funding did not start for many months. This funding contributed to the development of a new research center as part of Baylor Research Institute. Many of the projects investigated at Baylor dealt with applications of the free electron laser (FEL), after it became available. A staff was assembled and many projects are still ongoing. I would like to outline those which are in some way related to photodynamic therapy.

  20. Treatment of spontaneously occurring veterinary tumors with photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Panjehpour, Masoud; Legendre, Alfred; Sneed, Rick E.; Overholt, Bergein F.

    1992-06-01

    Chloroaluminum phthalocyanine tetrasulfonate was administered intravenously (1.0 mg/kg) to client owned cats and a dog with spontaneously occurring squamous cell carcinoma of head and neck. Light was delivered 48 hours post injection of the photosensitizer. An argon- pumped dye-laser was used to illuminate the lesions with 675 nm light delivered through a microlens fiber and/or a cylindrical diffuser. The light dose was 100 J/cm2 superficially or 300 J/cm interstitially. Eleven photodynamic therapy treatments in seven cats and one dog were performed. Two cats received a second treatment in approximately sixty days after the initial treatment. The superficial dose of light was increased to 200 J/cm2 for the second treatment. While the longest follow-up is twelve months, the responses are encouraging. The dog had a complete response. Among the cats, three showed complete response, three showed partial response and one showed no response. One cat expired two days post treatment. It is early to evaluate the response in two cats that received second treatments. Photodynamic therapy with chloroaluminum phthalocyanine tetrasulfonate was effective in treating squamous cell carcinoma in pet animals.

  1. Photodynamic inactivation of contaminated blood with Staphylococcus aureus

    NASA Astrophysics Data System (ADS)

    Corrêa, Thaila Q.; Inada, Natalia M.; Pratavieira, Sebastião.; Blanco, Kate C.; Kurachi, Cristina; Bagnato, Vanderlei S.

    2016-03-01

    The presence of bacteria in the bloodstream can trigger a serious systemic inflammation and lead to sepsis that cause septic shock and death. Studies have shown an increase in the incidence of sepsis over the years and it is mainly due to the increased resistance of microorganisms to antibiotics, since these drugs are still sold and used improperly. The bacterial contamination of blood is also a risk to blood transfusions. Thus, bacteria inactivation in blood is being studied in order to increase the security of the blood supply. The purpose of this study was to decontaminate the blood using the photodynamic inactivation (PDI). Human blood samples in the presence of Photogem® were illuminated at an intensity of 30 mW/cm2, and light doses of 10 and 15 J/cm2. Blood counts were carried out for the quantitative evaluation and blood smears were prepared for qualitative and morphological evaluation by microscopy. The results showed normal viability values for the blood cells analyzed. The light doses showed minimal morphological changes in the membrane of red blood cells, but the irradiation in the presence of the photosensitizer caused hemolysis in red blood cells at the higher concentrations of the photosensitizer. Experiments with Staphylococcus aureus, one of the responsible of sepsis, showed 7 logs10 of photodynamic inactivation with 50 μg/mL and 15 J/cm2 and 1 log10 of this microorganism in a co-culture with blood.

  2. Photodynamic evaluation of tetracarboxy-phthalocyanines in model systems.

    PubMed

    Alonso, Lais; Sampaio, Renato N; Souza, Thalita F M; Silva, Rodrigo C; Neto, Newton M Barbosa; Ribeiro, Anderson O; Alonso, Antonio; Gonçalves, Pablo J

    2016-08-01

    The present work reports the synthesis, photophysical and photochemical characterization and photodynamic evaluation of zinc, aluminum and metal free-base tetracarboxy-phthalocyanines (ZnPc, AlPc and FbPc, respectively). To evaluate the possible application of phthalocyanines as a potential photosensitizer the photophysical and photochemical characterization were performed using aqueous (phosphate-buffered solution, PBS) and organic (dimethyl sulfoxide, DMSO) solvents. The relative lipophilicity of the compounds was estimated by the octanol-water partition coefficient and the photodynamic activity evaluated through the photooxidation of a protein and photohemolysis. The photooxidation rate constants (k) were obtained and the hemolytic potential was evaluated by the maximum percentage of hemolysis achieved (Hmax) and the time (t50) to reach 50% of the Hmax. Although these phthalocyanines are all hydrophilic and possess very low affinity for membranes (log PO/W=-2.0), they led to significant photooxidation of bovine serum albumin (BSA) and photohemolysis. Our results show that ZnPc was the most efficient photosensitizer, followed by AlPc and FbPc; this order is the same as the order of the triplet and singlet oxygen quantum yields (ZnPc>AlPc>FbPc). Furthermore, together, the triplet, fluorescence and singlet oxygen quantum yields of zinc tetracarboxy-phthalocyanines suggest their potential for use in theranostic applications, which simultaneously combines photodiagnosis and phototherapy.

  3. Phthalocyanines And Their Sulfonated Derivatives As Photosensitizers In Photodynamic Therapy.

    NASA Astrophysics Data System (ADS)

    Riesz, Peter; Krishna, C. Murali

    1988-02-01

    Photodynamic therapy (PDT) of human tumors with hematoporphyrin derivative (HpD) has achieved encouraging results. However, HpD is a complex mixture whose composition varies in different preparations and with time of storage. The future promise of PDT for cancer treatment depends on the development of new chemically defined sensitizers which absorb more strongly than HpD in the 600-800 nm region. A shift to higher wavelengths is desirable since it allows increased light penetration in human tissues. In vivo, these sensitizers should be non-toxic, localize selectively in tumors and generate cytotoxic species upon illumination with a high quantum yield. These damaging species may be singlet oxygen (1O2) produced by the transfer of energy from the triplet state of the sensitizer to oxygen (Type II) or superoxide anion radicals formed by electron transfer to oxygen or substrate radicals generated by electron or hydrogen transfer directly from the sensitizer (Type I). The recent work of several groups indicating that phthalocyanines and their water soluble derivatives are promising candidates for PDT is reviewed. The photophysics, photochemistry, photosensitized killing of cultured mammalian cells and the use for in vivo photodynamic therapy of phthalocyanines is outlined. Our studies of the post-illumination photohemolysis of human red blood cells as a model system for membrane photomodification sensitized by phthalocyanine sulfonates are consistent with the predominant role of 1O2 as the damaging species.

  4. Active and passive control of zinc phthalocyanine photodynamics.

    PubMed

    Sharma, Divya; Huijser, Annemarie; Savolainen, Janne; Steen, Gerwin; Herek, Jennifer L

    2013-01-01

    In this work we report on the ultrafast photodynamics of the photosensitizer zinc phthalocyanine (ZnPc) and manipulation thereof. Two approaches are followed: active control via pulse shaping and passive control via strategic manipulation in the periphery of the molecular structure. The objective of both of these control experiments is the same: to enhance the yield of the functional pathway and to minimize loss channels. The aim of the active control experiments is to increase the intersystem crossing yield in ZnPc, which is important for application in photodynamic therapy (PDT). Pulse shaping allowed an improvement in triplet to singlet ratio of 15% as compared to a transform-limited pulse. This effect is ascribed to a control mechanism that utilizes multiphoton pathways to higher-lying states from where intersystem crossing is more likely to occur. The passive control experiments are performed on ZnPc derivatives deposited onto TiO2, serving as a model system of a dye-sensitized solar cell (DSSC). Modification of the anchoring ligand of the molecular structure resulted in an increased rate for electron injection into TiO2 and slower back electron transfer, improving the DSSC efficiency.

  5. Computer model for photodynamic therapy of the prostate

    NASA Astrophysics Data System (ADS)

    Jankun, Jerzy; Zaim, Amjad; Jankun-Kelly, Monika; Keck, Rick W.; Selman, Steven H.

    2000-05-01

    Photodynamic therapy (PDT) is an emerging minimally invasive treatment that can be employed in many human diseases including prostate cancer. This treatment of human prostate cancer depends on the localization of a drug (photosensitizer) into the prostate. The photosensitizer is activated by high- energy laser light and the active drug destroys cancerous tissue. The success of PDT depends on precise placement of light diffusers in the prostate. Since the prostate is irregular in shape, with different dimensions, a transurethral light delivery that is circular in distribution cannot be used in most cases of carcinoma of the prostate. Sources of light and their spatial distribution must be tailored to each individual patient. More uniform, therapeutic light distribution can be achieved by interstitial light irradiation. In this case, the light is delivered by diffusers placed within the substance of the prostate parallel to the urethra at a distance optimized to deliver adequate levels of light and to create the desired photodynamic effect. For this reason, we are developing a computer program that can calculate the distribution of energy depending on the number of light sources placed in the prostate, their position in the gland, the dimension of the prostate, and the attenuation coefficient. A patient's three-dimensional prostate model is built based on ultrasound images. Then the program is being designated to predict the best set of parameters and position of light diffusers in space, displays them in graphical form or in numerical form. The program is amenable for interfacing with robotic treatment systems.

  6. Predicting photodynamic therapy efficacy with photoacoustic imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Mallidi, Srivalleesha; Mai, Zhiming; Khan, Amjad P.; Hasan, Tayyaba

    2016-03-01

    Photodynamic therapy (PDT) is a photochemistry based cytotoxic technique that imparts cellular damage via excitation of a photosensitizer with drug-specific wavelength of light. The dose at the treatment site for type II PDT is determined by three factors: photosensitizer (PS) concentration, oxygenation status and delivered light irradiance. Most of the FDA approved photosensitizers in their triplet-excited state generate cytotoxic species by reacting with the ground state oxygen that is available in the surrounding environment. Given the inter- and intra-subject variability in the uptake of the photosensitizer and the distribution of oxygen in the tumor, understanding the interplay between these dose parameters could aid in determining photodynamic therapy efficacy. Previously several studies have discussed the interplay between the dose parameters using shown point measurements and 2D imaging systems. Using various subcutaneous and orthotopic mouse models we will demonstrate the utility of a non-invasive non-ionizing photoacoustic imaging modality to determine efficacy and predict treatment response in Benzoporphyrin derivative (BPD) or Aminolevulinic acid (ALA) based PDT. We further compare the predictive capability of photoacoustic imaging with the more predominantly used fluorescence imaging and immunohistochemistry techniques.

  7. Photodynamic therapy: a review of applications in neurooncology and neuropathology

    NASA Astrophysics Data System (ADS)

    Uzdensky, Anatoly B.; Berezhnaya, Elena; Kovaleva, Vera; Neginskaya, Marya; Rudkovskii, Mikhail; Sharifulina, Svetlana

    2015-06-01

    Photodynamic therapy (PDT) effect is a promising adjuvant modality for diagnosis and treatment of brain cancer. It is of importance that the bright fluorescence of most photosensitizers provides visualization of brain tumors. This is successfully used for fluorescence-guided tumor resection according to the principle "to see and to treat." Non-oncologic application of PDT effect for induction of photothrombotic infarct of the brain tissue is a well-controlled and reproducible stroke model, in which a local brain lesion is produced in the predetermined brain area. Since normal neurons and glial cells may also be damaged by PDT and this can lead to unwanted neurological consequences, PDT effects on normal neurons and glial cells should be comprehensively studied. We overviewed the current literature data on the PDT effect on a range of signaling and epigenetic proteins that control various cell functions, survival, necrosis, and apoptosis. We hypothesize that using cell-specific inhibitors or activators of some signaling proteins, one can selectively protect normal neurons and glia, and simultaneously exacerbate photodynamic damage of malignant gliomas.

  8. Hematoporphyrin derivative uptake and photodynamic therapy in pancreatic carcinoma

    SciTech Connect

    Schroder, T.; Chen, I.W.; Sperling, M.; Bell, R.H. Jr.; Brackett, K.; Joffe, S.N.

    1988-05-01

    Little information is currently available concerning the uptake of porphyrins by pancreatic tumors, or the effect of photodynamic therapy (PDT) on pancreatic cancer. In Syrian golden hamsters (n = 33), the organ distribution of /sup 125/I-labeled dihematoporphyrin ether (DHE) was studied in a pancreatic cancer model. In the same animal model the effect of PDT was studied using a gold vapor laser for energy delivery 3 hr after the injection of DHE (n = 7). DHE was 2.4 times more concentrated in the pancreatic tumor than in the nontumorous pancreas at 3 hr. Simultaneously there was a considerable accumulation of DHE in the surrounding gastrointestinal tract, causing perforation of the duodenum and jejunum with resultant death in four (57%) animals after PDT. Photodynamic therapy caused extensive tumor necrosis without any obvious effect on the nontumor-bearing pancreas. Damage to the surrounding tissue in the hamster indicates that precautions should be taken if PDT is to be used clinically in pancreatic cancer. Intratumoral injection of DHE may give higher drug concentrations with greater specificity for tumor treatment.

  9. Effects of photodynamic action on respiration in nonphosphorylating mitochondria.

    PubMed

    Salet, C; Moreno, G; Ricchelli, F

    1998-10-15

    We have studied the effects of singlet oxygen produced by photodynamic action on respiration in nonphosphorylating mitochondria (state 4). Isolated rat liver mitochondria were incubated with 3 microM hematoporphyrin and irradiated at 365 nm with a fluence rate of 25 W/m2. After short durations of irradiation, state 4 respiration with beta-hydroxybutyrate as substrate increases while respiration with succinate is negligibly affected. When mitochondria have been uncoupled with carbonylcyanide-p-trifluoromethoxyphenyl hydrazone before irradiation, no change occurs in beta-hydroxybutyrate-driven respiration, while succinate-driven respiration strongly decreases. Stimulation of state 4 NADH respiration cannot be explained by slippage of the NADH ubiquinone oxidoreductase because the stoichiometry of the redox pump was found insensitive to photodynamic action. In the light of the metabolite theory for linear enzymatic chains applied to state 4 respiration (Brand et al., Biochem. J. 255, 535-539, 1988), these results suggest that stimulation of NADH respiration is simply due to an increase of membrane leaks which occurs after irradiation. In the case of succinate-driven respiration, a strong inhibition of succinate dehydrogenase activity has been demonstrated after irradiation. It can be suggested that this inhibition introduces a negative control coefficient over state 4 respiration, counterbalancing the effects due to leakage.

  10. Simultaneous two-photon excitation of photodynamic therapy agents

    NASA Astrophysics Data System (ADS)

    Wachter, Eric A.; Partridge, W. P., Jr.; Fisher, Walter G.; Dees, Craig; Petersen, Mark G.

    1998-07-01

    The spectroscopic and photochemical properties of several photosensitive compounds are compared using conventional single-photon excitation (SPE) and simultaneous two-photon excitation (TPE). TPE is achieved using a mode-locked titanium:sapphire laser, the near infrared output of which allows direct promotion of non-resonant TPE. Excitation spectra and excited state properties of both type I and type II photodynamic therapy (PDT) agents are examined. In general, while SPE and TPE selection rules may be somewhat different, the excited state photochemical properties are equivalent for both modes of excitation. In vitro promotion of a two-photon photodynamic effect is demonstrated using bacterial and human breast cancer models. These results suggest that use of TPE may be beneficial for PDT, since the technique allows replacement of visible or ultraviolet excitation with non- damaging near infrared light. Further, a comparison of possible excitation sources for TPE indicates that the titanium:sapphire laser is exceptionally well suited for non- linear excitation of PDT agents in biological systems due to its extremely short pulse width and high repetition rate; these features combine to effect efficient PDT activation with minimal potential for non-specific biological damage.

  11. Optical Imaging, Photodynamic Therapy and Optically-Triggered Combination Treatments

    PubMed Central

    Hasan, Tayyaba

    2015-01-01

    Optical imaging is becoming increasingly promising for real-time image-guided resections and combined with photodynamic therapy (PDT), a photochemistry-based treatment modality, optical approaches can be intrinsically “theranostic”. Challenges in PDT include precise light delivery, dosimetry and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of molecular escape pathways are often attributable to tumor heterogeneity. Key advances in molecular imaging, target-activatable photosensitizers and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism, have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional and molecular information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clinical PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy and radiation. PMID:26049699

  12. Dual imaging-guided photothermal/photodynamic therapy using micelles

    PubMed Central

    Guo, Miao; Mao, Huajian; Li, Yanli; Zhu, Aijun; He, Hui; Yang, Hong; Wang, Yangyun; Tian, Xin; Ge, Cuicui; Peng, Qiaoli; Wang, Xiaoyong; Yang, Xiangliang; Chen, Xiaoyuan; Liu, Gang; Chen, Huabing

    2015-01-01

    We report a type of photosensitizer (PS)-loaded micelles integrating cyanine dye as potential theranostic micelles for precise anatomical tumor localization via dual photoacoustic (PA)/near-infrared fluorescent (NIRF) imaging modalities, and simultaneously superior cancer therapy via sequential synergistic photothermal therapy (PTT)/photodynamic therapy (PDT). The micelles exhibit enhanced photostability, cell internalization and tumor accumulation. The dual NIRF/PA imaging modalities of the micelles cause the high imaging contrast and spatial resolution of tumors, which provide precise anatomical localization of the tumor and its inner vasculature for guiding PTT/PDT treatments. Moreover, the micelles can generate severe photothermal damage on cancer cells and destabilization of the lysosomes upon PTT photo-irradiation, which subsequently facilitate synergistic photodynamic injury via PS under PDT treatment. The sequential treatments of PTT/PDT trigger the enhanced cytoplasmic delivery of PS, which contributes to the synergistic anticancer efficacy of PS. Our strategy provides a dual-modal cancer imaging with high imaging contrast and spatial resolution, and subsequent therapeutic synergy of PTT/PDT for potential multimodal theranostic application. PMID:24613048

  13. Photodynamic therapy for circumscribed choroidal haemangioma: a case report.

    PubMed

    Bhatt, Chirag; Bandyopadhyay, Samir Kumar; Chatterjee, P K; Paul, R C; Bagchi, S C; Chatterjee, Arkendu

    2011-10-01

    Choroidal haemangioma is a benign tumour with visual acuity diminution due to subretinal fluid accumulation. There are many modalities of treatment of this visually disabling syndrome, some of them being argon laser photocoagulation, cryotherapy, external beam irradiation, proton beam radiotherapy, episcleral plaque radiotherapy and transpupillary thermotherapy. Another new modality of treatment with remarkable success rate is photodynamic therapy. In this modality a photosensitiser is injected intravenously followed by irradiation of a specific wave length for a specified time period. The photosensitiser concentrates within the vascular channels and after irradiation these channels are irreversibly obliterated. A 62 years old female patient of choroidal haemangioma, who presented in eye outpatient department was treated with the standard protocol used for photodynamic therapy. On follow-up of this patient it was found that there was improvement in the visual acuity from 6/12 in the left eye (affected eye) to 6/9. Not only was there an improvement in the visual acuity but there was anatomical improvement too as was evident by regressed cystoid macular oedema and circumscribed choroidal haemangioma. After six months of follow-up there was no leakage of dye with digital fluorescein angiography and indocyanine green.

  14. The photosensitizer talaporfinum caused microvascular embolization for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Li, Liming; Aizawa, Katsuo

    2005-07-01

    Photodynamic therapy (PDT) has been evolving rapidly in the recent years. A second-generation Photosensitizer mono-1-aspartyl chlorine 6 (Talaporfin / Npe6 / ME2906, Japan Meiji Seika, Ltd.) has been sanctified for the lung cancer clinical PDT by the Japan Ministry of Health, Labor and Welfare. In this paper, Talaporfin was injected to the implant cancer of a mouse a Talaporfin dose of 5mg/kg through intravenous. After 6 hours, the fluorescence images of the mouse were observed with a microscope and a 664 nm diode laser. Effects of therapy were clarified using the different irradiation energies of the laser (50, 100, 200 J/cm2). Both in plasma and in cancer, the concentrations of Talaporfin were analyzed using High Performance Liquid Chromatography (HPLC). Authors find that the higher concentrations of Talaporfin in plasma, the better PDD effect. It is experimentally verified that local microvascular embolisms in the cancer are formed for photodynamic therapy after the Talaporfin injection and the laser irradiation.

  15. Nanostructured Polymeric Micelles Carrying Xanthene Dyes for Photodynamic Evaluation.

    PubMed

    de Freitas, Camila Fabiano; Pellosi, Diogo Silva; Estevão, Bianca Martins; Calori, Italo Rodrigo; Tsubone, Tayana Mazin; Politi, Mário José; Caetano, Wilker; Hioka, Noboru

    2016-11-01

    It was evaluated the properties of the xanthene dyes Erythrosin B, Eosin Y and theirs Methyl, Butyl and Decyl ester derivatives as possible photosensitizers (PS) for photodynamic treatments. The more hydrophobic dyes self-aggregate in water/ethanol solutions above 70% water (vol/vol) in the mixture. In buffered water, these PS were encapsulated in Pluronic polymeric surfactants of P-123 and F-127 by two methodologies: direct addition and the thin-film solid dispersion methods. The thin-film solid method provided formulations with higher stabilities besides effective encapsulation of the PS as monomers. Size measurements demonstrated that Pluronic forms self-assembled micelles with uniform size, which present slightly negative surface potential and a spherical form detected by TEM microscopy. The ester length modulates xanthene localization in the micelle, which is deeper with the increase in the alkyl chain. Moreover, some PS are distributed into two populations: one on the corona micelle interface shell (PEO layer) and the other into the core (PPO region). Although all PS formulations show high singlet oxygen quantum yield, promising results were obtained for Erythrosin B esters with the hydrophobic P-123, which ensures their potential as drug for clinical photodynamic applications.

  16. Fast elimination of onychomycosis by hematoporphyrin derivative-photodynamic therapy.

    PubMed

    Silva, Ana Paula da; Kurachi, Cristina; Bagnato, Vanderlei Salvador; Inada, Natalia Mayumi

    2013-09-01

    Onychomycosis is a fungal nail disease and is one of the major onychopathy worldwide. Topical or oral antifungal therapies are used to treat this disease, but often they are inefficient and oral medications can even cause several side effects. Photodynamic therapy (PDT) is a well established technique and hence, may represent an alternative non invasive technique for the treatment of onychomycosis. In this work, we present a case of onychomycosis that was completely cured by using the porphyrin-photodynamic therapy. A 59-year-old patient, who had two nails with onychomycosis (the right and the left hallux, with more than thirty and ten years, respectively) caused by fungi was treated once a week for a period of six weeks. The nails were first treated and prepared by a specialist. An hour after the photosensitization, the nail was illuminated using a light source based on light emitting diodes (LEDs) in the red wavelength (630 nm, at a total dose of 54 J/cm(2)).

  17. Enhancement of tumor responsiveness to aminolevulinate-photodynamic therapy (ALA-PDT) using differentiation-promoting agents in mouse models of skin carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Sanjay; Honari, Golara; Paliwal, Akshat; Hasan, Tayyaba; Maytin, Edward V.

    2009-06-01

    Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is an emerging treatment for cancers. ALA, given as a prodrug, selectively accumulates and is metabolized in cancer cells to form protoporphyrin IX (PpIX). Targeted local irradiation with light induces cell death. Since the efficacy of ALA-PDT for large or deep tumors is currently limited, we are developing a new approach that combines differentiation-inducing agents with ALA-PDT to improve the clinical response. Here, we tested this new combination paradigm in the following two models of skin carcinoma in mice: 1) tumors generated by topical application of chemical carcinogens (DMBA-TPA); 2) human SCC cells (A431) implanted subcutaneously. To achieve a differentiated state of the tumors, pretreatment with a low concentration of methotrexate (MTX) or Vitamin D (Vit D) was administered for 72 h prior to exposure to ALA. Confocal images of histological sections were captured and digitally analyzed to determine relative PpIX levels. PpIX in the tumors was also monitored by real-time in vivo fluorescence dosimetry. In both models, a significant increase in levels of PpIX was observed following pretreatment with MTX or Vit D, as compared to no-pretreatment controls. This enhancing effect was observed at very low, non-cytotoxic concentrations, and was highly specific to cancer cells as compared to normal cells. These results suggest that use of differentiating agents such as MTX or Vit D, as a short-term combination therapy given prior to ALA-PDT, can increase the production of PpIX photosensitizer and enhance the therapeutic response of skin cancers.

  18. Zinc phthalocyanine-conjugated with bovine serum albumin mediated photodynamic therapy of human larynx carcinoma

    NASA Astrophysics Data System (ADS)

    Silva, E. P. O.; Santos, E. D.; Gonçalves, C. S.; Cardoso, M. A. G.; Soares, C. P.; Beltrame, M., Jr.

    2016-10-01

    Phthalocyanines, which are classified as second-generation photosensitizers, have advantageous photophysical properties, and extensive studies have demonstrated their potential applications in photodynamic therapy. The present work describes the preparation of a new zinc phthalocyanine conjugated to bovine serum albumin (compound 4a) and its photodynamic efficiency in human larynx-carcinoma cells (HEp-2 cells). The unconjugated precursor (compound 4) was also studied. Compounds 4 and 4a penetrated efficiently into the cell, exhibiting cytoplasmic localization, and showed no cytotoxicity in the dark. However, high photodynamic activities were observed in HEp-2 cells after treatments with 5 µM photosensitizers and 4.5 J cm-2 light. These conditions were sufficient to decrease the cell viability to 57.93% and 32.75% for compounds 4 and 4a, respectively. The present results demonstrated high photodynamic efficiency of zinc phthalocyanine conjugated with bovine serum albumin in destroying the larynx-carcinoma cells.

  19. Self-Monitoring Artificial Red Cells with Sufficient Oxygen Supply for Enhanced Photodynamic Therapy

    NASA Astrophysics Data System (ADS)

    Luo, Zhenyu; Zheng, Mingbin; Zhao, Pengfei; Chen, Ze; Siu, Fungming; Gong, Ping; Gao, Guanhui; Sheng, Zonghai; Zheng, Cuifang; Ma, Yifan; Cai, Lintao

    2016-03-01

    Photodynamic therapy has been increasingly applied in clinical cancer treatments. However, native hypoxic tumoural microenvironment and lacking oxygen supply are the major barriers hindering photodynamic reactions. To solve this problem, we have developed biomimetic artificial red cells by loading complexes of oxygen-carrier (hemoglobin) and photosensitizer (indocyanine green) for boosted photodynamic strategy. Such nanosystem provides a coupling structure with stable self-oxygen supply and acting as an ideal fluorescent/photoacoustic imaging probe, dynamically monitoring the nanoparticle biodistribution and the treatment of PDT. Upon exposure to near-infrared laser, the remote-triggered photosensitizer generates massive cytotoxic reactive oxygen species (ROS) with sufficient oxygen supply. Importantly, hemoglobin is simultaneously oxidized into the more active and resident ferryl-hemoglobin leading to persistent cytotoxicity. ROS and ferryl-hemoglobin synergistically trigger the oxidative damage of xenograft tumour resulting in complete suppression. The artificial red cells with self-monitoring and boosted photodynamic efficacy could serve as a versatile theranostic platform.

  20. Electrochemical microsensor system for cancer research on photodynamic therapy in vitro

    NASA Astrophysics Data System (ADS)

    Marzioch, J.; Kieninger, J.; Sandvik, J. A.; Pettersen, E. O.; Peng, Q.; Urban, G.

    2016-10-01

    An electrochemical microsensor system to investigate photodynamic therapy of cancer cells in vitro was developed and applied to monitor the cellular respiration during and after photodynamic therapy. The redox activity and therefore influence of the photodynamic drug on the sensor performance was investigated by electrochemical characterization. It was shown, that appropriate operation conditions avoid cross-sensitivity of the sensors to the drug itself. The presented system features a cell culture chamber equipped with microsensors and a laser source to photodynamically treat the cells while simultaneous monitoring of metabolic parameter in situ. Additionally, the optical setup allows to read back fluorescence signals from the photosensitizer itself or other marker molecules parallel to the microsensor readings.

  1. In vitro study for photodynamic therapy using Fotolon in glioma treatment

    NASA Astrophysics Data System (ADS)

    Abdel Hamid, Sara; Zimmermann, Wolfgang; Huettenberger, Dirk; Wittig, Rainer; Abdel Kader, Mahmoud; Stepp, Herbert

    2015-07-01

    Several forms of Chlorin e6 and its derivatives are reported as efficient photosensitizers (PS) studied in Photodynamic Therapy (PDT) for oncologic applications. Fotolon® is a pure form of Chlorin e6 trisodium salt developed by Apocare Pharma.

  2. Photodynamic Inactivation of Antigenic Determinants of Single-Stranded DNA Bacteriophage φX174

    PubMed Central

    Khan, Narayan C.; Poddar, Ramendra K.

    1974-01-01

    Bacteriophage φX174 when photodynamically inactivated (i.e., when rendered unable to produce plaques as a result of exposure to visible light in air in the presence of proflavine) progressively lost their capacity to bind efficiently with homologous antiserum. Such loss of serum-blocking power was evident with heat-inactivated but not with UV-irradiated phage. The ability of the phages to adsorb to host cells, however, remained practically unaltered even after photodynamic inactivation. It thus appears that photodynamic damages in the so-called “jacket” component of the φX174 coat proteins are partly responsible for the loss of plaque-forming ability, whereas the “spikes” are either poor antigens or insensitive to photodynamic treatment. PMID:4132921

  3. Device for fluorescent control and photodynamic therapy of age-related macula degeneration

    NASA Astrophysics Data System (ADS)

    Loschenov, Victor B.; Meerovich, Gennadii A.; Budzinskaya, M. V.; Ermakova, N. A.; Shevchik, S. A.; Kharnas, Sergey S.

    2004-07-01

    Age-related macula degeneration (AMD) is a wide spread disease the appearance of which leads to poor eyesight and blindness. A method of treatment is not determined until today. Traditional methods, such as laser coagulation and surgical operations are rather traumatic for eye and often bring to complications. That's why recently a photodynamic method of AMD treatment is studied. Based on photodynamic occlusion of choroidal neovascularization (CNV) with minimal injury to overlying neurosensory retina what increases the efficiency.

  4. Aluminium hydroxide tetra-3-phenylthiophthalocyanine as new photosensitizer for photodynamic therapy and fluorescent diagnostics

    NASA Astrophysics Data System (ADS)

    Meerovich, I. G.; Smirnova, Z. S.; Oborotova, N. A.; Lukyanets, E. A.; Meerovich, G. A.; Derkacheva, V. M.; Polozkova, A. P.; Kubasova, I. Y.; Baryshnikov, A. Y.

    2005-08-01

    This work is devoted to investigation of possibility to use the liposomal form of aluminium hydroxide tetra-3-phenylthiophthalocyanine as photosensitizer of near-infrared range. Aluminium hydroxide tetra-3-phenylthiophthalocyanine has shown high selectivity of accumulation in tumor comparing to normal tissue of mice as well as high photodynamic efficiency on mice bearing Erlich tumor (ELD) and lympholeucosis P-388. This compozition can be used to develop new effective photosensitizer for photodynamic therapy and fluorescent diagnostics.

  5. Development of Singlet Oxygen Luminescence Kinetics during the Photodynamic Inactivation of Green Algae.

    PubMed

    Bornhütter, Tobias; Pohl, Judith; Fischer, Christian; Saltsman, Irena; Mahammed, Atif; Gross, Zeev; Röder, Beate

    2016-04-13

    Recent studies show the feasibility of photodynamic inactivation of green algae as a vital step towards an effective photodynamic suppression of biofilms by using functionalized surfaces. The investigation of the intrinsic mechanisms of photodynamic inactivation in green algae represents the next step in order to determine optimization parameters. The observation of singlet oxygen luminescence kinetics proved to be a very effective approach towards understanding mechanisms on a cellular level. In this study, the first two-dimensional measurement of singlet oxygen kinetics in phototrophic microorganisms on surfaces during photodynamic inactivation is presented. We established a system of reproducible algae samples on surfaces, incubated with two different cationic, antimicrobial potent photosensitizers. Fluorescence microscopy images indicate that one photosensitizer localizes inside the green algae while the other accumulates along the outer algae cell wall. A newly developed setup allows for the measurement of singlet oxygen luminescence on the green algae sample surfaces over several days. The kinetics of the singlet oxygen luminescence of both photosensitizers show different developments and a distinct change over time, corresponding with the differences in their localization as well as their photosensitization potential. While the complexity of the signal reveals a challenge for the future, this study incontrovertibly marks a crucial, inevitable step in the investigation of photodynamic inactivation of biofilms: it shows the feasibility of using the singlet oxygen luminescence kinetics to investigate photodynamic effects on surfaces and thus opens a field for numerous investigations.

  6. Quantum dot-folic acid conjugates as potential photosensitizers in photodynamic therapy of cancer.

    PubMed

    Morosini, Vincent; Bastogne, Thierry; Frochot, Céline; Schneider, Raphaël; François, Aurélie; Guillemin, François; Barberi-Heyob, Muriel

    2011-05-01

    This study examined the in vitro potential of bioconjugated quantum dots (QDs) as photosensitizers for photodynamic therapy (PDT). According to our previous approaches using photosensitizers, folic acid appears to be an optimal targeting ligand for selective delivery of attached therapeutic agents to cancer tissues. We synthesized hydrophilic near infrared emitting CdTe(S)-type QDs conjugated with folic acid using different spacers. Photodynamic efficiency of QDs conjugated or not with folic acid was evaluated on KB cells, acting as a positive control due to their overexpression of FR-α, and HT-29 cells lacking FR-α, as negative control. A design of experiments was suggested as a rational solution to evaluate the impacts of each experimental factor (QD type and concentration, light fluence and excitation wavelength, time of contact before irradiation and cell phenotype). We demonstrated that, for concentrations lower than 10 nM, QDs displayed practically no cytotoxic effect without light exposure for both cell lines. Whereas QDs at 2.1 nM displayed a weak photodynamic activity, a concentration of 8 nM significantly enhanced the photodynamic efficiency characterized by a light dose-dependent response. A statistically significant difference in photodynamic efficiency between KB and HT-29 cells was evidenced in the case of folic acid-conjugated QDs. Optimal conditions led to an enhanced photocytotoxicity response, allowing us to validate the ability of QDs to generate a photodynamic effect and of folic acid-conjugated QDs for targeted PDT.

  7. Photodynamic dye adsorption and release performance of natural zeolite

    PubMed Central

    Hovhannisyan, Vladimir; Dong, Chen-Yuan; Chen, Shean-Jen

    2017-01-01

    Clinoptilolite type of zeolite (CZ) is a promising material for biomedicine and pharmaceutics due to its non-toxicity, thermal stability, expanded surface area, and exceptional ability to adsorb various atoms and organic molecules into micropores. Using multiphoton microscopy, we demonstrated that individual CZ particles produce two-photon excited luminescence and second harmonic generation signal at femtosecond laser excitation, and adsorb photo-dynamically active dyes such as hypericin and methylene blue. Furthermore, the release of hypericin from CZ pores in the presence of biomolecules is shown, and CZ can be considered as an effective material for drug delivery and controlled release in biological systems. The results may open new perspectives in application of CZ in biomedical imaging, and introducing of the optical approaches into the clinical environment. PMID:28361968

  8. On the Origin of Photodynamic activity of Perylene Quinone Framework

    NASA Astrophysics Data System (ADS)

    Parida, Dibyajyoti; Pancharatna, Pattath D.; Balakrishnarajan, Musiri M.

    2016-10-01

    The basic skeleton of perylenequinone is surprisingly ubiquitous in several naturally occurring pigments, such as Hypocrellins, Cercosporin, etc. to name a few. Several of these molecules and their derivatives are also experimentally characterized as potent candidates for photodynamic therapy and are predicted to be aiding the formation singlet Oxygen. Theoretical calculations that unravel the mystery behind the perylenequinone motif in these bio-molecules. Perylenequinone framework has a unique frontier MOs that aid in facile intersystem crossing of the π-π* excitation. The resulting triplet state remarkably resists phosphorescence that presumably leads to high quantum yield of singlet oxygen production. The excitation assisted change in the nature of conjugation and the attendant out-of-plane distortion of the perylene framework is found to be the general characteristic of all these systems and the substituents at the bay region favourably assist the excited state behavior as shown by time dependent/ independent DFT calculations.

  9. Antimicrobial Photodynamic Therapy for Methicillin-Resistant Staphylococcus aureus Infection

    PubMed Central

    Fu, Xiu-jun; Fang, Yong; Yao, Min

    2013-01-01

    Nowadays methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multidrug resistant bacteria both in hospitals and in the community. In the last two decades, there has been growing concern about the increasing resistance to MRSA of the most potent antibiotic glycopeptides. MRSA infection poses a serious problem for physicians and their patients. Photosensitizer-mediated antimicrobial photodynamic therapy (PDT) appears to be a promising and innovative approach for treating multidrug resistant infection. In spite of encouraging reports of the use of antimicrobial PDT to inactivate MRSA in large in vitro studies, there are only few in vivo studies. Therefore, applying PDT in the clinic for MRSA infection is still a long way off. PMID:23555074

  10. Advanced optical techniques for monitoring dosimetric parameters in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Li, Buhong; Qiu, Zhihai; Huang, Zheng

    2012-12-01

    Photodynamic therapy (PDT) is based on the generation of highly reactive singlet oxygen through interactions of photosensitizer, light and molecular oxygen. PDT has become a clinically approved, minimally invasive therapeutic modality for a wide variety of malignant and nonmalignant diseases. The main dosimetric parameters for predicting the PDT efficacy include the delivered light dose, the quantification and photobleaching of the administrated photosensitizer, the tissue oxygen concentration, the amount of singlet oxygen generation and the resulting biological responses. This review article presents the emerging optical techniques that in use or under development for monitoring dosimetric parameters during PDT treatment. Moreover, the main challenges in developing real-time and noninvasive optical techniques for monitoring dosimetric parameters in PDT will be described.

  11. Photodynamic activity of plant extracts from Sarawak, Borneo.

    PubMed

    Jong, Wan Wui; Tan, Pei Jean; Kamarulzaman, Fadzly Adzhar; Mejin, Michele; Lim, Diana; Ang, Ida; Naming, Margarita; Yeo, Tiong Chia; Ho, Anthony Siong Hock; Teo, Soo Hwang; Lee, Hong Boon

    2013-08-01

    Photodynamic therapy (PDT) is a medical treatment that involves the irradiation of an administered photosensitizing drug with light of a particular wavelength to activate the photosensitizer to kill abnormal cells. To date, only a small number of photosensitizers have been clinically approved for PDT, and researchers continue to look for new molecules that have more desirable properties for clinical applications. Natural products have long been important sources of pharmaceuticals, and there is a great potential for discovery of novel chemotypes from under-explored biodiversities in the world. The objective of this study is to mine the terrestrial plants in Sarawak, Borneo Island, for new photosensitizers for PDT. In a screening program from 2004 to 2008, we prepared and studied 2,400 extracts from 888 plants for their photosensitizing activities. This report details the bioprospecting process, preparation and testing of extracts, analysis of the active samples, fractionation of four samples, and isolation and characterization of photosensitizers.

  12. [Photodynamic therapy in dermatology, a new therapeutic tool].

    PubMed

    Salomon, Denis

    2005-04-20

    Photodynamic therapy is a treatment aimed at to destroy pathological tissues. The therapeutical effect is obtained by the joint action of a photosensitizer and exposure to a mono or polychromatic light. The selectivity of PDT is based on the concentration of the photosensitizer in cells distinct from normal tissue due to their metabolic or proliferative state. The wave length of the excitation light is adapted to the absorption spectrum of the photosensitizer. The photochemical reaction induced by the energy of photons will produce hydroxyls radicals and oxygen singulet which will generate alterations ending up in cell necrosis or apoptosis. The main indications of PDT are the treatment of precancerous lesions and superficial skin carcinoma. Nevertheless, the therapeutical field of PDT is very large.

  13. Photodynamic therapy of head and neck cancer with different sensitizers

    NASA Astrophysics Data System (ADS)

    Vakoulovskaya, Elena G.; Shental, Victor V.; Abdoullin, N. A.; Kuvshinov, Yury P.; Tabolinovskaia, T. D.; Edinak, N. J.; Poddubny, Boris K.; Kondratjeva, T. T.; Meerovich, Gennadii A.; Stratonnikov, Alexander A.; Linkov, Kirill G.; Agafonov, Valery V.

    1997-12-01

    This paper deals with the results of clinical trials for sulfated aluminum phthalocyanine (PHS) (Photosens, Russia; Photogeme (PG) in Russia. The results of photodynamic therapy (PDT) of head and neck tumors (HNT), side effects and ways of their correction and prevention, as well as possibility to work out less toxic regimes of PDT with photosense, choice of laser and type of irradiation are discussed. PDT have been provided in 79 patients with different head and neck tumors. Efficacy of PDT depended on tumor size and its histological type. Undesirable changes in plasma content of antioxidants by means of high pressure liquid chromatography (HLPC) have been found in patients after PHS injection. Influence of short-term and long-term supplementation with beta-carotene and vitamin E on this parameters are discussed.

  14. Nanosized ZSM-5 will improve photodynamic therapy using Methylene blue.

    PubMed

    Kariminezhad, H; Habibi, M; Mirzababayi, N

    2015-07-01

    Nowadays, nanotechnology is growing to improve Photodynamic Therapy and reduce its side effects. In this research, the synthesized co-polymeric Zeolite Secony Mobile-5 (ZSM-5) was employed to modify Methylene Blue (MB) for these reasons. UV-Visible, FTIR, XRD analysis and SEM images were used to investigate obtained nanostructure. The crystal size for these nanostructures were determined 75 nm and maximum adsorption capacity of MB in the nanostructure was estimated 111 (mg g(-1)). Also, the role of Polyethylene Glycol (PEG) was studied as a capable non-toxic polymeric coating to overcome biological barriers. Moreover, potential of singlet oxygen production of the synthesized nanostructure was compared with MB and ZSM-5 nanoparticles control samples. Synthesized nanodrugs show impressive light induced singlet oxygen production efficiency.

  15. TransOral Robotic Photodynamic Therapy for the Oropharynx

    PubMed Central

    Quon, Harry; Finlay, Jarod; Cengel, Keith; Zhu, Timothy; O’Malley, Bert; Weinstein, Gregory

    2015-01-01

    Photodynamic therapy (PDT) has been used for head and neck carcinomas with little experience in the oropharynx due to technical challenges in achieving adequate exposure. We present the case of a patient with a second right tonsil carcinoma following previous treatment with transoral robotic surgery (TORS) and postoperative chemoradiation for a left tonsil carcinoma. Repeat TORS for the right tonsil carcinoma reviewed multiple positive surgical margins. The power output from the robotic camera was modified to facilitate safe intraoperative three dimensional visualization of the tumor bed. The robotic arms facilitated clear exposure of the tonsil and tongue base with stable administration of the fluence. Real-time measurements confirmed stable photobleaching with augmentation of the prescribed light fluence secondary to light scatter in the oropharynx. We report a potential new role using TORS for exposure and accurate PDT in the oropharynx. PMID:21333937

  16. Photodynamic therapy-driven induction of suicide cytosine deaminase gene.

    PubMed

    Bil, Jacek; Wlodarski, Pawel; Winiarska, Magdalena; Kurzaj, Zuzanna; Issat, Tadeusz; Jozkowicz, Alicja; Wegiel, Barbara; Dulak, Jozef; Golab, Jakub

    2010-04-28

    Photodynamic therapy (PDT) of tumors is associated with induction of hypoxia that results in activation of hypoxia-inducible factors (HIFs). Several observations indicate that increased HIFs transcriptional activity in tumor cells is associated with cytoprotective responses that limit cytotoxic effectiveness of PDT. Therefore, we decided to examine whether this cytoprotective mechanism could be intentionally used for designing more efficient tumor cell cytotoxicity. To this end we transfected tumor cells with a plasmid vector carrying a suicide cytosine deaminase gene driven by a promoter containing hypoxia response elements (HRE). The presence of such a genetic molecular beacon rendered tumor cells sensitive to cytotoxic effects of a non-toxic prodrug 5-fluorocytosine (5-FC). The results of this study provides a proof of concept that inducible cytoprotective mechanisms can be exploited to render tumor cells more susceptible to cytotoxic effects of prodrugs activated by products of suicide genes.

  17. Physical and mathematical modeling of antimicrobial photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Bürgermeister, Lisa; López, Fernando Romero; Schulz, Wolfgang

    2014-07-01

    Antimicrobial photodynamic therapy (aPDT) is a promising method to treat local bacterial infections. The therapy is painless and does not cause bacterial resistances. However, there are gaps in understanding the dynamics of the processes, especially in periodontal treatment. This work describes the advances in fundamental physical and mathematical modeling of aPDT used for interpretation of experimental evidence. The result is a two-dimensional model of aPDT in a dental pocket phantom model. In this model, the propagation of laser light and the kinetics of the chemical reactions are described as coupled processes. The laser light induces the chemical processes depending on its intensity. As a consequence of the chemical processes, the local optical properties and distribution of laser light change as well as the reaction rates. The mathematical description of these coupled processes will help to develop treatment protocols and is the first step toward an inline feedback system for aPDT users.

  18. Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer

    PubMed Central

    Kim, Yi Rang; Kim, Seonghoon; Choi, Jin Woo; Choi, Sung Yong; Lee, Sang-Hee; Kim, Homin; Hahn, Sei Kwang; Koh, Gou Young; Yun, Seok Hyun

    2015-01-01

    Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture in vitro incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm2 for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT. PMID:26000054

  19. Enhancing antibiofilm efficacy in antimicrobial photodynamic therapy: effect of microbubbles

    NASA Astrophysics Data System (ADS)

    Kishen, Anil; George, Saji

    2013-02-01

    In this study, we tested the hypothesis that a microbubble containing photosensitizer when activated with light would enable comprehensive disinfection of bacterial biofilms in infected root dentin by antimicrobial photodynamic therapy (APDT). Experiments were conducted in two stages. In the stage-1, microbubble containing photosensitizing formulation was tested for its photochemical properties. In the stage-2, the efficacy of microbubble containing photosensitizing formulation was tested on in vitro infected root canal model, developed with monospecies biofilm models of Enterococcus faecalis on root dentin substrate. The findings from this study showed that the microbubble containing photosensitizing formulation was overall the most effective formulation for photooxidation, generation of singlet oxygen, and in disinfecting the biofilm bacteria in the infected root canal model. This modified photosensitizing formulation will have potential advantages in eliminating bacterial biofilms from infected root dentin.

  20. Bioluminescence-activated deep-tissue photodynamic therapy of cancer.

    PubMed

    Kim, Yi Rang; Kim, Seonghoon; Choi, Jin Woo; Choi, Sung Yong; Lee, Sang-Hee; Kim, Homin; Hahn, Sei Kwang; Koh, Gou Young; Yun, Seok Hyun

    2015-01-01

    Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture in vitro incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm(2) for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT.

  1. [History of photodynamic therapy--past, present and future].

    PubMed

    Kato, H

    1996-01-01

    Photodynamic therapy is achieved by a photodynamic reaction which is induced by excitation of photosensitizer exposed to light. This phenomenon was first reported by Raab et al in 1990. In 1960 Lipson et al reported hematoporphyrin derivative (HpD) by treating hematoporphyrin chloride with hydrochloric acid and sulfuric acid. The development of HpD established the basis of today's photodynamic therapy (PDT). Dougherty reported the treatment of skin tumors by PDT first with an argon dye laser in 1978. The author and his colleagues began basic studies of this treatment using HpD supplied by Dougherty and argon dye laser in canine lung cancer in 1978. These studies confirmed the effectiveness and safety of the method. Bronchofiberscopic PDT for early stage central type squamous cell carcinoma was performed by the authors in 1980 for the first time in the world and complete cure was obtained. Since then PDT has been attracted much attention. The photosensitizer and the laser with a specific wavelength are the key point of PDT. Photofrin, a porfimer sodium (Japan Lederle Co. Ltd., Tokyo, Japan) and excimer dye laser (Hamamatsu Photonics Co. Ltd., Hamamatsu, Japan) obtained governmental approval for clinical use in Japan in 1994, which is equivalent to FDA approval in the US. This method is now used clinically in Canada for certain indications and the Netherlands. In the US it is only approved for compassionate use in cancer of the esophagus. A total of more than 3,000 tumors in the various organs have been treated by PDT so far in 32 countries. The most frequently treated organ is the lung, with 808 cases. A phase II clinical study of PDT for early stage cancer cases of the lung, esophagus, stomach, cervix and urinary bladder was performed in 15 institutions from 1989 to early 1992. The results showed that PDT can successfully treat more than at least 50% of patients with early stage cancer cancer that would otherwise have to be treated by surgery and this means that

  2. Photodynamic therapy: current role in the treatment of chorioretinal conditions

    PubMed Central

    Newman, D K

    2016-01-01

    Verteporfin photodynamic therapy (vPDT) is a selective vaso-occlusive treatment that targets choroidal vascular abnormalities. It was initially developed to treat neovascular age-related macular degeneration using the ‘standard' vPDT protocol (verteporfin 6 mg/m2, vPDT laser fluence 50 J/cm2). vPDT therapy has subsequently evolved as an important treatment modality for a range of other chorioretinal conditions including choroidal haemangioma, central serous chorioretinopathy, polypoidal choroidal vasculopathy, and peripapillary choroidal neovascularisation. Various ‘safety-enhanced' vPDT protocols have been devised to optimise treatment outcomes, typically using reduced dose verteporfin (verteporfin 3 mg/m2) or reduced fluence vPDT (vPDT laser fluence 25 J/cm2). This paper reviews the current role of vPDT therapy in the treatment of chorioretinal conditions. PMID:26742867

  3. 5-ALA-assisted photodynamic therapy in canine prostates

    NASA Astrophysics Data System (ADS)

    Sroka, Ronald; Muschter, Rolf; Knuechel, Ruth; Steinbach, Pia; Perlmutter, Aaron P.; Martin, Thomas; Baumgartner, Reinhold

    1996-05-01

    Photodynamic therapy (PDT) and interstitial thermotherapy are well known treatment modalities in urology. The approach of this study is to combine both to achieve a selective treatment procedure for benign prostatic hyperplasia (BPH) and prostate carcinoma. Measurements of thy in-vivo pharmacokinetics of 5-ALA induced porphyrins by means of fiber assisted ratiofluorometry showed a maximum fluorescence intensity at time intervals of 3 - 4 h post administration. Fluorescence microscopy at that time showed bright fluorescence in epithelial cells while in the stroma fluorescence could not be observed. Interstitial PDT using a 635-nm dye laser with an irradiation of 50 J/cm2 resulted in a nonthermic hemorrhagic lesion. The lesion size did not change significantly when an irradiation of 100 J/cm2 was used. The usefulness of PDT for treating BPH as well as prostate carcinoma has to be proven in further studies.

  4. Photodynamic therapy in the management of acne: an update.

    PubMed

    Elsaie, Mohamed L; Choudhary, Sonal

    2010-09-01

    Acne, one of the most common dermatological diseases, is characterized by inflammatory and noninflammatory lesions that may progress to scars. Starting from pubertal age groups, it can affect adults in the age group 35-40 or more. The conventional therapies for treatment of acne are facing roadblocks because of the antibiotic resistance developing against Propionibacterium acnes. This has led to trying new therapies, of which photodynamic therapy (PDT) seems to be the one under intensive study. Promising results have been observed with PDT use in acne treatment, but it still has some more way to go to acquire the FDA approval for use in acne treatment. This is a review of the literature of use of PDT in treatment of acne, providing a starting point for dermatologists seeking to treat their patients with acne safely and effectively with this new method.

  5. Photodynamic therapy of Cervical Intraepithelial Neoplasia (CIN) high grade

    NASA Astrophysics Data System (ADS)

    Carbinatto, Fernanda M.; Inada, Natalia M.; Lombardi, Welington; da Silva, Eduardo V.; Belotto, Renata; Kurachi, Cristina; Bagnato, Vanderlei S.

    2016-02-01

    Cervical intraepithelial neoplasia (CIN) is the precursor of invasive cervical cancer and associated with human papillomavirus (HPV) infection. Photodynamic therapy (PDT) is a technique that has been used for the treatment of tumors. PDT is based on the accumulation of a photosensitizer in target cells that will generate cytotoxic reactive oxygen species upon illumination, inducing the death of abnormal tissue and PDT with less damaging to normal tissues than surgery, radiation, or chemotherapy and seems to be a promising alternative procedure for CIN treatment. The CIN high grades (II and III) presents potential indications for PDT due the success of PDT for CIN low grade treatment. The patients with CIN high grade that were treated with new clinic protocol shows lesion regression to CIN low grade 60 days after the treatment. The new clinical protocol using for treatment of CIN high grade shows great potential to become a public health technique.

  6. Photodynamic properties of vital dyes for vitreoretinal surgery.

    PubMed

    Brockmann, Tobias; Steger, Claudia; Dawczynski, Jens

    2012-01-01

    The purpose of this study was to evaluate photodynamic properties of indocyanine green (ICG), brilliant blue G (BBG) and trypan blue (TB) as currently used vital dyes for chromovitrectomy. Under consideration of intraoperative illumination intensities and dye concentrations, a simulative in vitro investigation was set up. Therefore, standardized dilutions of original ICG, BBG and TB vials were irradiated at a wavelength of 366 nm with an intensity of 14 µW/cm2 between 0 and 48 h. After this, all samples were measured spectroscopically in a 220- to 750-nm bandwidth. Analyzing the vital dyes over the time course, an exponential photolysis was observed for ICG, whereas BBG and TB presented photostable properties. Regarding ICG, 5% of the concentration was degraded to toxic metabolites every 20 min. For this reason, our study provides evidence that intraocular dye concentrations and modern endoillumination systems alone cannot fully prevent ICG photodegradation.

  7. Photodynamic therapy as an innovative treatment for malignant pleural mesothelioma.

    PubMed

    Friedberg, Joseph S

    2009-01-01

    Photodynamic therapy (PDT) of the pleura is an experimental treatment aimed at eradicating residual microscopic disease after macroscopic complete resection of malignant pleural mesothelioma (MPM) by means of intracavitary administration. A light-based treatment, PDT consists of 3 components: a nontoxic photosensitizing compound, oxygen, and visible light. The treatment is FDA-approved for several oncological targets, but remains experimental for MPM. PDT can be combined with lung-sparing pleurectomy and decortication and does not preclude other treatments such as adjuvant chemotherapy and/or radiation therapy. Additionally, PDT appears to bolster an immunologic effect by rendering the cancer cells that have been destroyed by the light-activated photosensitizer more presentable to the immune system. Local control and survival rates have been sufficiently rewarding to merit ongoing development of this combination of surgical technique and PDT.

  8. TOPICAL REVIEW: The physics, biophysics and technology of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Wilson, Brian C.; Patterson, Michael S.

    2008-05-01

    Photodynamic therapy (PDT) uses light-activated drugs to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections. This paper reviews the current status of PDT with an emphasis on the contributions of physics, biophysics and technology, and the challenges remaining in the optimization and adoption of this treatment modality. A theme of the review is the complexity of PDT dosimetry due to the dynamic nature of the three essential components—light, photosensitizer and oxygen. Considerable progress has been made in understanding the problem and in developing instruments to measure all three, so that optimization of individual PDT treatments is becoming a feasible target. The final section of the review introduces some new frontiers of research including low dose rate (metronomic) PDT, two-photon PDT, activatable PDT molecular beacons and nanoparticle-based PDT.

  9. Photodynamic dye adsorption and release performance of natural zeolite.

    PubMed

    Hovhannisyan, Vladimir; Dong, Chen-Yuan; Chen, Shean-Jen

    2017-03-31

    Clinoptilolite type of zeolite (CZ) is a promising material for biomedicine and pharmaceutics due to its non-toxicity, thermal stability, expanded surface area, and exceptional ability to adsorb various atoms and organic molecules into micropores. Using multiphoton microscopy, we demonstrated that individual CZ particles produce two-photon excited luminescence and second harmonic generation signal at femtosecond laser excitation, and adsorb photo-dynamically active dyes such as hypericin and methylene blue. Furthermore, the release of hypericin from CZ pores in the presence of biomolecules is shown, and CZ can be considered as an effective material for drug delivery and controlled release in biological systems. The results may open new perspectives in application of CZ in biomedical imaging, and introducing of the optical approaches into the clinical environment.

  10. Blue laser system for photo-dynamic therapy

    NASA Astrophysics Data System (ADS)

    Dabu, R.; Carstocea, B.; Blanaru, C.; Pacala, O.; Stratan, A.; Ursu, D.; Stegaru, F.

    2007-03-01

    A blue laser system for eye diseases (age related macular degeneration, sub-retinal neo-vascularisation in myopia and presumed ocular histoplasmosis syndrome - POHS) photo-dynamic therapy, based on riboflavin as photosensitive substance, has been developed. A CW diode laser at 445 nm wavelength was coupled through an opto-mechanical system to the viewing path of a bio-microscope. The laser beam power in the irradiated area is adjustable between 1 mW and 40 mW, in a spot of 3-5 mm diameter. The irradiation time can be programmed in the range of 1-19 minutes. Currently, the laser system is under clinic tests.

  11. Current evidence and applications of photodynamic therapy in dermatology

    PubMed Central

    Wan, Marilyn T; Lin, Jennifer Y

    2014-01-01

    In photodynamic therapy (PDT) a photosensitizer – a molecule that is activated by light – is administered and exposed to a light source. This leads both to destruction of cells targeted by the particular type of photosensitizer, and immunomodulation. Given the ease with which photosensitizers and light can be delivered to the skin, it should come as no surprise that PDT is an increasingly utilized therapeutic in dermatology. PDT is used commonly to treat precancerous cells, sun-damaged skin, and acne. It has reportedly also been used to treat other conditions including inflammatory disorders and cutaneous infections. This review discusses the principles behind how PDT is used in dermatology, as well as evidence for current applications of PDT. PMID:24899818

  12. Photodynamic therapy of cancer with the photosensitizer PHOTOGEM

    NASA Astrophysics Data System (ADS)

    Sokolov, Victor V.; Chissov, Valery I.; Filonenko, E. V.; Sukhin, Garry M.; Yakubovskaya, Raisa I.; Belous, T. A.; Zharkova, Natalia N.; Kozlov, Dmitrij N.; Smirnov, V. V.

    1995-01-01

    The first clinical trials of photodynamic therapy (PDT) in Russia were started in P. A. Hertzen Moscow Research Oncology Institute in October of 1992. Up to now, 61 patients with primary or recurrent malignant tumors of the larynx (3), trachea (1), bronchus (11), nose (1), mouth (3), esophagus (12), vagina and uterine cervix (3), bladder (2), skin (6), and cutaneous and subcutaneous metastases of breast cancer and melanomas (6) have been treated by PDT with the photosensitizer Photogem. At least partial tumor response was observed in all of the cases, but complete remission indicating no evident tumors has been reached in 51% of the cases. Among 29 patients with early and first stage cancer 14 patients had multifocal tumors. Complete remission of tumors in this group reached 86%.

  13. Photodynamic therapy: treatment of choice for actinic cheilitis?

    PubMed

    Rossi, R; Assad, G Bani; Buggiani, G; Lotti, T

    2008-01-01

    The major therapeutic approaches (5-fluorouracil, imiquimod, vermilionectomy, and CO(2) Laser ablation) for actinic cheilitis are aimed at avoiding and preventing a malignant transformation into invasive squamous cell carcinoma via destruction/removal of the damaged epithelium. Recently, photodynamic therapy (PDT) has been introduced as a therapeutic modality for epithelial skin tumors, with good efficacy/safety profile and good cosmetic results. Regarding actinic cheilitis, PDT could be considered a new therapeutic option? The target of our study was to evaluate the efficacy and tolerability of PDT in actinic cheilitis, using a methyl-ester of aminolevulinic acid (MAL) as topical photosensitizing agent and controlled the effects of the therapy for a 30-month follow-up period. MAL-PDT seems to be the ideal treatment for actinic cheilitis and other actinic keratosis, especially on exposed parts such as the face, joining tolerability and clinical efficacy with an excellent cosmetic outcome.

  14. Fat tissue staining and photodynamic/photothermal effects

    NASA Astrophysics Data System (ADS)

    Tuchin, Valery V.; Altshuler, Gregory B.; Yanina, Irina Yu.; Kochubey, Vyacheslav I.; Simonenko, Georgy V.

    2010-02-01

    Cellulite is considered as a disease of the subcutaneous fat layer that appears mostly in women and consists of changes in fat cell accumulation together with disturbed lymphatic drainage, affecting the external appearance of the skin. The photodynamic and selective photothermal treatments may provide reduction the volume of regional or sitespecific accumulations of subcutaneous adipose tissue on the cellular level. We hypothesize that light irradiation of stained fat tissue at selected temperature leads to fat cell lypolytic activity (the enhancement of lipolysis of cell triglycerides due to expression of lipase activity and cell release of free fat acids (FFAs) due to temporal cell membrane porosity), and cell killing due to apoptosis caused by the induced fat cell stress and/or limited cell necrosis.

  15. Physicochemical properties of potential porphyrin photosensitizers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Kempa, Marta; Kozub, Patrycja; Kimball, Joseph; Rojkiewicz, Marcin; Kuś, Piotr; Gryczyński, Zugmunt; Ratuszna, Alicja

    2015-07-01

    This research evaluated the suitability of synthetic photosensitizers for their use as potential photosensitizers in photodynamic therapy using steady state and time-resolved spectroscopic techniques. Four tetraphenylporphyrin derivatives were studied in ethanol and dimethyl sulfoxide. The spectroscopic properties namely electronic absorption and emission spectra, ability to generate singlet oxygen, lifetimes of the triplet state, as well as their fluorescence quantum yield were determined. Also time-correlated single photon counting method was used to precisely determine fluorescence lifetimes for all four compounds. Tested compounds exhibit high generation of singlet oxygen, low generation of fluorescence and they are chemical stable during irradiation. The studies show that the tested porphyrins satisfy the conditions of a potential drug in terms of physicochemical properties.

  16. The bystander effect in photodynamic inactivation of cells.

    PubMed

    Dahle, J; Bagdonas, S; Kaalhus, O; Olsen, G; Steen, H B; Moan, J

    2000-07-26

    Treatment of MDCK II cells with the lipophilic photosensitizer tetra(3-hydroxyphenyl)porphyrin and light was found to induce a rapid apoptotic response in a large fraction of the cells. Furthermore, the distribution of apoptotic cells in microcolonies of eight cells was found to be different from the binomial distribution, indicating that the cells are not inactivated independently, but that a bystander effect is involved in cell killing by photodynamic treatment. The observation of a bystander effect disagrees with the common view that cells are inactivated only by direct damage and indicates that communication between cells in a colony plays a role in photosensitized induction of apoptosis. The degree of bystander effect was higher for cells dying by necrosis than for cell dying by apoptosis.

  17. Effects of verteporfin-mediated photodynamic therapy on endothelial cells

    NASA Astrophysics Data System (ADS)

    Kraus, Daniel; Chen, Bin

    2015-03-01

    Photodynamic therapy (PDT) is a treatment modality in which cytotoxic reactive oxygen species are generated from oxygen and other biological molecules when a photosensitizer is activated by light. PDT has been approved for the treatment of cancers and age-related macular degeneration (AMD) due to its effectiveness in cell killing and manageable normal tissue complications. In this study, we characterized the effects of verteporfin-PDT on SVEC mouse endothelial cells and determined its underlying cell death mechanisms. We found that verteporfin was primarily localized in mitochondria and endoplasmic reticulum (ER) in SVEC cells. Light treatment of photosensitized SVEC cells induced a rapid onset of cell apoptosis. In addition to significant structural damages to mitochondria and ER, verteporfin-PDT caused substantial degradation of ER signaling molecules, suggesting ER stress. These results demonstrate that verteporfin-PDT triggered SVEC cell apoptosis by both mitochondrial and ER stress pathways. Results from this study may lead to novel therapeutic approaches to enhance PDT outcome.

  18. Towards Effective Photothermal/Photodynamic Treatment Using Plasmonic Gold Nanoparticles

    PubMed Central

    Bucharskaya, Alla; Maslyakova, Galina; Terentyuk, Georgy; Yakunin, Alexander; Avetisyan, Yuri; Bibikova, Olga; Tuchina, Elena; Khlebtsov, Boris; Khlebtsov, Nikolai; Tuchin, Valery

    2016-01-01

    Gold nanoparticles (AuNPs) of different size and shape are widely used as photosensitizers for cancer diagnostics and plasmonic photothermal (PPT)/photodynamic (PDT) therapy, as nanocarriers for drug delivery and laser-mediated pathogen killing, even the underlying mechanisms of treatment effects remain poorly understood. There is a need in analyzing and improving the ways to increase accumulation of AuNP in tumors and other crucial steps in interaction of AuNPs with laser light and tissues. In this review, we summarize our recent theoretical, experimental, and pre-clinical results on light activated interaction of AuNPs with tissues and cells. Specifically, we discuss a combined PPT/PDT treatment of tumors and killing of pathogen bacteria with gold-based nanocomposites and atomic clusters, cell optoporation, and theoretical simulations of nanoparticle-mediated laser heating of tissues and cells. PMID:27517913

  19. Self-assembled liposomal nanoparticles in photodynamic therapy

    PubMed Central

    Sadasivam, Magesh; Avci, Pinar; Gupta, Gaurav K.; Lakshmanan, Shanmugamurthy; Chandran, Rakkiyappan; Huang, Ying-Ying; Kumar, Raj; Hamblin, Michael R.

    2013-01-01

    Photodynamic therapy (PDT) employs the combination of non-toxic photosensitizers (PS) together with harmless visible light of the appropriate wavelength to produce reactive oxygen species that kill unwanted cells. Because many PS are hydrophobic molecules prone to aggregation, numerous drug delivery vehicles have been tested to solubilize these molecules, render them biocompatible and enhance the ease of administration after intravenous injection. The recent rise in nanotechnology has markedly expanded the range of these nanoparticulate delivery vehicles beyond the well-established liposomes and micelles. Self-assembled nanoparticles are formed by judicious choice of monomer building blocks that spontaneously form a well-oriented 3-dimensional structure that incorporates the PS when subjected to the appropriate conditions. This self-assembly process is governed by a subtle interplay of forces on the molecular level. This review will cover the state of the art in the preparation and use of self-assembled liposomal nanoparticles within the context of PDT. PMID:24348377

  20. Antifungal effect of TONS504-photodynamic therapy on Malassezia furfur.

    PubMed

    Takahashi, Hidetoshi; Nakajima, Susumu; Sakata, Isao; Iizuka, Hajime

    2014-10-01

    Numerous reports indicate therapeutic efficacy of photodynamic therapy (PDT) against skin tumors, acne and for skin rejuvenation. However, few reports exist regarding its efficacy for fungal skin diseases. In order to determine the antifungal effect, PDT was applied on Malassezia furfur. M. furfur was cultured in the presence of a novel cationic photosensitizer, TONS504, and was irradiated with a 670-nm diode laser. TONS504-PDT showed a significant antifungal effect against M. furfur. The effect was irradiation dose- and TONS504 concentration-dependent and the maximal effect was observed at 100 J/cm2 and 1 μg/mL, respectively. In conclusion, TONS504-PDT showed antifungal effect against M. furfur in vitro, and may be a new therapeutic modality for M. furfur-related skin disorders.

  1. Cationic porphycenes as potential photosensitizers for antimicrobial photodynamic therapy

    PubMed Central

    Ragàs, Xavier; Sánchez-García, David; Ruiz-González, Rubén; Dai, Tianhong; Agut, Montserrat; Hamblin, Michael R.; Nonell, Santi

    2010-01-01

    Structures of typical photosensitizers used in antimicrobial photodynamic therapy are based on porphyrins, phthalocyanines and phenothiazinium salts, with cationic charges at physiological pH values. However derivatives of the porphycene macrocycle (a structural isomer of porphyrin) have barely been investigated as antimicrobial agents. Therefore, we report the synthesis of the first tricationic water-soluble porphycene and its basic photochemical properties. We successfully tested it for in vitro photoinactivation of different Gram-positive and Gram-negative bacteria, as well as a fungal species (Candida) in a drug-dose and light-dose dependent manner. We also used the cationic porphycene in vivo to treat an infection model comprising mouse 3rd degree burns infected with a bioluminescent methicillin-resistant Staphylococcus aureus strain. There was a 2.6-log10 reduction (p < 0.001) of the bacterial bioluminescence for the PDT-treated group after irradiation with 180 J·cm-2 of red light. PMID:20936792

  2. Photodynamic therapy in dermatology: past, present, and future

    NASA Astrophysics Data System (ADS)

    Darlenski, Razvigor; Fluhr, Joachim W.

    2013-06-01

    Photodynamic therapy (PDT) is a noninvasive therapeutic method first introduced in the field of dermatology. It is mainly used for the treatment of precancerous and superficial malignant skin tumors. Today PDT finds new applications not only for nononcologic dermatoses but also in the field of other medical specialties such as otorhinolaryngology, ophthalmology, neurology, gastroenterology, and urology. We are witnessing a broadening of the spectrum of skin diseases that are treated by PDT. Since its introduction, PDT protocol has evolved significantly in terms of increasing method efficacy and patient safety. In this era of evidence-based medicine, it is expected that much effort will be put into creating a worldwide accepted consensus on PDT. A review on the current knowledge of PDT is given, and the historical basis of the method's evolution since its introduction in the 1900s is presented. At the end, future challenges of PDT are focused on discussing gaps that exist for research in the field.

  3. Photodynamic therapy in the treatment of subfoveal choroidal neovascularisation.

    PubMed

    Harding, S

    2001-06-01

    Subfoveal choroidal neovascularisation (CNV) is a major cause of visual disability, with age-related macular degeneration (AMD) the commonest cause. Confluent laser to CNV significantly reduces severe visual loss but the profound visual loss after treatment of subfoveal lesions and the high recurrence rate has meant its restriction to extrafoveal lesions. Developed initially as a treatment for cancers, photodynamic therapy (PDT) has been shown to successfully close CNV in the eye. Large international randomised placebo-controlled studies of the safety and efficacy of PDT with verteporfin are under way. The Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study has demonstrated a reduction of visual loss in treated patients with any classic CNV. Subgroup analysis showed a greater benefit in predominantly classic lesions (p < 0.001, NNT: 3.6), increasing further for lesions with no occult component, roughly equivalent to pure classic (p < 0.01, NNT: 2.2) A significant benefit at 12 months has been shown in patients with CNV secondary to myopia in the Verteporfin in AMD (VIP) trial, but no benefit in pure occult lesions. Further research is required to establish cost-effectiveness and appropriate referral patterns in the UK and optimise treatment strategies. Further data are awaited from TAP/VIP. At present verteporfin PDT is indicated in eyes with subfoveal predominantly classic CNV secondary to AMD with visual acuity of 6/60 or better and lesions < 5,400 microm in diameter. Juxtafoveal lesions meeting the above criteria and CNV secondary to pathological myopia should also be considered for treatment. The efficacy of treatment of larger lesions, juxtapapillary CNV, occult/no classic with high-risk characteristics (HRC) and CNV from other causes remains unclear. The treatment of minimally classic lesions and those with occult/no classic without HRC is not indicated.

  4. Dendritic nanoconjugates of photosensitizer for targeted photodynamic therapy.

    PubMed

    Yuan, Ahu; Yang, Bing; Wu, Jinhui; Hu, Yiqiao; Ming, Xin

    2015-07-01

    Application of photodynamic therapy for treating cancers has been restrained by suboptimal delivery of photosensitizers to cancer cells. Nanoparticle (NP)-based delivery has become an important strategy to improve tumor delivery of photosensitizers; however, the success is still limited. One problem for many NPs is poor penetration into tumors, and thus the photokilling is not complete. We aimed to use chemical conjugation method to engineer small NPs for superior cancer cell uptake and tumor penetration. Thus, Chlorin e6 (Ce6) was covalently conjugated to PAMAM dendrimer (generation 7.0) that was also modified by tumor-targeting RGD peptide. With multiple Ce6 molecules in a single nanoconjugate molecule, the resultant targeted nanoconjugates showed uniform and monodispersed size distribution with a diameter of 28 nm. The singlet oxygen generation efficiency and fluorescence intensity of the nanoconjugates in aqueous media were significantly higher than free Ce6. Targeted nanoconjugates demonstrated approximately 16-fold enhancement in receptor-specific cellular delivery of Ce6 into integrin-expressing A375 cells compared to free Ce6 and thus were able to cause massive cell killing at low nanomolar concentrations under photo-irradiation. In contrast, they did not cause significant toxicity up to 2 μM in dark. Due to their small size, the targeted nanoconjugates could penetrate deeply into tumor spheroids and produced strong photo-toxicity in this 3-D tumor model. As a result of their great cellular delivery, small size, and lack of dark cytotoxicity, the nanoconjugates may provide an effective tool for targeted photodynamic therapy of solid tumors.

  5. Antimicrobial Photodynamic Therapy to Kill Gram-negative Bacteria

    PubMed Central

    Sperandio, Felipe F; Huang, Ying-Ying; Hamblin, Michael R

    2013-01-01

    Antimicrobial photodynamic therapy (PDT) or photodynamic inactivation (PDI) is a new promising strategy to eradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria, yeasts and fungi. The search for new approaches that can kill bacteria but do not induce the appearance of undesired drug-resistant strains suggests that PDT may have advantages over traditional antibiotic therapy. PDT is a non-thermal photochemical reaction that involves the simultaneous presence of visible light, oxygen and a dye or photosensitizer (PS). Several PS have been studied for their ability to bind to bacteria and efficiently generate reactive oxygen species (ROS) upon photostimulation. ROS are formed through type I or II mechanisms and may inactivate several classes of microbial cells including Gram-negative bacteria such as Pseudomonas aeruginosa, which are typically characterized by an impermeable outer cell membrane that contains endotoxins and blocks antibiotics, dyes, and detergents, protecting the sensitive inner membrane and cell wall. This review covers significant peer-reviewed articles together with US and World patents that were filed within the past few years and that relate to the eradication of Gram-negative bacteria via PDI or PDT. It is organized mainly according to the nature of the PS involved and includes natural or synthetic food dyes; cationic dyes such as methylene blue and toluidine blue; tetrapyrrole derivatives such as phthalocyanines, chlorins, porphyrins, chlorophyll and bacteriochlorophyll derivatives; functionalized fullerenes; nanoparticles combined with different PS; other formulations designed to target PS to bacteria; photoactive materials and surfaces; conjugates between PS and polycationic polymers or antibodies; and permeabilizing agents such as EDTA, PMNP and CaCl2. The present review also covers the different laboratory animal models normally used to treat Gram-negative bacterial infections with antimicrobial PDT. PMID

  6. Porphyrin-based Nanostructure-Dependent Photodynamic and Photothermal Therapies

    NASA Astrophysics Data System (ADS)

    Jin, Cheng S.

    This thesis presents the investigation of nanostructure-dependent phototherapy. We reviewed the liposomal structures for delivery of photosensitizers, and introduced a novel class of phototransducing liposomes called "porphysomes". Porphysomes are self-assembled from high packing density of pyropheophorbide alpha-conjugated phospholipids, resulting in extreme self-quenching of porphyrin fluorescence and comparable optical absorption to gold nanoparticles for high photothermal efficiency. We demonstrated this self-assembly of porphyrin-lipid conjugates converts a singlet oxygen generating mechanism (photodynamic therapy PDT activity) of porphyrin to photothermal mechanism (photothermal therapy PTT activity). The efficacy of porphysome-enhanced PTT was then evaluated on two pre-clinical animal models. We validated porphysome-enabled focal PTT to treat orthotopic prostate cancer using MRI-guided focal laser placement to closely mimic the current clinic procedure. Furthermore, porphysome-enabled fluorescence-guided transbronchial PTT of lung cancer was demonstrated in rabbit orthotopic lung cancer models, which led to the development of an ultra-minimally invasive therapy for early-stage peripheral lung cancer. On the other hand, the nanostructure-mediated conversion of PDT to PTT can be switched back by nanoparticle dissociation. By incorporating folate-conjugated phospholipids into the formulation, porphysomes were internalized into cells rapidly via folate receptor-mediated endocytosis and resulted in efficient disruption of nanostructures, which turned back on the photodynamic activity of densely packed porphyrins, making a closed loop of conversion between PDT and PTT. The multimodal imaging and therapeutic features of porphysome make it ideal for future personalized cancer treatments.

  7. Comparative photodynamic therapy study using two phthalocyanine derivatives

    PubMed Central

    YSLAS, EDITH INÉS; MILLA, LAURA NATALIA; ROMANINI, SILVIA; DURANTINI, EDGARDO NÉSTOR; BERTUZZI, MABEL; RIVAROLA, VIVIANA ALICIA

    2010-01-01

    In the present study, a comparative photodynamic therapy (PDT) study was performed using the phthalocyanine derivatives, ZnPc(OCH3)4 and ZnPc(CF3)4, in a mouse tumor model, under identical experimental procedures. We studied the ablation of tumors induced by PDT. The end-point was to compare the photodynamic efficacy of ZnPc(OCH3)4 and ZnPc(CF3)4. ZnPc(OCH3)4 and ZnPc(CF3)4 were administered intraperitoneally at a dose of 0.2 mg/kg body weight. The injections of drugs were carried out in Balb/c mice bearing subcutaneously inoculated LM2 mouse mammary adenocarcinoma. Histological examination and serum biochemical parameters were used to evaluate hepatic and renal toxicity and function. Phototherapeutic studies were achieved employing a light intensity of 210 J/cm2. After PDT, tumoral regression analyses were carried out, and the degree of tumor cell death was measured utilizing the vital stain Evan’s blue. In this pilot study, we revealed that the cytotoxic effect of ZnPc(OCH3)4 after PDT led to a higher success rate compared to ZnPc(CF3)4-PDT when both were intraperitoneally injectioned. Both phthalocynanine derivatives were able to induce ablation in the tumors. In summary, these results demonstrate the feasibility of ZnPc(OCH3)4- or ZnPc(CF3)4-PDT and its potential as a treatment for small tumors. PMID:22993594

  8. Glucose modulates antimicrobial photodynamic inactivation of Candida albicans in biofilms.

    PubMed

    Suzuki, Luis Cláudio; Kato, Ilka Tiemy; Prates, Renato Araujo; Sabino, Caetano Padial; Yoshimura, Tania Mateus; Silva, Tamires Oliveira; Ribeiro, Martha Simões

    2017-03-01

    Candida albicans biofilm is a main cause of infections associated with medical devices such as catheters, contact lens and artificial joint prosthesis. The current treatment comprises antifungal chemotherapy that presents low success rates. Photodynamic inactivation (PDI) involves the combination of a photosensitizing compound (PS) and light to generate oxidative stress that has demonstrated effective antimicrobial activity against a broad-spectrum of pathogens, including C. albicans. This fungus senses glucose inducing an upregulation of membrane transporters that can facilitate PS uptake into the cell. The aim of this study was to evaluate the effects of glucose on methylene blue (MB) uptake and its influence on PDI efficiency when combined to a red LED with central wavelength at λ=660nm. C. albicans biofilms were grown on hydrogel disks. Prior to PDI assays, MB uptake tests were performed with and without glucose-sensitization. In this system, the optimum PS administration was determined as 500μM of MB in contact with the biofilm during 30min before irradiation. Irradiation was performed during 3, 6, 9, 12, 15 and 18min with irradiance of 127.3mW/cm(2). Our results showed that glucose was able to increase MB uptake in C. albicans cells. In addition, PDI without glucose showed a higher viability reduction until 6min; after 9min, glucose group demonstrated a significant decrease in cell viability when compared to glucose-free group. Taken together, our data suggest that glucose is capable to enhance MB uptake and modulate photodynamic inactivation of C. albicans biofilm.

  9. Phenylthio-substituted phthalocyanines as new photosensitizers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Meerovich, Igor G.; Derkacheva, Valentina M.; Meerovich, Gennady A.; Oborotova, Natalia A.; Smirnova, Zoya S.; Polozkova, Alevtina P.; Kubasova, Irina Yu.; Lukyanets, Evgeny A.; Baryshnikov, Anatoly Yu.

    2007-02-01

    Current work is devoted to investigation of tetra-3-phenylthio-tetra-5-t-butylphthalocyanine [(PhS) 4(t-Bu) 4PcH II], aluminium hydroxyde tetra-3-phenylthiophthalocyanine [(PhS) 4PcAlOH] and zinc tetra-3-phenylthiophthalocyanine [(PhS) 4PcZn] as potential photosensitizers of near-infrared range. Investigations were performed on F I mice bearing Erlich tumor. Photosensitizers were administered intravenously in liposomal form at doses of 4-10 mg/kg. Dynamic and selectivity of sensitizers' accumulation in tumor were estimated in vivo from fluorescence and absorption spectra of sensitized tissue. Photosensitizers have shown high selectivity of accumulation in tumor comparing to normal tissue of mice. Maxima of selectivity for (PhS) 4(t-Bu) 4PcH II, (PhS) 4PcZn and (PhS) 4PcAlOH achieve the values up to 2.5:1, 5:1 and 8:1 respectively. All photosensitizers completely clear from the normal tissue in 7-8 days. For PDT investigations tumors were irradiated using 732 nm laser with power density of 100-500 mW/cm2 and light dose density up to 400 J/cm2. The photodynamic efficiency was estimated using the parameter of tumor growth inhibition (TGI). All photosensitizers had shown high photodynamic efficiency of relatively large tumors. PDT using (PhS) 4PcAlOH and (PhS) 4(t-Bu) 4PcH II caused pronounced TGI exceeding 80%. Using (PhS) 4PcZn caused moderate TGI of 60%. Investigations have shown that liposomal forms of phenylthiosubstituted phthalocyanine derivatives may be used to develop new efficient photosensitizers for PDT.

  10. Antimicrobial photodynamic therapy to kill Gram-negative bacteria.

    PubMed

    Sperandio, Felipe F; Huang, Ying-Ying; Hamblin, Michael R

    2013-08-01

    Antimicrobial photodynamic therapy (PDT) or photodynamic inactivation (PDI) is a new promising strategy to eradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria, yeasts and fungi. The search for new approaches that can kill bacteria but do not induce the appearance of undesired drug-resistant strains suggests that PDT may have advantages over traditional antibiotic therapy. PDT is a non-thermal photochemical reaction that involves the simultaneous presence of visible light, oxygen and a dye or photosensitizer (PS). Several PS have been studied for their ability to bind to bacteria and efficiently generate reactive oxygen species (ROS) upon photo-stimulation. ROS are formed through type I or II mechanisms and may inactivate several classes of microbial cells including Gram-negative bacteria such as Pseudomonas aeruginosa, which are typically characterized by an impermeable outer cell membrane that contains endotoxins and blocks antibiotics, dyes, and detergents, protecting the sensitive inner membrane and cell wall. This review covers significant peer-reviewed articles together with US and World patents that were filed within the past few years and that relate to the eradication of Gram-negative bacteria via PDI or PDT. It is organized mainly according to the nature of the PS involved and includes natural or synthetic food dyes; cationic dyes such as methylene blue and toluidine blue; tetrapyrrole derivatives such as phthalocyanines, chlorins, porphyrins, chlorophyll and bacteriochlorophyll derivatives; functionalized fullerenes; nanoparticles combined with different PS; other formulations designed to target PS to bacteria; photoactive materials and surfaces; conjugates between PS and polycationic polymers or antibodies; and permeabilizing agents such as EDTA, PMNP and CaCl₂. The present review also covers the different laboratory animal models normally used to treat Gram-negative bacterial infections with antimicrobial PDT.

  11. The photodynamic antibacterial effects of silicon phthalocyanine (Pc) 4.

    PubMed

    Dimaano, Matthew L; Rozario, Chantal; Nerandzic, Michelle M; Donskey, Curtis J; Lam, Minh; Baron, Elma D

    2015-04-08

    The emergence of antibiotic-resistant strains in facultative anaerobic Gram-positive coccal bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), is a global health issue. Typically, MRSA strains are found associated with institutions like hospitals but recent data suggest that they are becoming more prevalent in community-acquired infections. It is thought that the incidence and prevalence of bacterial infections will continue to increase as (a) more frequent use of broad-spectrum antibiotics and immunosuppressive medications; (b) increased number of invasive medical procedures; and (c) higher incidence of neutropenia and HIV infections. Therefore, more optimal treatments, such as photodynamic therapy (PDT), are warranted. PDT requires the interaction of light, a photosensitizing agent, and molecular oxygen to induce cytotoxic effects. In this study, we investigated the efficacy and characterized the mechanism of cytotoxicity induced by photodynamic therapy sensitized by silicon phthalocyanine (Pc) 4 on (a) methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25923); (b) community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) (ATCC 43300); and (c) hospital acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) (PFGE type 300). Our data include confocal image analysis, which confirmed that Pc 4 is taken up by all S. aureus strains, and viable cell recovery assay, which showed that concentrations as low as 1.0 μM Pc 4 incubated for 3 h at 37 °C followed by light at 2.0 J/cm2 can reduce cell survival by 2-5 logs. These results are encouraging, but before PDT can be utilized as an alternative treatment for eradicating resistant strains, we must first characterize the mechanism of cell death that Pc 4-based PDT employs in eliminating these pathogens.

  12. The Photodynamic Antibacterial Effects of Silicon Phthalocyanine (Pc) 4

    PubMed Central

    Dimaano, Matthew L.; Rozario, Chantal; Nerandzic, Michelle M.; Donskey, Curtis J.; Lam, Minh; Baron, Elma D.

    2015-01-01

    The emergence of antibiotic-resistant strains in facultative anaerobic Gram-positive coccal bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), is a global health issue. Typically, MRSA strains are found associated with institutions like hospitals but recent data suggest that they are becoming more prevalent in community-acquired infections. It is thought that the incidence and prevalence of bacterial infections will continue to increase as (a) more frequent use of broad-spectrum antibiotics and immunosuppressive medications; (b) increased number of invasive medical procedures; and (c) higher incidence of neutropenia and HIV infections. Therefore, more optimal treatments, such as photodynamic therapy (PDT), are warranted. PDT requires the interaction of light, a photosensitizing agent, and molecular oxygen to induce cytotoxic effects. In this study, we investigated the efficacy and characterized the mechanism of cytotoxicity induced by photodynamic therapy sensitized by silicon phthalocyanine (Pc) 4 on (a) methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25923); (b) community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) (ATCC 43300); and (c) hospital acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) (PFGE type 300). Our data include confocal image analysis, which confirmed that Pc 4 is taken up by all S. aureus strains, and viable cell recovery assay, which showed that concentrations as low as 1.0 μM Pc 4 incubated for 3 h at 37 °C followed by light at 2.0 J/cm2 can reduce cell survival by 2–5 logs. These results are encouraging, but before PDT can be utilized as an alternative treatment for eradicating resistant strains, we must first characterize the mechanism of cell death that Pc 4-based PDT employs in eliminating these pathogens. PMID:25856680

  13. Photodynamic damage of glial cells in crayfish ventral nerve cord

    NASA Astrophysics Data System (ADS)

    Kolosov, M. S.; Duz, E.; Uzdensky, A. B.

    2011-03-01

    Photodynamic therapy (PDT) is a promising method for treatment of brain tumors, the most of which are of glial origin. In the present work we studied PDT-mediated injury of glial cells in nerve tissue, specifically, in abdominal connectives in the crayfish ventral nerve cord. The preparation was photosensitized with alumophthalocyanine Photosens and irradiated 30 min with the diode laser (670 nm, 0.1 or 0.15 W/cm2). After following incubation in the darkness during 1- 10 hours it was fluorochromed with Hoechst 33342 and propidium iodide to reveal nuclei of living, necrotic and apoptotic cells. The chain-like location of the glial nuclei allowed visualization of those enveloping giant axons and blood vessels. The level of glial necrosis in control preparations was about 2-5 %. Apoptosis was not observed in control preparations. PDT significantly increased necrosis of glial cells to 52 or 67 % just after irradiation with 0.1 or 0.15 W/cm2, respectively. Apoptosis of glial cells was observed only at 10 hours after light exposure. Upper layers of the glial envelope of the connectives were injured stronger comparing to deep ones: the level of glial necrosis decreased from 100 to 30 % upon moving from the connective surface to the plane of the giant axon inside the connective. Survival of glial cells was also high in the vicinity of blood vessels. One can suggest that giant axons and blood vessels protect neighboring glial cells from photodynamic damage. The mechanism of such protective action remains to be elucidated.

  14. Photodynamic damage of glial cells in crayfish ventral nerve cord

    NASA Astrophysics Data System (ADS)

    Kolosov, M. S.; Duz, E.; Uzdensky, A. B.

    2010-10-01

    Photodynamic therapy (PDT) is a promising method for treatment of brain tumors, the most of which are of glial origin. In the present work we studied PDT-mediated injury of glial cells in nerve tissue, specifically, in abdominal connectives in the crayfish ventral nerve cord. The preparation was photosensitized with alumophthalocyanine Photosens and irradiated 30 min with the diode laser (670 nm, 0.1 or 0.15 W/cm2). After following incubation in the darkness during 1- 10 hours it was fluorochromed with Hoechst 33342 and propidium iodide to reveal nuclei of living, necrotic and apoptotic cells. The chain-like location of the glial nuclei allowed visualization of those enveloping giant axons and blood vessels. The level of glial necrosis in control preparations was about 2-5 %. Apoptosis was not observed in control preparations. PDT significantly increased necrosis of glial cells to 52 or 67 % just after irradiation with 0.1 or 0.15 W/cm2, respectively. Apoptosis of glial cells was observed only at 10 hours after light exposure. Upper layers of the glial envelope of the connectives were injured stronger comparing to deep ones: the level of glial necrosis decreased from 100 to 30 % upon moving from the connective surface to the plane of the giant axon inside the connective. Survival of glial cells was also high in the vicinity of blood vessels. One can suggest that giant axons and blood vessels protect neighboring glial cells from photodynamic damage. The mechanism of such protective action remains to be elucidated.

  15. Insight into 2α-Chloro-2′(2′,6′)-(Di)Halogenopicropodophyllotoxins Reacting with Carboxylic Acids Mediated by BF3·Et2O

    PubMed Central

    Fan, Lingling; Zhi, Xiaoyan; Che, Zhiping; Xu, Hui

    2015-01-01

    Stereospecific nucleophilic substitution at the C-4α position of 2α-chloro-2′(2′,6′)-(di)halogenopicropodophyllotoxin derivatives with carboxylic acids mediated by BF3·Et2O was described. Interestingly, this stereoselective products were completely controlled by the reaction time. That is, if the reaction time was prolonged to 24.5–31 h, the resulting compounds were all transformed into the unusual C-ring aromatization products. Additionally, it demonstrated that BF3·Et2O and reaction temperature were the important factors for C-ring aromatization, and AlCl3 could be substituted for BF3·Et2O as a lewis acid for C-ring aromatization. Halogenation of E-ring of 2β-chloropodophyllotoxins with NCS or NBS also led to the same C-ring aromatization compounds. Especially compounds 5c, 6g and 7b exhibited insecticidal activity equal to that of toosendanin. PMID:26573374

  16. Insight into 2α-Chloro-2‧(2‧,6‧)-(Di)Halogenopicropodophyllotoxins Reacting with Carboxylic Acids Mediated by BF3·Et2O

    NASA Astrophysics Data System (ADS)

    Fan, Lingling; Zhi, Xiaoyan; Che, Zhiping; Xu, Hui

    2015-11-01

    Stereospecific nucleophilic substitution at the C-4α position of 2α-chloro-2‧(2‧,6‧)-(di)halogenopicropodophyllotoxin derivatives with carboxylic acids mediated by BF3·Et2O was described. Interestingly, this stereoselective products were completely controlled by the reaction time. That is, if the reaction time was prolonged to 24.5-31 h, the resulting compounds were all transformed into the unusual C-ring aromatization products. Additionally, it demonstrated that BF3·Et2O and reaction temperature were the important factors for C-ring aromatization, and AlCl3 could be substituted for BF3·Et2O as a lewis acid for C-ring aromatization. Halogenation of E-ring of 2β-chloropodophyllotoxins with NCS or NBS also led to the same C-ring aromatization compounds. Especially compounds 5c, 6g and 7b exhibited insecticidal activity equal to that of toosendanin.

  17. Meta-Analysis of Global Transcriptomics Suggests that Conserved Genetic Pathways are Responsible for Quercetin and Tannic Acid Mediated Longevity in C. elegans

    PubMed Central

    Pietsch, Kerstin; Saul, Nadine; Swain, Suresh C.; Menzel, Ralph; Steinberg, Christian E. W.; Stürzenbaum, Stephen R.

    2012-01-01

    Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid’s impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF-beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology-terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy. PMID:22493606

  18. Meta-Analysis of Global Transcriptomics Suggests that Conserved Genetic Pathways are Responsible for Quercetin and Tannic Acid Mediated Longevity in C. elegans.

    PubMed

    Pietsch, Kerstin; Saul, Nadine; Swain, Suresh C; Menzel, Ralph; Steinberg, Christian E W; Stürzenbaum, Stephen R

    2012-01-01

    Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid's impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF-beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology-terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy.

  19. DJ-1 plays an important role in caffeic acid-mediated protection of the gastrointestinal mucosa against ketoprofen-induced oxidative damage.

    PubMed

    Cheng, Yu-Ting; Ho, Cheng-Ying; Jhang, Jhih-Jia; Lu, Chi-Cheng; Yen, Gow-Chin

    2014-10-01

    Ketoprofen is widely used to alleviate pain and inflammation in clinical medicine; however, this drug may cause oxidative stress and lead to gastrointestinal (GI) ulcers. We previously reported that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in protecting cells against reactive oxygen species, and it facilitates the prevention of ketoprofen-induced GI mucosal ulcers. Recent reports suggested that Nrf2 becomes unstable in the absence of DJ-1/PARK7, attenuating the activity of Nrf2-regulated downstream antioxidant enzymes. Thus, increasing Nrf2 translocation by DJ-1 may represent a novel means for GI protection. In vitro, caffeic acid increases the nuclear/cytosolic Nrf2 ratio and the mRNA expression of the downstream antioxidant enzymes, ϒ-glutamyl cysteine synthetase, glutathione peroxidase, glutathione reductase, and heme oxygenase-1, by activating the JNK/p38 pathway in Int-407 cells. Moreover, knockdown of DJ-1 also reversed caffeic acid-induced nuclear Nrf2 protein expression in a JNK/p38-dependent manner. Our results also indicated that treatment of Sprague-Dawley rats with caffeic acid prior to the administration of ketoprofen inhibited oxidative damage and reversed the inhibitory effects of ketoprofen on the antioxidant system and DJ-1 protein expression in the GI mucosa. Our observations suggest that DJ-1 plays an important role in caffeic acid-mediated protection against ketoprofen-induced oxidative damage in the GI mucosa.

  20. Photosensitizers and light sources for photodynamic therapy of the Bowen's disease.

    PubMed

    Calin, M A; Diaconeasa, A; Savastru, D; Tautan, M

    2011-04-01

    Bowen's disease is a neoplastic skin disease, known as squamous cell carcinoma in situ. The treatment options for Bowen's disease are: cryotherapy, curettage, surgery, topical therapy and radiotherapy. In the past recent years, photodynamic therapy was used as a new treatment method. The purpose of this paper is to summarize the results of clinical and research studies with respect to the photodynamic therapy of Bowen's disease. A search of three databases was conducted using specific keywords and explicit inclusion and exclusion criteria for the study of photosensitizers, light sources and their efficacy in photodynamic therapy of Bowen's disease. Two photosensitizers have been used mainly for photodynamic therapy of Bowen's disease therapy: δ-aminolevulinic acid and methyl aminolevulinate. These photosensitizers have been activated with both coherent (lasers) and non-coherent (lamps and LEDs) light sources. Fluence has been set in a large domain (10-240 J/cm(2)) and irradiance was 0.23-100 mW/cm(2). All these light sources have the same efficacy. The high response rates were obtained using methyl aminolevulinate and light emitting diode as light source. These results have demonstrated that photodynamic therapy using methyl aminolevulinate as photosensitizer could be considered as one of the first therapeutic options for Bowen' disease.

  1. Silylation improves the photodynamic activity of tetraphenylporphyrin derivatives in vitro and in vivo.

    PubMed

    Horiuchi, Hiroaki; Hosaka, Masahiro; Mashio, Hiroyuki; Terata, Motoki; Ishida, Shintaro; Kyushin, Soichiro; Okutsu, Tetsuo; Takeuchi, Toshiyuki; Hiratsuka, Hiroshi

    2014-05-12

    The effects of silyl and hydrophilic groups on the photodynamic properties of tetraphenylporphyrin (TPP) derivatives have been studied in vitro and in vivo. Silylation led to an improvement in the quantum yield of singlet oxygen sensitization for both sulfo and carboxy derivatives, although the silylation did not affect other photophysical properties. Silylation also improved the cellular uptake efficiency for both sulfo and carboxy derivatives, enhancing the in vitro photodynamic activity of the photosensitizer in U251 human glioma cells. The carboxy derivative (SiTPPC4 ) was found to show higher cellular uptake efficiency and in vitro photodynamic activity than the corresponding sulfo derivative (SiTPPS4 ), which indicates that the carboxy group is a more promising hydrophilic group than the sulfo group in the silylated porphyrin. SiTPPC4 was found to show high selective accumulation efficiency in tumors, although almost no tumor selectivity was observed for the nonsilylated porphyrin. The concentration of SiTPPC4 in tumors was 13 times higher than that in muscle 12 h after drug administration. We also studied tumor response after treatment and found that silylation enhanced in vivo photodynamic activity significantly. SiTPPC4 shows higher photodynamic activity than NPe6 with white light irradiation.

  2. Oxidative photodamage induced by photodynamic therapy with methoxyphenyl porphyrin derivatives in tumour-bearing rats.

    PubMed

    Daicoviciu, D; Filip, A; Ion, R M; Clichici, S; Decea, N; Muresan, A

    2011-01-01

    The oxidative effects of photodynamic therapy with 5,10,15,20-tetrakis(4-methoxyphenyl) porphyrin (TMP) and Zn-5,10,15,20-tetrakis(4-methoxyphenyl) porphyrin (ZnTMP) were evaluated in Wistar rats subcutaneously inoculated with Walker 256 carcinoma. The animals were irradiated with red light (λ = 685 nm; D = 50 J/cm2; 15 min) 3 h after intra-peritoneal administration of 10 mg/kg body weight of porphyrins. The presence of free radicals in tumours after photodynamic therapy with TMP and ZnTMP revealed by chemiluminescence of luminol attained the highest level at 18 h after irradiation. Lipid peroxides measured as thiobarbituric-reactive substances and protein carbonyls, which are indices of oxidative effects produced on susceptible biomolecules, were significantly increased in tumour tissues of animals 24 h after photodynamic therapy. The levels of thiol groups and total antioxidant capacity in the tumours were decreased. The activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were also increased in tumour tissues after photodynamic therapy. Increased levels of plasma lipid peroxides as well as changes in the levels of erythrocyte antioxidant enzyme activities suggest possible systemic effects of photodynamic therapy with TMP and ZnTMP.

  3. Expression of potentially lethal damage in Chinese hamster cells exposed to hematoporphyrin derivative photodynamic therapy.

    PubMed

    Gomer, C J; Rucker, N; Ferrario, A; Murphree, A L

    1986-07-01

    Experiments were performed to determine whether the expression and/or repair of potentially lethal damage could be observed in mammalian cells exposed to hemataporphyrin derivative (HPD) photodynamic therapy (PDT). Photodynamic therapy was combined with posttreatment protocols known to inhibit the repair of potentially lethal damage in cells treated with X-rays, ultraviolet radiation, or alkylating agents. Potentiation of lethal damage from photodynamic therapy was induced by hypothermia (4 degrees C) following short (1 h) or extended (16 h) HPD incubation conditions. Caffeine potentiated the lethal effects of PDT only when cells were incubated with HPD for extended time periods. However, 3-aminobenzamide had no effect on the cytotoxic actions of PDT following either short or extended HPD incubations. Recovery from potentially lethal damage expressed by posttreatment hypothermia was complete within 1 h, while recovery from potentially lethal damage expressed by posttreatment caffeine required time periods of up to 24 h. The lack of effect of 3-aminobenzamide on expression of potentially lethal damage following photodynamic therapy may be related to direct inhibition of adenosine diphosphoribose transferase by photodynamic therapy. These results indicate that the expression and repair of potentially lethal damage can be observed in cells treated with PDT and will vary as a function of porphyrin incubation conditions.

  4. Specific inhibition of the ABCG2 transporter could improve the efficacy of photodynamic therapy.

    PubMed

    Bebes, Attila; Nagy, Tünde; Bata-Csörgo, Zsuzsanna; Kemény, Lajos; Dobozy, Attila; Széll, Márta

    2011-11-03

    Photodynamic therapy is based on the selective accumulation of a photosensitizer in tumors, followed by destruction of the target tissue by a light source. Protoporphyrin IX, a well-known photosensitizer, was recently reported as an endogenous substrate for the multidrug transporter ABCG2. We investigated the role of ABCG2 protein in the porphyrin extrusion ability of keratinocytes, with regard to the impact of the specific inhibition of ABCG2 by a non-toxic fumitremorgin C analog, Ko-134, on photodynamic therapy efficacy. We studied the level of porphyrin accumulation in response to delta-aminolevulinic acid pretreatment in proliferating and highly differentiated HaCaT keratinocytes. An in vitro model of photodynamic therapy on HaCaT cells was established with a therapeutically approved narrow-bandwidth red-light source. The porphyrin extrusion ability of HaCaT cells pr